Bertha Chen, MD

All Publications

• Chronic pelvic pain among transgender men and gender diverse adults assigned female at birth. Andrology Tordoff, D. M., Lunn, M. R., Flentje, A., Atashroo, D., Chen, B., Dastur, Z., Lubensky, M. E., Capriotti, M., Obedin-Maliver, J. 2024

  Abstract

  There are limited data on pelvic pain among transgender men and gender diverse people, and the impact of testosterone on pelvic pain is poorly understood.Characterize the prevalence and correlates of chronic pelvic pain (CPP) among transgender men and gender diverse people and examine the association between testosterone use and CPP.We used 2020-2022 data from The Population Research in Identity and Disparities for Equality (PRIDE) Study, an online prospective cohort study of sexual and gender minority adults in the United States, to conduct complementary cross-sectional and longitudinal analyses. Our primary outcome was self-reported CPP lasting 3 months or longer measured using the Michigan Body Map.Among 2579 transgender men and gender diverse people assigned female at birth included in our sample, 457 (18%) reported CPP. CPP correlates included: inflammatory bowel disease, irritable bowel syndrome (IBS), kidney stones, pelvic inflammatory disease, polycystic ovary syndrome (PCOS), uterine fibroids, current hormonal intrauterine device use, prior pregnancy, vaginal delivery, hysterectomy, and oophorectomy. Individuals with CPP reported a high prevalence of IBS (37%), PCOS (20%), uterine fibroids (9%), post-traumatic stress disorder (51%), and severe depression and anxiety symptoms (42% and 25%, respectively). Current testosterone use was associated with a 21% lower prevalence of CPP (adjusted prevalence ratio (aPR) 0.79, 95% confidence interval [CI]: 0.65-0.96). In longitudinal analyses (N = 79), 15 (19%) participants reported any CPP after initiating testosterone: eight (56%) of whom reported CPP prior to testosterone initiation, and seven (47%) who reported new-onset CPP.The relationship between CPP and testosterone is complex. Although testosterone use was associated with a lower prevalence of CPP, some transgender and gender diverse individuals experienced new-onset pelvic pain after testosterone initiation. Given the significant impact that CPP can have on mental health and quality of life, future research must examine the role of testosterone in specific underlying etiologies of CPP and identify potential therapies.

  View details for DOI 10.1111/andr.13703

  View details for PubMedID 39011578

• Functional outcome of the anterior vaginal wall in a pelvic surgery injury rat model after treatment with stem cell-derived progenitors of smooth muscle cells. Research square Wang, Y., Wen, Y., Kim, K., Wu, H., Zhang, J., Dobberfuhl, A. D., Chen, B. 2024

  Abstract

  Stem-cell-derived therapy is a promising option for tissue regeneration. Human iPSC-derived progenitors of smooth muscle cells (pSMCs) have limited proliferation and differentiation, which may minimize the risk of in vivo tumor formation while restoring smooth muscle cell deficiencies. Up to 30 % of women who suffer from recurrence of vaginal prolapse after prolapse surgery are faced with reoperation. Therefore, there is an unmet need for therapies that can restore vaginal tissue function. We hypothesize that human pSMCs can restore vaginal function in a vaginal-injury rat model.Female immune-compromised RNU rats were divided into 5 groups: intact controls (n=12), VSHAM (surgery + saline injection, n=33), and cell-injection group (surgery + cell injection using three patient pSMCs lines, n=14/cell line). The surgery, similar to what is done in vaginal prolapse surgery, involved ovariectomy, urethrolysis, and vagina injury. The vagina, urethra, bladder dome and trigone were harvested 10 weeks after surgery (5 weeks after injection). Organ bath myography was performed to evaluate the contractile function of vagina, and smooth muscle thickness was examined by tissue immunohistochemistry. Collagen I, collagen III, and elastin mRNA and protein expressions in tissues were assessed.When compared to the VSHAM group, cell-injection groups showed significantly increased vaginal smooth muscle contractions induced by carbachol (groups A and C) and by KCl (group C), and significantly higher collagen I protein expression in the vagina (groups A and B). Elastin mRNA and protein expressions in the vagina did not correlate with injection group. In the urethra, mRNA expressions of collagen I, collagen III, and elastin were all significantly higher in the cell-injection groups compared to the VSHAM group. Collagen I protein expression of the urethra was also higher in the cell-injection group compared to the VSHAM group. Elastin protein expression in the urethra did not correlate with injection group.Human iPSC-derived pSMCs improved contractile function of the post-surgery vagina. Additionally, pSMC injection modulated collagen I, collagen III and elastin mRNA and protein expressions in the vagina and urethra. These findings suggest that pSMCs may be a possible therapy for vaginal prolapse recurrence after surgical intervention.

  View details for DOI 10.21203/rs.3.rs-4172308/v1

  View details for PubMedID 38946968

  View details for PubMedCentralID PMC11213168

• Long-term effects of vaginal surgery and endogenous ovarian hormones on the vagina and bladder. Sexual medicine Ho, T., Zhang, J., Wen, Y., Guo, S., Dobberfuhl, A. D., Chen, B. 2023; 11 (6): qfad063

  Abstract

  Surgery is a common treatment for pelvic organ prolapse (POP); however, risk of recurrence and reoperation is high, resulting in a negative impact on quality of life and sexual function.To examine the long-term effects of POP surgery and endogenous circulating ovarian hormones on the vagina and bladder.Our animal model simulated surgical injury of the vagina and bladder during POP surgery. Female Rowett nude rats were divided into 4 groups: intact control (IC), vaginal surgery only (V), ovariectomy only (O), and ovariectomy + vaginal surgery (OV). Rats were euthanized 10 weeks postsurgery. Proximal vagina and bladder dome/trigone underwent (1) organ bath myography to assess smooth muscle contractility; (2) real-time quantitative polymerase chain reaction to quantify mRNA expression of elastin, collagen I and III, and PGP9.5 (protein gene product 9.5); (3) enzyme-linked immunosorbent assay for protein quantification of elastin and collagen I and III; and (4) hematoxylin-eosin/immunohistochemistry staining.The primary outcome was tissue contractility as measured by organ bath myography. Secondary outcomes included gene and protein expression of collagen I and III and elastin.O and OV showed reduced vaginal wall contractility vs IC and V (P < .002). Bladder dome and trigone displayed different contractile patterns, with significant differences between O and OV (P < .05), suggesting a negative effect from surgery rather than ovariectomy. OV demonstrated consistent reductions in contractility and elastin/collagen protein expression for the vagina and bladder vs IC. V had similar contractility and increased collagen I expression vs IC, suggesting a protective effect of ovarian hormones. Vaginal epithelium thinning was confirmed in the ovariectomized groups (P = .001), although there was no statistical significance in muscularis thinning with surgery or ovariectomy. O, V, and OV showed significant downregulation of PGP9.5 mRNA expression vs IC.These data allow researchers to gain insights into the long-term effects of surgery and deprivation of ovarian hormones. Future studies can use this animal model to investigate other mechanisms that may affect long-term tissue changes due to surgical intervention.Major strengths are long-term data on the effects of POP surgery and development of an animal model for future studies. However, the animal model limits our ability to extrapolate to humans, where tissue healing is modulated by many factors.Our animal model provides evidence that ovarian hormone deprivation and POP surgery result in negative long-term effects on tissue function and extracellular matrix.

  View details for DOI 10.1093/sexmed/qfad063

  View details for PubMedID 38074491

  View details for PubMedCentralID PMC10710297

• Differences in Menstrual Cytokine Profiles of Women with and without Symptomatic Uterine Fibroids. F&S science Dhanani, Z., Ramirez, N. J., Nguyen, J., Rosenberg-Hasson, Y., Naseri, S., Lum, D., Atashroo, D., Chen, B. 2023

  View details for DOI 10.1016/j.xfss.2023.09.006

  View details for PubMedID 37797816

• Testosterone Use and Sexual Function among Transgender Men and Gender Diverse People Assigned Female at Birth. American journal of obstetrics and gynecology Tordoff, D. M., Lunn, M. R., Chen, B., Flentje, A., Dastur, Z., Lubensky, M. E., Capriotti, M., Obedin-Maliver, J. 2023

  Abstract

  Testosterone use among transgender people likely impacts their experience of sexual function and vulvovaginal pain via several complex pathways. Testosterone use is associated with decreased estrogen in the vagina and atrophic vaginal tissue, which may be associated with decreased vaginal lubrication and/or discomfort during sexual activity. At the same time, increased gender affirmation through testosterone use may be associated with improved sexual function. However, data on pelvic and vulvovaginal pain among transgender men and nonbinary people assigned female at birth is scarce.To assess the association between testosterone and sexual function, with a focus on symptoms that are commonly associated with vaginal atrophy.We conducted a cross-sectional analysis of 1,219 participants ages 18-72 years old using 2019-2021 data from an online, prospective, longitudinal, cohort study of sexual and/or gender minority people in the US (The PRIDE Study). Our analysis included adult transgender men and gender diverse participants assigned female at birth who were categorized as never, current, and former testosterone users. Sexual function was measured across eight Patient-Reported Outcomes Measurement Information System (PROMIS) Sexual Function and Satisfaction (SexFS) domains.Overall, 516 (42.3%) had never used testosterone and 602 (49.4%) currently used testosterone. Median duration of use was 37.7 months (range 7 days to >27 years). Most participants (64.6%) reported genital pain/discomfort during sexual activity in the past 30 days, most commonly in the vagina/frontal genital opening (52.2%), followed by the clitoris (29.1%) and labia (24.5%). Current testosterone use was associated with higher interest in sexual activity (β=6.32, 95% CI: 4.91-7.74) and more vaginal pain/discomfort during sexual activity (β=1.80, 95% CI: 0.61-3.00). No associations were observed between current testosterone use and satisfaction with sex life, lubrication, labial pain/discomfort, or orgasm pleasure.Testosterone use among transgender men and gender diverse people was associated with a higher interest in sexual activity and ability to orgasm as well as vaginal pain/discomfort during sexual activity. Notably, the available evidence demonstrates that >60% of transgender men experience vulvovaginal pain during sexual activity. The causes of pelvic and vulvovaginal pain are poorly understood but are likely multifactorial and include physiological (e.g., testosterone-associated vaginal atrophy) and psychological factors (e.g., gender affirmation). Given this high burden, there is an urgent need to identify effective and acceptable interventions for this population.

  View details for DOI 10.1016/j.ajog.2023.08.035

  View details for PubMedID 37678647

• What predicts durable symptom relief of uterine fibroids treated with MRI-guided focused ultrasound? A multicenter trial in 8 academic centers. European radiology Bitton, R. R., Fast, A., Vu, K. N., Lum, D. A., Chen, B., Hesley, G. K., Raman, S. S., Matsumoto, A. H., Price, T. M., Tempany, C., Dhawan, N., Dolen, E., Kohi, M., Fennessey, F. M., Ghanouni, P. 2023

  Abstract

  To identify variables predictive of durable clinical success after MRI-guided focused ultrasound (MRgFUS) treatment of uterine fibroids.In this prospective, multicenter trial, 99 women with symptomatic uterine fibroids were treated using MRgFUS. Pelvic MRI was obtained at baseline and treatment day. The Uterine Fibroid Symptom-Quality of Life questionnaire was used to calculate a symptom severity score (SSS) at baseline and 6, 12, 24, and 36 months following treatment. Clinical, imaging, and treatment variables were correlated with symptom reduction sustained through the 12- and 24-month time points using univariable and multivariable logistic regression analyses. A novel parameter, the ratio of non-perfused volume to total fibroid load (NPV/TFL), was developed to determine association with durable outcomes.Post-treatment, mean symptom severity decreased at the 6-, 12-, 24-, and 36-month follow-ups (p < 0.001, all time points). In univariable analysis, three variables predicted treatment success (defined by ≥ 30-point improvement in SSS) sustained at both the 12-month and 24-month time points: increasing ratio of NPV/TFL (p = 0.002), decreasing total fibroid load (p = 0.04), and the absence of T2-weighted Funaki type 2 fibroids (p = 0.02). In multivariable analysis, the NPV/TFL was the sole predictor of durable clinical success (p = 0.01). Patients with ratios below 30% had less improvement in SSS and lacked durable clinical response compared with those between 30-79 (p = 0.03) and ≥ 80% (p = 0.01).Increased non-perfused volume relative to total fibroid volume was significantly associated with durable reduction of symptoms of abnormal uterine bleeding and bulk bother.Patient selection for sustained clinical benefit should emphasize those with likelihood of achieving high ablation ratios, as determined by imaging (e.g., device access, Funaki type) and by considering the total fibroid load, not just the primary symptomatic fibroid.Clinical trial ID: NCT01285960.• Patient selection/treatment approach associated with durable symptom relief in MRI-guided focused ultrasound ablation of uterine fibroids remains unclear. • The ablation ratio, non-perfused volume/total fibroid volume, was positively associated with sustained symptom relief in both bleeding and bulk bother at 1- and 2-year follow-ups. • Selecting patients with imaging features that favor a high ratio of ablation to total fibroid load (including non-targeted fibroids) is the main factor in predicting durability of symptom relief after uterine fibroid treatment.

  View details for DOI 10.1007/s00330-023-09984-4

  View details for PubMedID 37553488

  View details for PubMedCentralID 4561549

• FUNCTIONAL AND HISTOLOGIC CHANGES OF THE VAGINA IN A RODENT MODEL FOR ANTERIOR VAGINAL PROLAPSE Chen, B., Guo, S., Ho, D., Wen, Y., Zhang, J., Dobberfuhl, A. WILEY. 2023: S42-S43

  View details for Web of Science ID 001043021100043

• DIFFERENCES IN MENSTRUAL CYTOKINE PROFILES OF WOMEN WITH AND WITHOUT UTERINE FIBROIDS Dhanani, Z., Ramirez, N., Nguyen, J., Hasson, Y., Naseri, S., Atashroo, D., Lum, D. A., Chen, B. ELSEVIER SCIENCE INC. 2022: E104-E105

  View details for Web of Science ID 000891804600257

• IMPACT OF COVID-19 INFECTION AND mRNA VACCINATION ON MENSTRUAL CYTOKINE PROFILES Dhanani, Z., Ramirez, N., Nguyen, J., Hasson, Y., Naseri, S., Chen, B., Kellogg, R. ELSEVIER SCIENCE INC. 2022: E215-E216

  View details for Web of Science ID 000891804600523

• Low-fat dietary pattern reduces urinary incontinence in postmenopausal women: post hoc analysis of the Women's Health Initiative Diet Modification Trial. AJOG global reports Rogo-Gupta, L. J., Yang, L., Stefanick, M. L., Hedlin, H., Wallace, R., Woods, N., Breyer, B. N., Sorensen, M. D., Chen, B. 2022; 2 (1): 100044

  Abstract

  BACKGROUND: Urinary incontinence affects >40% of women in the United States, with an annual societal cost of >$12 billion and demonstrated associations with depressive symptoms, social isolation, and loss of work productivity. Weight has been established as an exposure that increases urinary incontinence risk and certain dietary components have been associated with urinary incontinence symptoms. We hypothesized that diet plays a key role in the association between weight and urinary incontinence in US women.OBJECTIVE: This study aimed to examine the effect of a low-fat diet on urinary incontinence in postmenopausal women as a post hoc analysis of a randomized controlled trial of diet modification.STUDY DESIGN: This was a post hoc analysis of the Women's Health Initiative Dietary Modification randomized controlled trial of 48,835 postmenopausal women from 40 US centers assigned to a dietary intervention (20% energy from fat, 5 fruits or vegetable servings, and 6 whole grain servings daily and an intensive behavioral modification program) or to the usual diet comparison group. The outcome was urinary incontinence at 1 year.RESULTS: Of the participants, 60% were randomized to the usual diet comparison group and 40% to the dietary modification intervention. After adjusting for weight change, women assigned to the dietary modification intervention were less likely to report urinary incontinence (odds ratio, 0.94; 95% confidence interval, 0.90-0.98; P=.003), more likely to report urinary incontinence resolution (odds ratio, 1.11; 95% confidence interval, 1.03-1.19; P=.01), and less likely to develop urinary incontinence (odds ratio, 0.92; 95% confidence interval, 0.87-0.98; P=.01) in adjusted models.CONCLUSION: Dietary modification may be a reasonable treatment for postmenopausal women with incontinence and also a urinary incontinence prevention strategy for continent women. Our results provide evidence to support a randomized clinical trial to determine whether a reduced fat-intake dietary modification is an effective intervention for the prevention and treatment of urinary incontinence. In addition to providing further insights into mechanisms of lower urinary tract symptoms, these findings may have a substantial impact on public health based on the evidence that diet seems to be a modifiable risk factor for urinary incontinence.

  View details for DOI 10.1016/j.xagr.2021.100044

  View details for PubMedID 36274962

• peri-Adventitial delivery of smooth muscle cells in porous collagen scaffolds for treatment of experimental abdominal aortic aneurysm. Biomaterials science Mulorz, J., Shayan, M., Hu, C., Alcazar, C., Chan, A. H., Briggs, M., Wen, Y., Walvekar, A. P., Ramasubramanian, A. K., Spin, J. M., Chen, B., Tsao, P. S., Huang, N. F. 2021

  Abstract

  Abdominal aortic aneurysm (AAA) is associated with the loss of vascular smooth muscle cells (SMCs) within the vessel wall. Direct delivery of therapeutic cells is challenging due to impaired mechanical integrity of the vessel wall. We hypothesized that porous collagen scaffolds can be an effective vehicle for the delivery of human-derived SMCs to the site of AAA. The purpose was to evaluate if the delivery of cell-seeded scaffolds can abrogate progressive expansion in a mouse model of AAA. Collagen scaffolds seeded with either primary human aortic SMCs or induced pluripotent stem cell derived-smooth muscle progenitor cells (iPSC-SMPs) had >80% in vitro cell viability and >75% cell penetrance through the scaffold's depth, while preserving smooth muscle phenotype. The cell-seeded scaffolds were successfully transplanted onto the murine aneurysm peri-adventitia on day 7 following AAA induction using pancreatic porcine elastase infusion. Ultrasound imaging revealed that SMC-seeded scaffolds significantly reduced the aortic diameter by 28 days, compared to scaffolds seeded with iPSC-SMPs or without cells (acellular scaffold), respectively. Bioluminescence imaging demonstrated that both cell-seeded scaffold groups had cellular localization to the aneurysm but a decline in survival with time. Histological analysis revealed that both cell-seeded scaffold groups had more SMC retention and less macrophage invasion into the medial layer of AAA lesions, when compared to the acellular scaffold treatment group. Our data suggest that scaffold-based SMC delivery is feasible and may constitute a platform for cell-based AAA therapy.

  View details for DOI 10.1039/d1bm00685a

  View details for PubMedID 34522940

• Physical Activity, Diet, and Incident Urinary Incontinence in Postmenopausal Women: Women's Health Initiative Observational Study. The journals of gerontology. Series A, Biological sciences and medical sciences Bauer, S. R., Kenfield, S. A., Sorensen, M., Subak, L. L., Phelan, S., Gupta, L. R., Chen, B., Suskind, A. M., Park, A. J., Iglesia, C., Gass, M., Hohensee, C., Breyer, B. N. 2021

  Abstract

  BACKGROUND: Physical activity and macronutrient intake, important contributors to energy balance, may be independently associated with female urinary incontinence (UI).METHODS: We evaluated the association of baseline self-reported physical activity and macronutrient intake, via food-frequency questionnaire, with incident UI subtypes after 3 years among 19,741 post-menopausal women in the Women's Health Initiative Observational Study. Odds ratios (OR) for incident urgency, stress, and mixed UI were calculated using multivariable logistic regression.RESULTS: Women who reported total physical activity (MET-hours/week) ≥30 vs <0.1 were 16% less likely to develop urgency UI (OR=0.84; 95% CI 0.70, 1.00) and 34% less likely for mixed UI (OR=0.66; 0.46, 0.95), although linear trends were no longer statistically significant after adjusting for baseline weight and weight change (P-trend=0.15 and 0.16, respectively). The association between physical activity and incident stress UI was less consistent. Higher uncalibrated protein intake was associated with increased odds of incident urgency UI (≥19.4% versus <14.1% of energy intake OR=1.14; 95% CI 0.99, 1.30; P-trend=0.02), while confidence intervals were wide and included 1.0 for calibrated protein intake. Other macronutrients were not associated with urgency UI and macronutrient intake was not associated with incident stress or mixed UI (P-trend>0.05 for all).CONCLUSIONS: Among post-menopausal women, higher physical activity was associated with lower risk of incident urgency and mixed UI, but not stress UI, independent of baseline weight and weight change. Higher protein intake was associated with increase urgency UI, but no associations were observed between other macronutrient and UI subtypes.

  View details for DOI 10.1093/gerona/glab118

  View details for PubMedID 33963837

• Secretomes of human pluripotent stem cell-derived smooth muscle cell progenitors upregulate extracellular matrix metabolism in the lower urinary tract and vagina. Stem cell research & therapy Zhuang, G., Wen, Y., Briggs, M., Shao, Q., Tran, D., Wang, H., Chen, B. 2021; 12 (1): 228

  Abstract

  BACKGROUND: Adult mesenchymal stem cells (MSCs) have been studied extensively for regenerative medicine; however, they have limited proliferation in vitro, and the long culture time induces cell senescence. MSCs also contribute to tissue repair through their paracrine function. In this study, we sought to examine the paracrine effects of human smooth muscle cell progenitors (pSMC) on the urethra and adjacent vagina of stress urinary incontinence rodents. We use human pluripotent stem cell (PSC) lines to derive pSMCs to overcome the issue of decreased proliferation in tissue culture and to obtain a homogenous cell population.METHOD: Three human PSC lines were differentiated into pSMCs. The conditioned medium (CM) from pSMC culture, which contain pSMC secretomes, was harvested. To examine the effect of the CM on the extracellular matrix of the lower urinary tract, human bladder smooth muscle cells (bSMCs) and vaginal fibroblasts were treated with pSMC-CM in vitro. Stress urinary incontinence (SUI) was induced in rats by surgical injury of the urethra and adjacent vagina. SUI rats were treated with pSMC-CM and monitored for 5weeks. Urethral pressure testing was performed prior to euthanasia, and tissues were harvested for PCR, Western blot, and histological staining. Kruskal-Wallis one-way ANOVA test and Student t test were used for statistical comparisons.RESULTS: pSMC-CM upregulated MMP-2, TIMP-2, collagen, and elastin gene expression, and MMP-9 activity in the human bladder and vaginal cells consistent with elastin metabolism modulation. pSMC-CM treatment in the SUI rat improved urethral pressure (increase in leak point pressure compared to intact controls, p<0.05) and increased collagen and elastin expression in the urethra and the adjacent vagina.CONCLUSION: Conditioned media from smooth muscle cell progenitors derived from human pluripotent stem cells improved urethral leak point pressure and collagen and elastin content in the SUI rat. These findings suggest a novel therapeutic potential for PSC-based treatments for SUI and pelvic floor disorders where tissues are affected by collagen, elastin, and smooth muscle loss.

  View details for DOI 10.1186/s13287-021-02292-y

  View details for PubMedID 33823931

• Postoperative complications and recurrence rates after rectal prolapse surgery versus combined rectal prolapse and pelvic organ prolapse surgery. International urogynecology journal Wallace, S. L., Enemchukwu, E. A., Mishra, K. n., Neshatian, L. n., Chen, B. n., Rogo-Gupta, L. n., Sokol, E. R., Gurland, B. H. 2021

  Abstract

  Our primary objectives were to compare < 30-day postoperative complications and RP recurrence rates after RP-only surgery and combined surgery. Our secondary objectives were to determine preoperative predictors of < 30-day complications and RP recurrence.A prospective IRB-approved cohort study was performed at a single tertiary care center from 2017 to 2020. Female patients with symptomatic RP underwent either RP-only surgery or combined surgery based on the discretion of the colorectal and FPMRS surgeons. Primary outcome measures were < 30-day complications separated into Clavien-Dindo (CD) classes and rectal prolapse on physical examination.Seventy women had RP-only surgery and 45 had combined surgery with a mean follow-up time of 208 days. Sixty-eight percent underwent abdominal RP repair, and 32% underwent perineal RP repair. Twenty percent had one or more complications, 14% in the RP-only group and 29% in the combined surgery group (p = 0.06). On multivariate analysis, combined surgery patients had a 30% increased risk of complications compared to RP-only surgery patients (RR = 1.3). Most of these complications were minor (14/17, 82.4%) and categorized as CD I or II, including urinary retention and UTI. Twelve percent of this cohort had RP recurrence, 11% in the RP-only group and 13% in the combined surgery group (p = 0.76). Preoperative risk factors for RP recurrence included a primary complaint of rectal bleeding (RR 5.5) and reporting stools consistent with Bristol Stool Scale of 1 (RR 2.1).Patients undergoing combined RP + POP surgery had a higher risk of complications and equivalent RP recurrence rates compared to patients undergoing RP-only surgery.

  View details for DOI 10.1007/s00192-021-04778-y

  View details for PubMedID 33864476

• Does Fibroid Size and Bulk Affect Uterine Fibroid Symptom (UFS) Scores in Asian Compared to Caucasian Women? Dhanani, Z., Ramirez, N., Ghanouni, P., Chen, B. LIPPINCOTT WILLIAMS & WILKINS. 2020: 21S

  View details for Web of Science ID 000554572900069

• Characterizing relaxin receptor expression and exploring relaxin's effect on tissue remodeling/fibrosis in the human bladder. BMC urology Diaz, E. C., Briggs, M., Wen, Y., Zhuang, G., Wallace, S. L., Dobberfuhl, A. D., Kao, C., Chen, B. C. 2020; 20 (1): 44

  Abstract

  BACKGROUND: Relaxin is an endogenous protein that has been shown to have antifibrotic properties in various organ systems. There has been no characterization of relaxin's role in the human bladder. Our objective was to characterize relaxin receptor expression in the human bladder and assess relaxin's effect on tissue remodeling/fibrosis pathways in bladder smooth muscle cells.METHODS: Relaxin family peptide receptor 1 (RXFP1) and RXFP2 expression was assessed using quantitative reverse transcriptase-PCR (qRT-PCR) and immunohistochemistry (IHC) on primary bladder tissue. Primary human smooth muscle bladder cells were cultured and stimulated with various concentrations of relaxin. Western blot, qRTPCR, ELISA, and zymogram assays were used to analyze fibrosis/tissue remodeling pathway proteins.RESULTS: There was universal mRNA transcript detection and protein expression of relaxin receptors in primary bladder specimens. Immunohistochemistry demonstrated RXFP1 and RXFP2 localizing to both urothelial and smooth muscle cell layers of the bladder. 24h of in vitro relaxin stimulation did not affect mRNA expression of selected proteins in human bladder smooth muscle cells. However, 48h of in vitro relaxin stimulation resulted in upregulation of active (p=0.004) and latent (p=0.027) MMP-2 in cell lysate, and upregulation of active MMP-2 in supernatant (p=0.04). There was a dose dependent relationship with increasing expression of MMP-2 with increasing relaxin concentration. Relaxin stimulation resulted in decreased levels of active and total TGF-beta1 in supernatant and extracellular matrix (p<0.005 with 100ng/mL relaxin stimulation).CONCLUSIONS: In the human bladder, relaxin receptors are expressed at the dome and trigone and localize to the urothelium and smooth muscle cell layers. Stimulation of human bladder SMCs with relaxin in vitro affects expression of MMP-2 and TGF-beta1.

  View details for DOI 10.1186/s12894-020-00607-4

  View details for PubMedID 32321501

• Does Fibroid Size and Bulk Affect Uterine Fibroid Symptom (UFS) Scores in Asian Compared to Caucasian Women? Ramirez, N., Dhanani, Z., Ghanouni, P., Chen, B. SPRINGER HEIDELBERG. 2020: 134A

  View details for Web of Science ID 000525432600201

• Optogenetic chronic neuromodulation of the diabetic cystopathy mouse model - histology and bladder tissue analysis Wallace, S., Tran, D., Briggs, M., Wen, Y., Montgomery, K., Zhuang, G., Dibberfuhl, A., Delp, S., Chen, B. WILEY. 2020: S48–S49

  View details for Web of Science ID 000519661200055

• Optogenetic chronic neuromodulation of the diabetic cystopathy mouse model - functional effect Wallace, S., Briggs, M., Wen, Y., Tran, D., Montgomery, K., Zhuang, G., Dobberfuhl, A., Delp, S., Chen, B. WILEY. 2020: S47–S48

  View details for Web of Science ID 000519661200054

• Optogenetic chronic neuromodulation of the diabetic cystopathy mouse model - study design Wallace, S., Wan, Y., Briggs, M., Tran, D., Montgomery, K., Zhuang, G., Dobberfuhl, A., Delp, S., Chen, B. WILEY. 2020: S44–S45

  View details for Web of Science ID 000519661200050

• Urinary Phthalate Biomarker Concentrations and Postmenopausal Breast Cancer Risk JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Reeves, K. W., Santana, M., Manson, J. E., Hankinson, S. E., Zoeller, R., Bigelow, C., Sturgeon, S. R., Spiegelman, D., Tinker, L., Luo, J., Chen, B., Meliker, J., Bonner, M. R., Cote, M. L., Cheng, T., Calafat, A. M. 2019; 111 (10): 1059–67

  View details for DOI 10.1093/jnci/djz002

  View details for Web of Science ID 000491252900008

• Evaluation of the routine use of pelvic MRI in women presenting with symptomatic uterine fibroids: When is pelvic MRI useful? JOURNAL OF MAGNETIC RESONANCE IMAGING Kim-Nhien Vu, Fast, A. M., Shaffer, R. K., Rosenberg, J., Dababou, S., Marrocchio, C., Vasanawala, S. S., Lum, D. A., Chen, B., Hovsepian, D. M., Ghanouni, P. 2019; 49 (7): E271–E281

  View details for DOI 10.1002/jmri.26620

  View details for Web of Science ID 000474612300028

• Urodynamic factors associated with the large capacity bladder and incomplete emptying after prolapse repair (2009-2015) NEUROUROLOGY AND URODYNAMICS Dobberfuhl, A. D., Shaffer, R. K., Goodman, S. N., Chen, B. H. 2019; 38 (5): 1322–31

  View details for DOI 10.1002/nau.23982

  View details for Web of Science ID 000471901900016

• Are fibroid and bony pelvis characteristics associated with urinary and pelvic symptom severity? Shaffer, R. K., Dobberfuhl, A. D., Vu, K., Fast, A. M., Dababou, S., Marrocchio, C., Lum, D. A., Hovsepian, D. M., Ghanouni, P., Chen, B. MOSBY-ELSEVIER. 2019

  View details for DOI 10.1016/j.ajog.2019.01.230

  View details for Web of Science ID 000467043800011

• INTRADETRUSOR IPSC-DERIVED HUMAN PROGENITOR SMOOTH MUSCLE CELLS IN A ROWETT NUDE RAT MODEL OF RADIATION CYSTITIS Dobberfuhl, A. D., Briggs, M. A., Wallace, S. L., Wen, Y., Zhou, Y., Graves, E. E., Diaz, E. C., Knox, S. J., Chen, B. LIPPINCOTT WILLIAMS & WILKINS. 2019: E155

  View details for Web of Science ID 000473345200333

• Urodynamic factors associated with the large capacity bladder and incomplete emptying after prolapse repair (2009-2015). Neurourology and urodynamics Dobberfuhl, A. D., Shaffer, R. K., Goodman, S. N., Chen, B. H. 2019

  Abstract

  AIMS: To identify the clinical and urodynamic factors associated with the large capacity bladder and incomplete bladder emptying after prolapse repair.METHODS: We identified 592 women who underwent anterior and/or apical prolapse repair at our institution from 2009 to 2015. Women were stratified by urodynamic capacity. The primary outcome was incomplete emptying at the longest follow-up (postvoid residual [PVR]>200mL). Data were analyzed in the Statistical Analysis System software.RESULTS: Two hundred and sixty-six women (mean age, 61 years) had preoperative urodynamic tracings available for review. After surgery, there were 519 PVRs in 239 women recorded at up to 2949 days (mean, 396) and nine time points (median, 2; IQR, 1-3). The receiver operator curve for predicted probability of longest follow-up PVR greater than 200mL (area under curve=0.67) identified the 600mL cutpoint which defined large capacity bladder. Large capacity bladders (capacity, >600mL [n=79] vs ≤600mL, [n=160]) had a mean: detrusor pressure at maximum flow (21 vs 22cm H2 O; P=0.717), maximum flow rate (19 vs 17mL/s; P=0.148), significantly elevated PVR (202 vs 73mL; P<0.001), and significantly lower voiding efficiency (VE) (74 vs 82%, P<0.05). Following prolapse repair, elevated PVR was associated with large capacity (PVR 101 vs 49mL, P<0.05). Large bladders had a two- to three-fold risk of longest follow-up PVR greater than 200mL (14.3%-20.3% [capacity, >600mL] vs 4.1%-7.0% [capacity, ≤600mL]). VE was similar after surgery regardless of the capacity (87% vs 88%, P=0.772).CONCLUSIONS: The decision to pursue prolapse repair should be individualized and take into account, the bladder capacity and goals for PVR improvement after surgery.

  View details for PubMedID 30912192

• Ambulatory and ex-vivo effect of intradetrusor ipsc-derived human progenitor smooth muscle cells in a rat model of radiation induced bladder dysfunction Dobberfuhl, A. D., Briggs, M. A., Wallace, S. L., Wen, Y., Zhou, Y., Graves, E. E., Diaz, E. C., Chen, B. WILEY. 2019: S27–S28

  View details for Web of Science ID 000462357800031

• Primary culture optimization and in-vitro characterization of urothelial cells Briggs, M., Wen, Y., Zhuang, G., Dobberfuhl, A. D., Wallace, S. L., Chen, B., Diaz, E. C. WILEY. 2019: S45–S47

  View details for Web of Science ID 000462357800053

• A murine model of chronic sacral neuromodulation using the optogenetic technique Wallace, S. L., Briggs, M. A., Wen, Y., Montgomery, K., Dobberfuhl, A. D., Zhuang, G., Diaz, E. C., Delp, S., Chen, B. WILEY. 2019: S15

  View details for Web of Science ID 000462357800015

• The asymptomatic bladder: gross and histological findings in a series of patients Briggs, M., Wen, Y., Zhuang, G., Kao, C., Wallace, S. L., Dobberfuhl, A. D., Chen, B., Diaz, E. C. WILEY. 2019: S37–S38

  View details for Web of Science ID 000462357800042

• Are Fibroid and Bony Pelvis Characteristics Associated with Urinary and Pelvic Symptom Severity? American journal of obstetrics and gynecology Shaffer, R. K., Dobberfuhl, A. D., Vu, K., Fast, A. M., Dababou, S., Marrocchio, C., Lum, D. A., Hovsepian, D. M., Ghanouni, P., Chen, B. 2019

  Abstract

  BACKGROUND: Urinary and pelvic floor symptoms are often attributed to size and location of uterine fibroids. However, direct supporting evidence linking increased size to worsening symptoms is scant and limited to ultrasound evaluation of fibroids. Because management of fibroids is targeted towards symptomatic relief, identification of fibroid and pelvic characteristics associated with worse symptoms is vital to optimizing therapies and preventing needless interventions.OBJECTIVES: We examined the correlation between urinary, pelvic floor and fibroid symptoms, and fibroid size and location using precise uterine fibroid and bony pelvis characteristics obtained from magnetic resonance imaging (MRI).STUDY DESIGN: A retrospective review (2013-2017) of a multidisciplinary fibroid clinic identified 338 women examined via pelvic MRI, Pelvic Floor Distress Inventory questionnaire (PFDI; score 0-300), and a Uterine Fibroid Symptoms questionnaire (UFS; score 1-100). Multiple linear regression analysis was used to assess the influence of clinical factors and MRI findings on scaled PFDI and UFS scores. Data were analyzed in STATA.RESULTS: Our cohort of 338 women had a median PFDI of 72.7 (IQR 41-112.3). Increased PFDI score was associated with clinical factors of higher BMI (p<0.001), non-commercial insurance (p<0.001), increased parity (p=0.001) and history of incontinence surgery (p=0.003). Uterine volume, dominant fibroid volume, dimension and location, and fibroid location relative to the bony pelvis structure did not reach significance when compared with pelvic floor symptom severity. The mean UFS score was 52.0 (SD 23.5). Increased UFS score was associated with dominant submucosal fibroid (p=0.011) as well as BMI (p<0.0016), and a clinical history of anemia (p<0.001) or any hormonal treatment for fibroids (p=0.009).CONCLUSION: Contrary to common belief, in this cohort of women presenting for fibroid care, size and position of fibroids or uterus were not associated with pelvic floor symptom severity. Whereas, bleeding symptom severity was associated with dominant submucosal fibroid and prior hormonal treatment. Careful attention to clinical factors such as BMI and medical history is recommended when evaluating pelvic floor symptoms in women with uterine fibroids.

  View details for PubMedID 30711512

• Urinary Phthalate Biomarker Concentrations and Postmenopausal Breast Cancer Risk. Journal of the National Cancer Institute Reeves, K. W., Santana, M. D., Manson, J. E., Hankinson, S. E., Zoeller, R. T., Bigelow, C., Sturgeon, S. R., Spiegelman, D., Tinker, L., Luo, J., Chen, B., Meliker, J., Bonner, M. R., Cote, M. L., Cheng, T. D., Calafat, A. M. 2019

  Abstract

  Background: Growing laboratory and animal model evidence supports the potentially carcinogenic effects of some phthalates, chemicals used as plasticizers in a wide variety of consumer products, including cosmetics, medications, and vinyl flooring. However, prospective data on whether phthalates are associated with human breast cancer risk are lacking.Methods: We conducted a nested case-control study within the Women's Health Initiative (WHI) prospective cohort (N=419 invasive cases and 838 controls). Controls were matched 2:1 to cases on age, enrollment date, follow-up time, and WHI study group. We quantified thirteen phthalate metabolites and creatinine in two or three urine samples per participant over one to three years. Multivariable conditional logistic regression analysis was used to estimate odds ratios and 95% confidence intervals (OR, 95% CI) for breast cancer risk associated with each phthalate biomarker over up to 19 years of follow-up.Results: Overall, we did not observe statistically significant positive associations between phthalate biomarkers and breast cancer risk in multivariable analyses (e.g. 4th vs 1st quartile of diethylhexyl phthalate OR 1.03, 95% CI 0.91 - 1.17). Results were generally similar in analyses restricted to disease subtypes, to non-users of postmenopausal hormone therapy, stratified by body mass index, or to cases diagnosed within three, five, or ten years.Conclusions: In the first prospective analysis of phthalates and postmenopausal breast cancer, phthalate biomarker concentrations did not result in an increased risk of developing invasive breast cancer.

  View details for PubMedID 30629220

• Evaluation of the routine use of pelvic MRI in women presenting with symptomatic uterine fibroids: When is pelvic MRI useful? Journal of magnetic resonance imaging : JMRI Vu, K., Fast, A. M., Shaffer, R. K., Rosenberg, J., Dababou, S., Marrocchio, C., Vasanawala, S. S., Lum, D. A., Chen, B., Hovsepian, D. M., Ghanouni, P. 2019

  Abstract

  BACKGROUND: Pelvic ultrasound (US) diagnosis of uterine fibroids may overlook coexisting gynecological conditions that contribute to women's symptoms.PURPOSE: To determine the added value of pelvic MRI for women diagnosed with symptomatic fibroids by US, and to identify clinical factors associated with additional MRI findings.STUDY TYPE: Retrospective observational study.POPULATION: In all, 367 consecutive women with fibroids diagnosed by US and referred to our multidisciplinary fibroid center between 2013-2017.FIELD STRENGTH/SEQUENCE: All patients had both pelvic US and MRI prior to their consultations. MRIs were performed at 1.5 T or 3 T and included multiplanar T2 -weighted sequences, and precontrast and postcontrast T1 -weighted imaging.ASSESSMENT: Demographics, symptoms, uterine fibroid symptom severity scores, and health-related quality of life scores, as well as imaging findings were evaluated.STATISTICAL TESTS: Patients were separated into two subgroups according to whether MRI provided additional findings to the initial US. Univariate and multivariate regression analyses were performed.RESULTS: Pelvic MRI provided additional information in 162 patients (44%; 95% confidence interval [CI] 39-49%). The most common significant findings were adenomyosis (22%), endometriosis (17%), and partially endocavitary fibroids (15%). Women with pelvic pain, health-related quality of life scores less than 30 out of 100, or multiple fibroids visualized on US had greater odds of additional MRI findings (odds ratio [OR] 1.68, 2.26, 1.63; P = 0.02, 0.004, 0.03, respectively), while nulliparous women had reduced odds (OR 0.55, P = 0.01). Patients with additional MRI findings were treated less often with uterine fibroid embolization (14% vs. 36%, P < 0.001) or MR-guided focused US (1% vs. 5%, P = 0.04), and more often with medical management (17% vs. 8%, P = 0.01).DATA CONCLUSION: Pelvic MRI revealed additional findings in more than 40% of women presenting with symptoms initially ascribed to fibroids by US. Further evaluation using MRI is particularly useful for parous women with pelvic pain, poor quality of life scores, and/or multiple fibroids.LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019.

  View details for PubMedID 30614145

• Do Induced Pluripotent Stem Cell Characteristics Correlate with Efficient In Vitro Smooth Muscle Cell Differentiation? A Comparison of Three Patient-Derived Induced Pluripotent Stem Cell Lines STEM CELLS AND DEVELOPMENT Zhou, Y., Kang, G., Wen, Y., Briggs, M., Sebastiano, V., Pederson, R., Chen, B. 2018; 27 (20): 1438-1448

  View details for DOI 10.1089/scd.2018.0031

  View details for Web of Science ID 000447295100005

• Do Induced Pluripotent Stem Cell Characteristics Correlate with Efficient In Vitro Smooth Muscle Cell Differentiation? A Comparison of Three Patient-Derived Induced Pluripotent Stem Cell Lines. Stem cells and development Zhou, Y., Kang, G., Wen, Y., Briggs, M., Sebastiano, V., Pederson, R., Chen, B. 2018

  Abstract

  Human induced pluripotent stem cells (iPSCs) have the potential to repair/regenerate smooth muscle cells (SMCs) in different organs. However, there are many challenges in their translation to clinical therapies. In this study, we describe our observations of in vitro SMC differentiation in three iPSC lines derived from human fibroblasts using retroviral, episomal, and mRNA/miRNA reprogramming methods. We sought to elucidate correlations between differentiation characteristics and efficiencies that can facilitate large-scale production of differentiated cells for clinical applications, and to report differences in pluripotency marker expression in differentiated cells from different iPSC lines. A standardized SMC differentiation protocol was used to induce the CD31+/CD34+ vascular progenitor cell phenotype. These were sorted by magnetic-activated (MACS) and fluorescence-activated cell sorting (FACS), and then treated with PDGF-BB and smooth muscle growth medium for further differentiation into smooth muscle progenitor cells (pSMCs). The expression of SMC and pluripotency markers in early- and late-passage (P1 and P4) pSMCs was analyzed. A total of 36 differentiation runs was performed on the three patient iPSC lines. All pSMC populations expressed SMC markers and Ki67 consistent with the progenitor phenotype. Initial iPSC density correlated positively with the sorted cell FACS efficiency, and this correlation could be fit to a quadratic equation. We also observed that a specific "honeycomb" pattern of the starting cultured iPSCs cultured correlated with higher efficiency in all three iPSC lines. Pluripotency marker expression decreased significantly to nearly undetectable levels in all three lines. There was no significant change in SMC and pluripotent marker expression between passage 1 and 4. In summary, our observations suggest that the method of iPSC reprogramming does not affect iPSC differentiation into pSMCs. Protocol efficiency can be modeled mathematically and coupled with the initial "honeycomb" cell pattern to optimize production of large cell numbers for clinical therapies.

  View details for PubMedID 30153084

• Automated Cell Segmentation for Quantitative Phase Microscopy IEEE TRANSACTIONS ON MEDICAL IMAGING Loewke, N. O., Pai, S., Cordeiro, C., Black, D., King, B. L., Contag, C. H., Chen, B., Baer, T. M., Solgaard, O. 2018; 37 (4): 929–40

  Abstract

  Automated cell segmentation and tracking is essential for dynamic studies of cellular morphology, movement, and interactions as well as other cellular behaviors. However, accurate, automated, and easy-to-use cell segmentation remains a challenge, especially in cases of high cell densities, where discrete boundaries are not easily discernable. Here, we present a fully automated segmentation algorithm that iteratively segments cells based on the observed distribution of optical cell volumes measured by quantitative phase microscopy. By fitting these distributions to known probability density functions, we are able to converge on volumetric thresholds that enable valid segmentation cuts. Since each threshold is determined from the observed data itself, virtually no input is needed from the user. We demonstrate the effectiveness of this approach over time using six cell types that display a range of morphologies, and evaluate these cultures over a range of confluencies. Facile dynamic measures of cell mobility and function revealed unique cellular behaviors that relate to tissue origins, state of differentiation, and real-time signaling. These will improve our understanding of multicellular communication and organization.

  View details for DOI 10.1109/TMI.2017.2775604

  View details for Web of Science ID 000428886700010

  View details for PubMedID 29610072

  View details for PubMedCentralID PMC5907807

• 36-Item Short Form Survey (SF-36) Versus Gait Speed As Predictor of Preclinical Mobility Disability in Older Women: The Women's Health Initiative JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Laddu, D. R., Wertheim, B. C., Garcia, D. O., Woods, N. F., LaMonte, M. J., Chen, B., Anton-Culver, H., Zaslavsky, O., Cauley, J. A., Chlebowski, R., Manson, J. E., Thomson, C. A., Stefanick, M. L., Womens Hlth Initiative Investigato 2018; 66 (4): 706–13

  Abstract

  To compare the value of clinically measured gait speed with that of the self-reported Medical Outcomes Study 36-item Short-Form Survey Physical Function Index (SF-36 PF) in predicting future preclinical mobility disability (PCMD) in older women.Prospective cohort study.Forty clinical centers in the United States.Women aged 65 to 79 enrolled in the Women's Health Initiative Clinical Trials with gait speed and SF-36 assessed at baseline (1993-1998) and follow-up Years 1, 3, and 6 (N = 3,587).Women were categorized as nondecliners or decliners based on changes (from baseline to Year 1) in gait speed and SF-36 PF scores. Logistic regression models were used to estimate incident PCMD (gait speed <1.0 m/s) at Years 3 and 6. Area under the receiver operating characteristic curve (AUC) was used to compare the predictive value of SF-36 PF with that of measured gait speed.Slower baseline gait speed and lower SF-36 PF scores were associated with higher adjusted odds of PCMD at Years 3 and 6 (all P < .001). For gait speed, decliners were 2.59 times as likely to have developed PCMD as nondecliners by Year 3 and 2.35 times as likely by Year 6. Likewise, for SF-36, decliners were 1.42 times as likely to have developed PCMD by Year 3 and 1.49 times as likely by Year 6. Baseline gait speed (AUC = 0.713) was nonsignificantly better than SF-36 (AUC = 0.705) at predicting PCMD over 6 years (P = .21); including measures at a second time point significantly improved model discrimination for predicting PCMD (all P < .001).Gait speed identified PCMD risk in older women better than the SF-36 PF did, although the results may be limited given that gait speed served as a predictor and to define the PCMD outcome. Nonetheless, monitoring trajectories of change in mobility are better predictors of future mobility disability than single measures.

  View details for PubMedID 29427503

  View details for PubMedCentralID PMC5906155

• THE NATURAL HISTORY OF RADIATION CYSTITIS IN A RAT MODEL OF ACUTE AND CHRONIC LOWER URINARY TRACT DYSFUNCTION Dobberfuhl, A. D., Briggs, M. A., Wen, Y., Ning, S., Graves, E. E., Diaz, E. C., Chen, B. WILEY. 2018: S538

  View details for Web of Science ID 000427016100034

• CHARACTERIZATION OF RELAXIN RECEPTOR EXPRESSION IN HUMAN BLADDER SMOOTH MUSCLE CELLS AND EVALUATION OF ITS EFFECT ON TISSUE REMODELING AND FIBROSIS Diaz, E., Briggs, M., Wen, Y., Dobberfuhl, A., Chen, B. WILEY. 2018: S533

  View details for Web of Science ID 000427016100026

• Cell sex affects extracellular matrix protein expression and proliferation of smooth muscle progenitor cells derived from human pluripotent stem cells STEM CELL RESEARCH & THERAPY Li, Y., Wen, Y., Green, M., Cabral, E. K., Wani, P., Zhang, F., Wei, Y., Baer, T. M., Chen, B. 2017; 8: 156

  Abstract

  Smooth muscle progenitor cells (pSMCs) differentiated from human pluripotent stem cells (hPSCs) hold great promise for treating diseases or degenerative conditions involving smooth muscle pathologies. However, the therapeutic potential of pSMCs derived from men and women may be very different. Cell sex can exert a profound impact on the differentiation process of stem cells into somatic cells. In spite of advances in translation of stem cell technologies, the role of cell sex and the effect of sex hormones on the differentiation towards mesenchymal lineage pSMCs remain largely unexplored.Using a standard differentiation protocol, two human embryonic stem cell lines (one male line and one female line) and three induced pluripotent stem cell lines (one male line and two female lines) were differentiated into pSMCs. We examined differences in the differentiation of male and female hPSCs into pSMCs, and investigated the effect of 17β-estradiol (E2) on the extracellular matrix (ECM) metabolisms and cell proliferation rates of the pSMCs. Statistical analyses were performed by using Student's t test or two-way ANOVA, p < 0.05.Male and female hPSCs had similar differentiation efficiencies and generated morphologically comparable pSMCs under a standard differentiation protocol, but the derived pSMCs showed sex differences in expression of ECM proteins, such as MMP-2 and TIMP-1, and cell proliferation rates. E2 treatment induced the expression of myogenic gene markers and suppressed ECM degradation activities through reduction of MMP activity and increased expression of TIMP-1 in female pSMCs, but not in male pSMCs.hPSC-derived pSMCs from different sexes show differential expression of ECM proteins and proliferation rates. Estrogen appears to promote maturation and ECM protein expression in female pSMCs, but not in male pSMCs. These data suggest that intrinsic cell-sex differences may influence progenitor cell biology.

  View details for PubMedID 28676082

• Evaluation of diet pattern and weight gain in postmenopausal women enrolled in the Women's Health Initiative Observational Study. British journal of nutrition Ford, C., Chang, S., Vitolins, M. Z., Fenton, J. I., Howard, B. V., Rhee, J. J., Stefanick, M., Chen, B., Snetselaar, L., Urrutia, R., Frazier-Wood, A. C. 2017: 1-10

  Abstract

  It is unclear which of four popular contemporary diet patterns is best for weight maintenance among postmenopausal women. Four dietary patterns were characterised among postmenopausal women aged 49-81 years (mean 63·6 (sd 7·4) years) from the Women's Health Initiative Observational Study: (1) a low-fat diet; (2) a reduced-carbohydrate diet; (3) a Mediterranean-style (Med) diet; and (4) a diet consistent with the US Department of Agriculture's Dietary Guidelines for Americans (DGA). Discrete-time hazards models were used to compare the risk of weight gain (≥10 %) among high adherers of each diet pattern. In adjusted models, the reduced-carbohydrate diet was inversely related to weight gain (OR 0·71; 95 % CI 0·66, 0·76), whereas the low-fat (OR 1·43; 95 % CI 1·33, 1·54) and DGA (OR 1·24; 95 % CI 1·15, 1·33) diets were associated with increased risk of weight gain. By baseline weight status, the reduced-carbohydrate diet was inversely related to weight gain among women who were normal weight (OR 0·72; 95 % CI 0·63, 0·81), overweight (OR 0·67; 95 % CI 0·59, 0·76) or obese class I (OR 0·63; 95 % CI 0·53, 0·76) at baseline. The low-fat diet was associated with increased risk of weight gain in women who were normal weight (OR 1·28; 95 % CI 1·13, 1·46), overweight (OR 1·60; 95 % CI 1·40, 1·83), obese class I (OR 1·73; 95 % CI 1·43, 2·09) or obese class II (OR 1·44; 95 % CI 1·08, 1·92) at baseline. These findings suggest that a low-fat diet may promote weight gain, whereas a reduced-carbohydrate diet may decrease risk of postmenopausal weight gain.

  View details for DOI 10.1017/S0007114517000952

  View details for PubMedID 28509665

• Efficacy and Safety of Immuno-Magnetically Sorted Smooth Muscle Progenitor Cells Derived from Human-Induced Pluripotent Stem Cells for Restoring Urethral Sphincter Function STEM CELLS TRANSLATIONAL MEDICINE Li, Y., Green, M., Wen, Y., Wei, Y., Wani, P., Wang, Z., Pera, R. R., Chen, B. 2017; 6 (4): 1158-1167

  Abstract

  Human-induced pluripotent stem cells (hiPSCs)-based cell therapy holds promise for treating stress urinary incontinence (SUI). However, safety concerns, especially tumorgenic potential of residual undifferentiated cells in hiPSC derivatives, are major barriers for its clinical translation. An efficient, fast and clinical-scale strategy for purifying committed cells is also required. Our previous studies demonstrated the regenerative effects of hiPSC-derived smooth muscle progenitor cells (pSMCs) on the injured urethral sphincter in SUI, but the differentiation protocol required fluorescence-activated cell sorting (FACS) which is not practical for autologous clinical applications. In this study, we examined the efficacy and safety of hiPSC-derived pSMC populations sorted by FDA-approved magnetic-activated cell sorting (MACS) using cell-surface marker CD34 for restoring urethral sphincter function. Although the heterogeneity of MACS-sorted pSMCs was higher than that of FACS-sorted pSMCs, the percentage of undifferentiated cells dramatically decreased after directed differentiation in vitro. In vivo studies demonstrated long-term cell integration and no tumor formation of MACS-sorted pSMCs after transplantation. Furthermore, transplantation of MACS-sorted pSMCs into immunodeficient SUI rats was comparable to transplantation with FACS-sorted pSMCs for restoration of the extracellular matrix metabolism and function of the urethral sphincter. In summary, purification of hiPSC derivatives using MACS sorting for CD34 expression represent an efficient approach for production of clinical-scale pSMCs for autologous stem cell therapy for regeneration of smooth muscle tissues. Stem Cells Translational Medicine 2017;6:1158-1167.

  View details for DOI 10.1002/sctm.16-0160

  View details for Web of Science ID 000398206500011

• Efficacy and Safety of Immuno-Magnetically Sorted Smooth Muscle Progenitor Cells Derived from Human-Induced Pluripotent Stem Cells for Restoring Urethral Sphincter Function. Stem cells translational medicine Li, Y., Green, M., Wen, Y., Wei, Y., Wani, P., Wang, Z., Reijo Pera, R., Chen, B. 2017

  Abstract

  Human-induced pluripotent stem cells (hiPSCs)-based cell therapy holds promise for treating stress urinary incontinence (SUI). However, safety concerns, especially tumorgenic potential of residual undifferentiated cells in hiPSC derivatives, are major barriers for its clinical translation. An efficient, fast and clinical-scale strategy for purifying committed cells is also required. Our previous studies demonstrated the regenerative effects of hiPSC-derived smooth muscle progenitor cells (pSMCs) on the injured urethral sphincter in SUI, but the differentiation protocol required fluorescence-activated cell sorting (FACS) which is not practical for autologous clinical applications. In this study, we examined the efficacy and safety of hiPSC-derived pSMC populations sorted by FDA-approved magnetic-activated cell sorting (MACS) using cell-surface marker CD34 for restoring urethral sphincter function. Although the heterogeneity of MACS-sorted pSMCs was higher than that of FACS-sorted pSMCs, the percentage of undifferentiated cells dramatically decreased after directed differentiation in vitro. In vivo studies demonstrated long-term cell integration and no tumor formation of MACS-sorted pSMCs after transplantation. Furthermore, transplantation of MACS-sorted pSMCs into immunodeficient SUI rats was comparable to transplantation with FACS-sorted pSMCs for restoration of the extracellular matrix metabolism and function of the urethral sphincter. In summary, purification of hiPSC derivatives using MACS sorting for CD34 expression represent an efficient approach for production of clinical-scale pSMCs for autologous stem cell therapy for regeneration of smooth muscle tissues. Stem Cells Translational Medicine 2017;6:1158-1167.

  View details for DOI 10.1002/sctm.16-0160

  View details for PubMedID 28213970

• AMBULATORY AND CYSTOMETRIC RESPONSE FOLLOWING SINGLE VERSUS MULTIPLE ONABOTULINUMTOXINA DETRUSOR INJECTIONS IN A RAT MODEL OF OVERACTIVE BLADDER INDUCED BY INTRAVESICAL ACETIC ACID Dobberfuhl, A. D., Chen, B., Han, X., Diaz, E., Comiter, C. V. WILEY-BLACKWELL. 2017: S19–S20

  View details for Web of Science ID 000394664900028

• PERFORMANCE ASSESSMENT AND VALIDATION OF AN ENHANCED 12-RAT METABOLIC CAGE EQUIPPED WITH A NOVEL 100-GRAM LOAD CELL SENSOR INTERFACE Dobberfuhl, A. D., Chen, B., Han, X., Diaz, E., Comiter, C. V. WILEY-BLACKWELL. 2017: S19

  View details for Web of Science ID 000394664900027

• Smooth Muscle Progenitor Cells Derived From Human Pluripotent Stem Cells Induce Histologic Changes in Injured Urethral Sphincter STEM CELLS TRANSLATIONAL MEDICINE Li, Y., Wen, Y., Wang, Z., Wei, Y., Wani, P., Green, M., Swaminathan, G., Ramamurthi, A., Pera, R. R., Chen, B. 2016; 5 (12): 1719-1729

  Abstract

  : Data suggest that myoblasts from various sources, including bone marrow, skeletal muscle, and adipose tissue, can restore muscle function in patients with urinary incontinence. Animal data have indicated that these progenitor cells exert mostly a paracrine effect on the native tissues rather than cell regeneration. Limited knowledge is available on the in vivo effect of human stem cells or muscle progenitors on injured muscles. We examined in vivo integration of smooth muscle progenitor cells (pSMCs) derived from human pluripotent stem cells (hPSCs). pSMCs were derived from a human embryonic stem cell line (H9-ESCs) and two induced pluripotent stem cell (iPSC) lines. pSMCs were injected periurethrally into urethral injury rat models (2 × 10(6) cells per rat) or intramuscularly into severe combined immunodeficiency mice. Histologic and quantitative image analysis revealed that the urethras in pSMC-treated rats contained abundant elastic fibers and thicker muscle layers compared with the control rats. Western blot confirmed increased elastin/collagen III content in the urethra and bladder of the H9-pSMC-treated rats compared with controls. iPSC-pSMC treatment also showed similar trends in elastin and collagen III. Human elastin gene expression was not detectable in rodent tissues, suggesting that the extracellular matrix synthesis resulted from the native rodent tissues rather than from the implanted human cells. Immunofluorescence staining and in vivo bioluminescence imaging confirmed long-term engraftment of pSMCs into the host urethra and the persistence of the smooth muscle phenotype. Taken together, the data suggest that hPSC-derived pSMCs facilitate restoration of urethral sphincter function by direct smooth muscle cell regeneration and by inducing native tissue elastin/collagen III remodeling.The present study provides evidence that a pure population of human smooth muscle progenitor cells (pSMCs) derived from human pluripotent stem cells (hPSCs) (human embryonic stem cells and patient induced pluripotent stem cells) restores urethral sphincter function by two mechanisms: modulation of extracellular matrix protein metabolism in vivo and pSMC proliferation and differentiation into smooth muscle cells to regenerate the muscle layer in the lower urinary tract. These findings on the in vivo effects of human pSMCs should aid in optimizing regenerative therapies using human myoblasts.

  View details for DOI 10.5966/sctm.2016-0035

  View details for PubMedID 27460854

• Assessing the use of the IUGA/ICS classification system for prosthesis/graft complications in publications from 2011 to 2015 INTERNATIONAL UROGYNECOLOGY JOURNAL English, E., Solomon, M., Chen, B., Rogo-Gupta, L. 2016; 27 (12): 1905-1911

  Abstract

  Complications of pelvic organ prolapse and urinary incontinence surgery have gained increasing attention from both lay media and medical societies. The International Urogynecological Association and International Continence Society proposed the category-time-site system to classify complications in 2011. Our objective is to assess the usage of the category-time-site system in the literature.We conducted a systematic review and identified records using PubMed search terms "mesh" and "prolapse or incontinence" and "complication or excision" (February 2011 to December 2015) to select publications following the introduction of category-time-site system. Relevant publications were included and reviewed for study design, initial procedure, number of patients assigned codes, number of unique codes applied, purpose of assigning codes, and duration of clinical follow-up.Of 167 eligible records, 23 (14 %) used the system, 137 (82 %) used no system, and 7 (4 %) used another system. They included three study designs: randomized control trials, case reports, and case series. Given the very limited amount of data, no statistical tests were performed, but trends were noted.Fourteen percent of the reports in the literature describing complications related to prosthesis/graft use in pelvic surgery utilize the category-time-site system. The system's limited and inconsistent use hinders the ability to draw conclusions useful for clinical practice. Effort should be directed toward improving appropriate usage or revising the system to increase its exposure in related publications. An improved system will better prepare pelvic surgeons for assessing future generations of prostheses/grafts.

  View details for DOI 10.1007/s00192-016-3056-y

  View details for Web of Science ID 000389203200017

  View details for PubMedID 27250834

• Sonographic Evaluation for Endometrial Polyps: The Interrupted Mucosa Sign. Journal of ultrasound in medicine Kamaya, A., Yu, P. C., Lloyd, C. R., Chen, B. H., Desser, T. S., Maturen, K. E. 2016; 35 (11): 2381-2387

  Abstract

  To evaluate the interrupted mucosa sign for identification of endometrial polyps, using pathologic confirmation as the reference standard, compared to other accepted sonographic findings.We reviewed 195 patients referred for pelvic sonographic evaluations for suspected endometrial polyps in this retrospective Institutional Review Board-approved study. Of these, 82 had tissue sampling of the endometrium and constituted the final study group. Patient data, including age, menopausal status, last menstrual period, and final pathologic diagnosis, were recorded. Sonograms were reviewed by 2 blinded board-certified radiologists for endometrial features, including thickness, echogenicity, vascularity, presence of a mass, and the interrupted mucosa sign. Descriptive statistics and multivariate logistic regression analysis were performed.The mean age of the patients was 44.99 (SD, 9.88) years, 79.1% of whom were premenopausal. Pathologic diagnosis confirmed polyps in 58 (70.73%). A single feeding vessel was visualized in 36 patients with polyps (62.07%), whereas the interrupted mucosa sign was visualized in 34 (58.62%). The presence of a feeding vessel, the interrupted mucosa sign, or both detected 48 (82.76%) of the polyps. In the multivariate analysis, only the interrupted mucosa sign was a statistically significant predictor of pathologic diagnosis of a polyp (P = .035), with an odds ratio of 3.83 (95% confidence interval, 1.10-13.29). Other sonographic findings were not independent predictors of a polyp: mass (P = .35), single feeding vessel (P = .31), endometrial thickness (P = .88), and endometrial echogenicity (P = .45). The sensitivity, specificity, and positive predictive value of the interrupted mucosa sign were 59%, 75%, and 85%, respectively.The interrupted mucosa sign is a promising sonographic sign for identification of endometrial polyps, with greater predictive power than previously described signs. It has the potential to improve the diagnostic performance of sonography, especially when used in combination with other described signs.

  View details for PubMedID 27629758

• Spatiotemporal Reconstruction of the Human Blastocyst by Single-Cell Gene-Expression Analysis Informs Induction of Naive Pluripotency DEVELOPMENTAL CELL Durruthy-Durruthy, J., Wossidlo, M., Pai, S., Takahashi, Y., Kang, G., Omberg, L., Chen, B., Nakauchi, H., Pera, R. R., Sebastiano, V. 2016; 38 (1): 100-115

  Abstract

  Human preimplantation embryo development involves complex cellular and molecular events that lead to the establishment of three cell lineages in the blastocyst: trophectoderm, primitive endoderm, and epiblast. Owing to limited resources of biological specimens, our understanding of how the earliest lineage commitments are regulated remains narrow. Here, we examined gene expression in 241 individual cells from early and late human blastocysts to delineate dynamic gene-expression changes. We distinguished all three lineages and further developed a 3D model of the inner cell mass and trophectoderm in which individual cells were mapped into distinct expression domains. We identified in silico precursors of the epiblast and primitive endoderm lineages and revealed a role for MCRS1, TET1, and THAP11 in epiblast formation and their ability to induce naive pluripotency in vitro. Our results highlight the potential of single-cell gene-expression analysis in human preimplantation development to instruct human stem cell biology.

  View details for DOI 10.1016/j.devcel.2016.06.014

  View details for Web of Science ID 000380073400013

  View details for PubMedID 27404362

• Smooth Muscle Precursor Cells Derived from Human Pluripotent Stem Cells for Treatment of Stress Urinary Incontinence. Stem cells and development Wang, Z., Wen, Y., Li, Y. H., Wei, Y., Green, M., Wani, P., Zhang, P., Pera, R. R., Chen, B. 2016; 25 (6): 453-461

  Abstract

  There is great interest in using stem cells (SC) to regenerate a deficient urethral sphincter in patients with urinary incontinence. The smooth muscle component of the sphincter is a significant contributor to sphincter function. However, current translational efforts for sphincter muscle restoration focus only on skeletal muscle regeneration because they rely on adult mesenchymal SC as cell source. These adult SC do not yield sufficient smooth muscle cells (SMCs) for transplantation. We may be able to overcome this limitation by using pluripotent stem cell (PSC) to derive SMCs. Hence, we sought to investigate whether smooth muscle precursor cells (pSMCs) derived from human PSCs can restore urethral function in an animal model generated by surgical urethrolysis and ovariectomy. Rats were divided into four groups: control (no intervention), sham saline (surgery + saline injection), bladder SMC (surgery + human bladder SMC injection), and treatment (surgery + pSMC injection, which includes human embryonic stem cell (hESC) H9-derived pSMC, episomal reprogrammed induced pluripotent stem cells (iPSCs)-derived pSMC, or viral reprogrammed iPSC-derived pSMC). pSMCs (2 × 10(6) cells/rat) were injected periurethrally 3 weeks postsurgery. Leak point pressure (LPP) and baseline external urethral sphincter electromyography were measured 5 weeks postinjection. Both iPSC-derived pSMC treatment groups showed significantly higher LPP compared to the sham saline group, consistent with restoration of urethral sphincter function. While the difference between the H9-derived pSMC treatment and sham saline group was not significant, it did show a trend toward restoration of the LPP to the level of intact controls. Our data indicate that pSMCs derived from human PSCs (hESC and iPSC) can restore sphincter function.

  View details for DOI 10.1089/scd.2015.0343

  View details for PubMedID 26785911

  View details for PubMedCentralID PMC4818543

• IN VIVO INTEGRATION AND MECHANISM OF ACTION OF SMOOTH MUSCLE CELL PRECURSORS DERIVED FROM HUMAN PLURIPOTENT STEM CELLS Li, Y., Wen, Y., Wang, Z., Wei, Y., Green, M., Wani, P., Swaminathan, G., Ramamurthi, A., Pera, R., Chen, B. WILEY-BLACKWELL. 2016: S18–S19

  View details for Web of Science ID 000369726700032

• PRECURSOR OF SMOOTH MUSCLE CELLS DERIVED FROM HUMAN PLURIPOTENT STEM CELLS FOR TREATMENT OF STRESS URINARY INCONTINENCE Wang, Z., Wen, Y., Li, Y., Wei, Y., Green, M., Wani, P., Zhang, P., Pera, R., Chen, B. WILEY-BLACKWELL. 2016: S20

  View details for Web of Science ID 000369726700035

• LONG TERM PERSISTENCE OF INCONTINENCE IN THREE STRESS INCONTINENCE RATMODELS: VAGINAL DISTENSION, URETHROLYSIS, AND PUBO-URETHRAL LIGAMENT INJURY Zhu, F., Wang, Z., Wen, Y., Wei, Y., Chan, M., Chen, B. WILEY-BLACKWELL. 2016: S10–S11

  View details for Web of Science ID 000369726700012

• Dynamic and social behaviors of human pluripotent stem cells SCIENTIFIC REPORTS Phadnis, S. M., Loewke, N. O., Dimov, I. K., Pai, S., Amwake, C. E., Solgaard, O., Baer, T. M., Chen, B., Pera, R. A. 2015; 5

  Abstract

  Human pluripotent stem cells (hPSCs) can self-renew or differentiate to diverse cell types, thus providing a platform for basic and clinical applications. However, pluripotent stem cell populations are heterogeneous and functional properties at the single cell level are poorly documented leading to inefficiencies in differentiation and concerns regarding reproducibility and safety. Here, we use non-invasive time-lapse imaging to continuously examine hPSC maintenance and differentiation and to predict cell viability and fate. We document dynamic behaviors and social interactions that prospectively distinguish hPSC survival, self-renewal, and differentiation. Results highlight the molecular role of E-cadherin not only for cell-cell contact but also for clonal propagation of hPSCs. Results indicate that use of continuous time-lapse imaging can distinguish cellular heterogeneity with respect to pluripotency as well as a subset of karyotypic abnormalities whose dynamic properties were monitored.

  View details for DOI 10.1038/srep14209

  View details for Web of Science ID 000361369100001

  View details for PubMedID 26381699

  View details for PubMedCentralID PMC4585647

• Bilayered vascular graft derived from human induced pluripotent stem cells with biomimetic structure and function REGENERATIVE MEDICINE Nakayama, K. H., Joshi, P. A., Lai, E. S., Gujar, P., Joubert, L., Chen, B., Huang, N. F. 2015; 10 (6): 745-755

  Abstract

  We developed an aligned bi-layered vascular graft derived from human induced pluripotent stem cells (iPSCs) that recapitulates the cellular composition, orientation, and anti-inflammatory function of blood vessels.The luminal layer consisted of longitudinal-aligned nanofibrillar collagen containing primary endothelial cells (ECs) or iPSC-derived ECs (iPSC-ECs). The outer layer contained circumferentially oriented nanofibrillar collagen with primary smooth muscle cells (SMCs) or iPSC-derived SMCs(iPSC-SMCs).On the aligned scaffolds, cells organized F-actin assembly within 8º from the direction of nanofibrils. When compared to randomly-oriented scaffolds, EC-seeded aligned scaffolds had significant reduced inflammatory response, based on adhesivity to monocytes.This study highlights the importance of anisotropic scaffolds in directing cell form and function, and has therapeutic significance as physiologically relevant blood vessels.

  View details for DOI 10.2217/rme.15.45

  View details for Web of Science ID 000364574000005

  View details for PubMedID 26440211

• Dynamic and social behaviors of human pluripotent stem cells. Scientific reports Phadnis, S. M., Loewke, N. O., Dimov, I. K., Pai, S., Amwake, C. E., Solgaard, O., Baer, T. M., Chen, B., Reijo Pera, R. A. 2015; 5: 14209-?

  Abstract

  Human pluripotent stem cells (hPSCs) can self-renew or differentiate to diverse cell types, thus providing a platform for basic and clinical applications. However, pluripotent stem cell populations are heterogeneous and functional properties at the single cell level are poorly documented leading to inefficiencies in differentiation and concerns regarding reproducibility and safety. Here, we use non-invasive time-lapse imaging to continuously examine hPSC maintenance and differentiation and to predict cell viability and fate. We document dynamic behaviors and social interactions that prospectively distinguish hPSC survival, self-renewal, and differentiation. Results highlight the molecular role of E-cadherin not only for cell-cell contact but also for clonal propagation of hPSCs. Results indicate that use of continuous time-lapse imaging can distinguish cellular heterogeneity with respect to pluripotency as well as a subset of karyotypic abnormalities whose dynamic properties were monitored.

  View details for DOI 10.1038/srep14209

  View details for PubMedID 26381699

  View details for PubMedCentralID PMC4585647

• Proliferative behavior of vaginal fibroblasts from women with pelvic organ prolapse. European journal of obstetrics, gynecology, and reproductive biology Sun, B., Zhou, L., Wen, Y., Wang, C., Baer, T. M., Pera, R. R., Chen, B. 2014; 183: 1-4

  Abstract

  Pelvic organ prolapse (POP) significantly impacts quality of life of women, especially with advancing age. Cell proliferation is a critical parameter in both normal and pathophysiological processes. We sought to examine fibroblast proliferation in premenopausal women with and without POP and menopausal women with POP, and examine whether TGF-β1, a fibroblast mitogen, could stimulate proliferation in vaginal fibroblasts from these populations.Vaginal wall biopsies were obtained from asymptomatic women (controls) and women with POP (cases). Fibroblasts were cultured from these tissues. Vaginal fibroblasts were treated with or without TGF-β1. Cell proliferation rate (mitotic index) was measured with time-lapse dark-field microscopy. Cell mitosis was counted with ImageJ software after analysis of time-lapse images as Quick time movies.There was no significant difference in mitotic index throughout different time points of observation between premenopausal controls and cases of similar ages. However, a significant difference in mitotic index was seen between premenopausal and menopausal cases (p=0.01), with the menopausal group exhibiting significantly lower mitotic indices. When treated with different doses of TGF-β1, premenopausal control fibroblast proliferation increased with 5ng/ml of TGF-β1 compared to non-treated fibroblasts (p=0.04). TGF-β1 stimulation did not affect fibroblasts from either premenopausal or menopausal cases.Vaginal fibroblast proliferation decreases with age and this association does not appear to be affected by the presence of pelvic organ prolapse. TGF-β1 stimulation increased cell proliferation of premenopausal control fibroblasts. In contrast, there was no response seen in fibroblasts from premenopausal and menopausal cases.

  View details for DOI 10.1016/j.ejogrb.2014.09.040

  View details for PubMedID 25461341

• A modified method for implantation of pluripotent stem cells under the rodent kidney capsule. Stem cells and development Zhu, F., Sun, B., Wen, Y., Wang, Z., Reijo Pera, R., Chen, B. 2014; 23 (17): 2119-2125

  Abstract

  Teratoma formation, the standard in vivo pluripotency assay, is also frequently used as a tumorigenicity assay. A common concern in therapeutic stem cell applications is the tumorigenicity potential of a small number of cell impurities in the final product. Estimation of this small number is hampered by the inaccurate methodology of the tumorigenicity assay. Hence, a protocol for tumorigenicity assay that can deliver a defined number of cells, without error introduced by leakage or migration of cells is needed. In this study, we tested our modified transplantation method that allows for transplant of small numbers of pluripotent stem cells (PSCs) under the kidney capsule with minimal cell leakage. A glass capillary with a finely shaped tip and an attached mouth pipette was used to inject PSCs into the rodent kidney capsule. H9 embryonic and induced PSCs were tagged with Fluc and green fluorescence protein reporter genes and divided in different cell doses for transplantation. Bioluminescence imaging (BLI) on the day of surgery showed that the cell signal was confined to the kidney and signal intensity correlated with increasing transplant cell numbers. The overall cell leakage rate was 17% and the rodent survival rate was 96%. Teratoma formation was observed in rodents transplanted with cell numbers between 1×10(5)-2×10(6). We conclude that this modified procedure for transplanting PSCs under the kidney capsule allows for transplantation of a defined number of PSCs with significant reduction of error associated with cell leakage from the transplant site.

  View details for DOI 10.1089/scd.2014.0099

  View details for PubMedID 24800694

  View details for PubMedCentralID PMC4142776

• A Modified Method for Implantation of Pluripotent Stem Cells Under the Rodent Kidney Capsule STEM CELLS AND DEVELOPMENT Zhu, F., Sun, B., Wen, Y., Wang, Z., Pera, R. R., Chen, B. 2014; 23 (17): 2119-2125

  Abstract

  Teratoma formation, the standard in vivo pluripotency assay, is also frequently used as a tumorigenicity assay. A common concern in therapeutic stem cell applications is the tumorigenicity potential of a small number of cell impurities in the final product. Estimation of this small number is hampered by the inaccurate methodology of the tumorigenicity assay. Hence, a protocol for tumorigenicity assay that can deliver a defined number of cells, without error introduced by leakage or migration of cells is needed. In this study, we tested our modified transplantation method that allows for transplant of small numbers of pluripotent stem cells (PSCs) under the kidney capsule with minimal cell leakage. A glass capillary with a finely shaped tip and an attached mouth pipette was used to inject PSCs into the rodent kidney capsule. H9 embryonic and induced PSCs were tagged with Fluc and green fluorescence protein reporter genes and divided in different cell doses for transplantation. Bioluminescence imaging (BLI) on the day of surgery showed that the cell signal was confined to the kidney and signal intensity correlated with increasing transplant cell numbers. The overall cell leakage rate was 17% and the rodent survival rate was 96%. Teratoma formation was observed in rodents transplanted with cell numbers between 1×10(5)-2×10(6). We conclude that this modified procedure for transplanting PSCs under the kidney capsule allows for transplantation of a defined number of PSCs with significant reduction of error associated with cell leakage from the transplant site.

  View details for DOI 10.1089/scd.2014.0099

  View details for Web of Science ID 000341017900011

  View details for PubMedCentralID PMC4142776

• Challenges and future prospects for tissue engineering in female pelvic medicine and reconstructive surgery. Current urology reports Chen, B., Dave, B. 2014; 15 (8): 425-?

  Abstract

  With advances in material engineering there is now a wide array of new materials for augmentation of tissue repairs in Female Pelvic Medicine and Reconstructive Surgery (FPMRS). However, clinical outcomes are discrepant and long term complications debilitating. In this manuscript, we describe the molecular and cellular host environments and biomechanical considerations that affect optimal integration of implant materials. There is growing interest in biodegradable scaffolds with cellular implants. It is thought that the cellular component could regenerate host tissue while the scaffold provides temporary mechanical properties. Current findings are promising, but detailed in vivo and long term testing is needed before clinical applications.

  View details for DOI 10.1007/s11934-014-0425-2

  View details for PubMedID 24993035

• Histologic characteristics of vaginal cuff tissue from patients with vaginal cuff dehiscence. Journal of minimally invasive gynecology Klauschie, J., Wen, Y., Chen, B., Zhou, L., Nunez-Nateras, R., Ocal, I. T., Lam-Himlin, D., Kho, R. 2014; 21 (3): 442-446

  Abstract

  To describe the histologic characteristics of vaginal tissue in patients with vaginal cuff dehiscence (VCD) after robotic hysterectomy and to compare this group with patients without dehiscence.Retrospective analysis (Canadian Task Force classification II-3).Academic center.Seven patients with VCD and 6 patients without VCD.Vaginal cuff tissue was obtained from all patients and was stained using hematoxylin-eosin and evaluated for acute and chronic inflammation markers including neutrophils, lymphocytes, and plasma cells. Immunohistochemical staining was performed and evaluated using the semiquantitative method for collagen types I and III, smooth muscle actin, and SM22α (myofibroblast) content. Grading was performed by 4 blinded investigators. The Mann-Whitney test was used to evaluate the 2 groups, and correlation coefficients for interobserver variability.The VCD group, compared with the non-VCD group, demonstrated significantly greater numbers of neutrophils (1.71 vs 1.0; p = .04), lymphocytes (2.85 vs 1.33; p = .002), and plasma cells (2.2 vs 1.0; p = .001). There was no statistical difference between the groups in amounts of collagen I (1.71 vs 1.27; p = .09) and collagen III (1.66 vs 1.38; p = .37), smooth muscle actin (1.23 vs 1.33; p = .65), and SM22α (1.85 vs 1.27; p = .09). Interobserver variability was low (κ = 0.86; p = .76).Compared with the control group, patients with VCD demonstrated significantly higher levels of acute and chronic inflammatory cells. This finding suggests that a prolonged inflammatory phase may be delaying normal progression to reparation in patients with dehiscence.

  View details for DOI 10.1016/j.jmig.2013.11.013

  View details for PubMedID 24316139

• Concurrent Generation of Functional Smooth Muscle and Endothelial Cells via a Vascular Progenitor. Stem cells translational medicine Marchand, M., Anderson, E. K., Phadnis, S. M., Longaker, M. T., Cooke, J. P., Chen, B., Reijo Pera, R. A. 2014; 3 (1): 91-97

  Abstract

  Smooth muscle cells (SMCs) and endothelial cells (ECs) are typically derived separately, with low efficiencies, from human pluripotent stem cells (hPSCs). The concurrent generation of these cell types might lead to potential applications in regenerative medicine to model, elucidate, and eventually treat vascular diseases. Here we report a robust two-step protocol that can be used to simultaneously generate large numbers of functional SMCs and ECs from a common proliferative vascular progenitor population via a two-dimensional culture system. We show here that coculturing hPSCs with OP9 cells in media supplemented with vascular endothelial growth factor, basic fibroblast growth factor, and bone morphogenetic protein 4 yields a higher percentage of CD31(+)CD34(+) cells on day 8 of differentiation. Upon exposure to endothelial differentiation media and SM differentiation media, these vascular progenitors were able to differentiate and mature into functional endothelial cells and smooth muscle cells, respectively. Furthermore, we were able to expand the intermediate population more than a billionfold to generate sufficient numbers of ECs and SMCs in parallel for potential therapeutic transplantations.

  View details for DOI 10.5966/sctm.2013-0124

  View details for PubMedID 24311701

  View details for PubMedCentralID PMC3902294

• Improving the accuracy of prolapse and incontinence procedure epidemiology by utilizing both inpatient and outpatient data INTERNATIONAL UROGYNECOLOGY JOURNAL Elliott, C. S., Rhoads, K. F., Comiter, C. V., Chen, B., Sokol, E. R. 2013; 24 (11): 1939-1946

  Abstract

  INTRODUCTION AND HYPOTHESIS: The epidemiologic description of pelvic organ prolapse (POP) and stress urinary incontinence (SUI) procedures is documented in several large studies using national database cohorts. These studies, however, may underestimate the number of procedures performed because they only capture procedures performed in either the inpatient or outpatient settings alone. We present a complete annual description of all inpatient and outpatient surgeries for POP and SUI in California. METHODS: We reviewed a record of all inpatient and outpatient POP and SUI surgeries performed in California in 2008 using data from the Office of Statewide Health Planning (OSHPD). RESULTS: In 2008, 20,004 and 20,330 women in California underwent POP and SUI procedures, respectively. Of these, 3,134 (15.6 %) and 9,016 (44.3 %) were performed in an outpatient setting. The age-adjusted rates of POP and SUI were 1.20 and 1.20 per 1,000 US females, respectively. This correlates to 186,000 POP and 186,000 SUI procedures per year nationally. Vaginal apical suspensions were more common in those undergoing surgery as an inpatient (45.1 vs 19.4 %). The use of mesh to augment prolapse repairs was similar (22.3 % inpatient vs 19.3 % outpatient). SUI procedures performed in the outpatient setting were more likely to be performed as stand-alone procedures (82.9 vs 18.8 %, respectively). CONCLUSIONS: In California, 16 % of POP and 44 % of SUI procedures were performed in an outpatient surgical setting in 2008. Epidemiologic studies of POP and SUI should account for the fact that a substantial number of repairs are performed in the outpatient setting in order to achieve accuracy.

  View details for DOI 10.1007/s00192-013-2113-z

  View details for PubMedID 23640007

• To sling or not to sling at time of abdominal sacrocolpopexy: a cost-effectiveness analysis. journal of urology Richardson, M. L., Elliott, C. S., Shaw, J. G., Comiter, C. V., Chen, B., Sokol, E. R. 2013; 190 (4): 1306-1312

  Abstract

  OBJECTIVES: To compare the cost-effectiveness of three strategies for use of a mid-urethral sling (MUS) to prevent occult stress urinary incontinence (SUI) in those undergoing abdominal sacrocolpopexy (ASC). METHODS: Using decision-analysis modeling, we compared cost-effectiveness over a 1 year post-operative time period of three treatment approaches: 1) ASC alone with deferred option for MUS; 2) ASC with universal concomitant MUS; and 3) preoperative urodynamic study (UDS) for selective MUS. Using published data, we modeled probabilities of SUI after ASC with or without MUS, the predictive value of UDS to detect occult SUI, and the likelihood of complications after MUS. Costs were derived from Medicare 2010 reimbursement rates. The main outcome modeled was incremental cost effectiveness ratio (ICER) per quality-adjusted life years (QALY) gained. In addition to base-case analysis, one-way sensitivity analyses were performed. RESULTS: In our model, universally performing MUS at the time of ASC was the most cost-effective approach, with an incremental cost per QALY gained of $2867 when compared to performing ASC alone. Preoperative UDS was more costly and less effective than universally performing intraoperative MUS. The cost-effectiveness of ASC + MUS was robust to sensitivity analysis, with a cost-effectiveness ratio consistently below $20,000 per QALY. CONCLUSIONS: Universal concomitant MUS is the most cost-effective prophylaxis strategy for occult SUI in women undergoing ASC. The use of pre-operative UDS to guide MUS placement at the time of ASC is not cost-effective.

  View details for DOI 10.1016/j.juro.2013.03.046

  View details for PubMedID 23524201

• Impact of the 2011 FDA Transvaginal Mesh Safety Update on AUGS Members' Use of Synthetic Mesh and Biologic Grafts in Pelvic Reconstructive Surgery FEMALE PELVIC MEDICINE AND RECONSTRUCTIVE SURGERY Clemons, J. L., Weinstein, M., Guess, M. K., Alperin, M., Moalli, P., Gregory, W. T., Lukacz, E. S., Sung, V. W., Chen, B. H., Bradley, C. S. 2013; 19 (4): 191-198

  Abstract

  To describe the frequency of use and recent change in use of synthetic mesh and biologic grafts in pelvic organ prolapse (POP) and stress urinary incontinence surgery by American Urogynecology Society (AUGS) members.An electronic survey of AUGS members was conducted between December 2011 and January 2012. Frequency of graft use in POP (overall and by transvaginal and transabdominal approaches) and stress urinary incontinence surgery was queried relative to the timing of the 2011 Food and Drug Administration (FDA) safety update. Rates of materials' use before and after the statement were compared using Wilcoxon signed rank test.Fifty-three percent (507/962) of AUGS members responded and were included in analysis; 79% were urogynecologists. Before the FDA warning, in POP surgery, most (90%) used synthetic mesh and fewer (34%) used biologic grafts; 99% used synthetic mesh slings. After the FDA statement, respondents reported an overall decrease in the percent of POP cases in which they used synthetic mesh (P < 0.001) but no change in biologic graft use for POP (P = 0.37) or synthetic mesh sling use (P = 0.10). Specifically, transvaginal mesh use decreased: 40% reported decreased use and 12% stopped use. However, transvaginal mesh was still used by 61% of respondents in at least some cases. No change (62%) or increased use (12%) of mesh was reported for transabdominal POP procedures.Synthetic mesh use in transvaginal POP surgery decreased after the 2011 FDA safety update, but synthetic mesh use for transabdominal POP repair and sling procedures and overall biologic graft use in POP surgery did not decrease.

  View details for DOI 10.1097/SPV.0b013e31829099c1

  View details for Web of Science ID 000209179000002

• Impact of the 2011 FDA transvaginal mesh safety update on AUGS members' use of synthetic mesh and biologic grafts in pelvic reconstructive surgery. Female pelvic medicine & reconstructive surgery Clemons, J. L., Weinstein, M., Guess, M. K., Alperin, M., Moalli, P., Gregory, W. T., Lukacz, E. S., Sung, V. W., Chen, B. H., Bradley, C. S. 2013; 19 (4): 191-8

  Abstract

  To describe the frequency of use and recent change in use of synthetic mesh and biologic grafts in pelvic organ prolapse (POP) and stress urinary incontinence surgery by American Urogynecology Society (AUGS) members.An electronic survey of AUGS members was conducted between December 2011 and January 2012. Frequency of graft use in POP (overall and by transvaginal and transabdominal approaches) and stress urinary incontinence surgery was queried relative to the timing of the 2011 Food and Drug Administration (FDA) safety update. Rates of materials' use before and after the statement were compared using Wilcoxon signed rank test.Fifty-three percent (507/962) of AUGS members responded and were included in analysis; 79% were urogynecologists. Before the FDA warning, in POP surgery, most (90%) used synthetic mesh and fewer (34%) used biologic grafts; 99% used synthetic mesh slings. After the FDA statement, respondents reported an overall decrease in the percent of POP cases in which they used synthetic mesh (P < 0.001) but no change in biologic graft use for POP (P = 0.37) or synthetic mesh sling use (P = 0.10). Specifically, transvaginal mesh use decreased: 40% reported decreased use and 12% stopped use. However, transvaginal mesh was still used by 61% of respondents in at least some cases. No change (62%) or increased use (12%) of mesh was reported for transabdominal POP procedures.Synthetic mesh use in transvaginal POP surgery decreased after the 2011 FDA safety update, but synthetic mesh use for transabdominal POP repair and sling procedures and overall biologic graft use in POP surgery did not decrease.

  View details for DOI 10.1097/SPV.0b013e31829099c1

  View details for PubMedID 23797515

• THE EPIDEMIOLOGY OF INPATIENT AND OUTPATIENT PROLAPSE AND INCONTINENCE PROCEDURES IN THE STATE OF CALIFORNIA Elliott, C., Rhoads, K., Comiter, C., Chen, B., Sokol, E. WILEY-BLACKWELL. 2013: 193

  View details for Web of Science ID 000315223200198

• Reprogramming of fibroblasts from older women with pelvic floor disorders alters cellular behavior associated with donor age. Stem cells translational medicine Wen, Y., Wani, P., Zhou, L., Baer, T., Phadnis, S. M., Reijo Pera, R. A., Chen, B. 2013; 2 (2): 118-28

  Abstract

  We aimed to derive induced pluripotent stem cell (iPSC) lines from vaginal fibroblasts from older women with pelvic organ prolapse. We examined the effect of donor age on iPSCs and on the cells redifferentiated from these iPSCs. Vaginal fibroblasts were isolated from younger and older subjects for reprogramming. iPSCs were generated simultaneously using an excisable polycistronic lentiviral vector expressing Oct4, Klf4, Sox2, and cMyc. The pluripotent markers of iPSCs were confirmed by immunocytochemistry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Spectral karyotyping was performed. The ability of the iPSCs to differentiate into three germ layers was confirmed by embryoid body and teratoma formation. Senescence marker (p21, p53, and Bax) expressions were determined by qRT-PCR and Western blot. The iPSCs were redifferentiated to fibroblasts and were evaluated with senescence-associated β-galactosidase (SA) activity and mitotic index using time-lapse dark-field microscopy. iPSCs derived from both the younger and older subjects expressed pluripotency markers and showed normal karyotype and positive teratoma assays. There was no significant difference in expression of senescence and apoptosis markers (p21, p53, and Bax) in iPSCs derived from the younger subject compared with the older subject. Furthermore, fibroblasts redifferentiated from these iPSCs did not differ in SA activity or mitotic index. We report successful derivation of iPSCs from women with pelvic organ prolapse. Older age did not interfere with successful reprogramming. Donor age differences were not observed in these iPSCs using standard senescence markers, and donor age did not appear to affect cell mitotic activity in fibroblasts redifferentiated from iPSCs.

  View details for DOI 10.5966/sctm.2012-0092

  View details for PubMedID 23341439

  View details for PubMedCentralID PMC3659753

• Reprogramming of Fibroblasts From Older Women With Pelvic Floor Disorders Alters Cellular Behavior Associated With Donor Age STEM CELLS TRANSLATIONAL MEDICINE Wen, Y., Wani, P., Zhou, L., Baer, T., Phadnis, S. M., Pera, R. A., Chen, B. 2013; 2 (2): 118-128

  Abstract

  We aimed to derive induced pluripotent stem cell (iPSC) lines from vaginal fibroblasts from older women with pelvic organ prolapse. We examined the effect of donor age on iPSCs and on the cells redifferentiated from these iPSCs. Vaginal fibroblasts were isolated from younger and older subjects for reprogramming. iPSCs were generated simultaneously using an excisable polycistronic lentiviral vector expressing Oct4, Klf4, Sox2, and cMyc. The pluripotent markers of iPSCs were confirmed by immunocytochemistry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Spectral karyotyping was performed. The ability of the iPSCs to differentiate into three germ layers was confirmed by embryoid body and teratoma formation. Senescence marker (p21, p53, and Bax) expressions were determined by qRT-PCR and Western blot. The iPSCs were redifferentiated to fibroblasts and were evaluated with senescence-associated β-galactosidase (SA) activity and mitotic index using time-lapse dark-field microscopy. iPSCs derived from both the younger and older subjects expressed pluripotency markers and showed normal karyotype and positive teratoma assays. There was no significant difference in expression of senescence and apoptosis markers (p21, p53, and Bax) in iPSCs derived from the younger subject compared with the older subject. Furthermore, fibroblasts redifferentiated from these iPSCs did not differ in SA activity or mitotic index. We report successful derivation of iPSCs from women with pelvic organ prolapse. Older age did not interfere with successful reprogramming. Donor age differences were not observed in these iPSCs using standard senescence markers, and donor age did not appear to affect cell mitotic activity in fibroblasts redifferentiated from iPSCs.

  View details for DOI 10.5966/sctm.2012-0092

  View details for Web of Science ID 000314906400011

  View details for PubMedCentralID PMC3659753

• The Predictive Value of a Cystocele for Concomitant Vaginal Apical Prolapse JOURNAL OF UROLOGY Elliott, C. S., Yeh, J., Comiter, C. V., Chen, B., Sokol, E. R. 2013; 189 (1): 200-203

  Abstract

  Recent studies showing a correlation between descent of the anterior and apical vaginal compartments suggest that cystoceles may recur if associated apical prolapse is not corrected. However, to date the anatomical relationship of apical prolapse with respect to cystocele has been incompletely reported. We present the predictive value of a cystocele for clinically significant vaginal apical prolapse.We retrospectively reviewed the records of all new patient visits to a urogynecology clinic in a 30-month period. Women with a point Ba value of -1 or greater (stage 2 cystocele and above) were included in analysis. Predictive values of clinically significant apical prolapse, defined as point C -3 or greater, were calculated and stratified by cystocele stage.A total of 385 women were included in study. Point Ba was the leading edge of prolapse in 83.9% of cases. The position of Ba strongly correlated with that of the vaginal apex (Spearman ρ = 0.769, p <0.001). Overall 59.7% of patients had a point C of -3 or greater. The finding of clinically significant apical prolapse increased significantly with increasing Ba values. Of patients with stage 2, 3 and 4 cystocele point C was -3 or greater in 42%, 85% and 100%, respectively.The finding of stage 2 or greater cystocele is highly suggestive of clinically significant apical vaginal descent to -3 or greater. Furthermore, as cystocele stage increases, the predictive value of apical prolapse also increases. Surgeons contemplating cystocele repair should have high suspicion for vaginal apical prolapse and consider concomitant repair.

  View details for DOI 10.1016/j.juro.2012.08.177

  View details for PubMedID 23174246

• Trouble voiding in an adolescent girl. Diagnosis: Obstruced hemivagina and ipsilateral renal anomaly syndrome. Obstetrics and gynecology Kleinman, J. T., Chen, B. 2012; 120 (4): 944-947

  View details for PubMedID 22996114

• Biomechanical Properties and Associated Collagen Composition in Vaginal Tissue of Women with Pelvic Organ Prolapse JOURNAL OF UROLOGY Zhou, L., Lee, J. H., Wen, Y., Constantinou, C., Yoshinobu, M., Omata, S., Chen, B. 2012; 188 (3): 875-880

  Abstract

  The pelvic tissue of women with pelvic organ prolapse is stiffer than that of controls but there are scant data on the collagen composition that corresponds to these mechanical properties. We evaluated human vaginal wall stiffness using the novel scanning haptic microscope and correlated these measurements to collagen expression in women with and without pelvic organ prolapse. In this simultaneous biomechanical and biochemical assessment we evaluated the usefulness of this measurement technology for pelvic floor disorder research and confirmed an association between mechanical properties and composition.The elastic constant (a measure of stiffness) of vaginal wall tissue was measured with the scanning haptic microscope. Protein expression of collagen types I and III of the same tissues were determined by Western blot. The Student t test was used for comparisons between groups.The anterior and posterior vaginal walls of premenopausal and postmenopausal women with pelvic organ prolapse were significantly stiffer than those of controls (p <0.05). Collagen III protein expression in the anterior vaginal wall in the control group was higher than in menopausal women. Collagen I expression was not significantly different between controls and cases.The scanning haptic microscope produced reliable mechanical measurements in small tissue samples without tissue destruction. Vaginal wall tissues are stiffer in women with pelvic organ prolapse than in controls. This vaginal wall stiffness was associated with lower protein expression of collagen III in the vaginal wall compared to that in asymptomatic controls.

  View details for DOI 10.1016/j.juro.2012.05.017

  View details for PubMedID 22819408

• The effect of raloxifene, a SERM, on extracellular matrix protein expression of pelvic fibroblasts INTERNATIONAL UROGYNECOLOGY JOURNAL Lee, J. H., Wen, Y., Polan, M. L., Chen, B. 2012; 23 (3): 349-355

  Abstract

  We hypothesize that the abnormal extracellular matrix (ECM) turnover in pelvic tissues of women with prolapse may be attenuated by raloxifene. We examine the effect of raloxifene on ECM protein expression in pelvic fibroblasts.Pelvic fibroblasts were isolated from cases (N = 6) and controls (N = 3). Cells were treated with raloxifene. Dose-response analyses were performed by ANOVA. mRNA and protein expression of collagen I, III, MMPs, and TIMPs were determined by RT-PCR and Western blot. MMP activity was analyzed by zymography.The mRNA expression of TIMP-3 and protein expression of TIMP-1 and TIMP-3 were significantly increased by raloxifene in fibroblasts from both cases and controls (P < 0.05). Collagen I, III, and MMP mRNA and protein expressions were not affected.Raloxifene selectively attenuates abnormal matrix degradation by increasing inhibitors of proteases, TIMPs, in pelvic fibroblasts. This opens the possibility for SERMs to be used as preventive therapy for pelvic floor disorders.

  View details for DOI 10.1007/s00192-011-1567-0

  View details for Web of Science ID 000300552400014

  View details for PubMedID 21935668

• Robot-Assisted Versus Open Sacrocolpopexy: A Cost-Minimization Analysis JOURNAL OF UROLOGY Elliott, C. S., Hsieh, M. H., Sokol, E. R., Comiter, C. V., Payne, C. K., Chen, B. 2012; 187 (2): 638-643

  Abstract

  Abdominal sacrocolpopexy is considered a standard of care operation for apical vaginal vault prolapse repair. Using outcomes at our center we evaluated whether the robotic approach to sacrocolpopexy is as cost-effective as the open approach.After obtaining institutional review board approval we performed cost-minimization analysis in a retrospective cohort of patients who underwent sacrocolpopexy at our institution between 2006 and 2010. Threshold values, that is model variable values at which the most cost effective approach crosses over to an alternative approach, were determined by testing model variables over realistic ranges using sensitivity analysis. Hospital billing data were also evaluated to confirm our findings.Operative time was similar for robotic and open surgery (226 vs 221 minutes) but postoperative length of stay differed significantly (1.0 vs 3.3 days, p <0.001). Base case analysis revealed an overall 10% cost savings for robot-assisted vs open sacrocolpopexy ($10,178 vs $11,307). Tornado analysis suggested that the number of institutional robotic cases done annually, length of stay and cost per hospitalization day in the postoperative period were the largest drivers of cost. Analysis of our hospital billing data showed a similar trend with robotic surgery costing 4.2% less than open surgery.A robot-assisted approach to sacrocolpopexy can be equally or less costly than an open approach. This depends on a sufficient institutional robotic case volume and a shorter postoperative stay for patients who undergo the robot-assisted procedure.

  View details for DOI 10.1016/j.juro.2011.09.160

  View details for PubMedID 22177180

• THE ANATOMIC RELATIONSHIP BETWEEN THE ANTERIOR VAGINAL WALL AND THE VAGINAL APEX IN WOMEN WITH STAGE 2 OR GREATER CYSTOCELE Elliott, C., Comiter, C., Chen, B., Sokol, E. WILEY-BLACKWELL. 2012: 218–19

  View details for Web of Science ID 000300502400020

• Identification of protein marker in vaginal wall tissues of women with stress urinary incontinence by protein chip array JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH Wen, Y., Whitin, J., Yu, T., Cohen, H., Polan, M. L., Chen, B. 2012; 38 (1): 89-96

  Abstract

  We sought to investigate protein biomarkers for stress urinary incontinence (SUI) in vaginal tissues using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) and examine if this is a reliable methodology to examine proteins in small tissue specimens.  We compared protein expression profile of vaginal tissue from women with SUI and continent controls. A 22.6kDa peak was identified by subsequent weak cation-exchange, reverse-phase fractionation, gel electrophoresis, and trypsin digestion, then analyzed by matrix assisted laser desorption/ionization mass spectrometry (MALDI MS) and MALDI MS-MS. Biomarker identity and expression level were confirmed by Western-blotting and immunohistochemistry.Expression of the 22.6kDa protein, identified as SM-22α, was significantly higher in women with SUI versus controls. A 3×3-mm tissue sample was sufficient for identification. Western-blot/immunohistochemistry confirmed the SELDI-TOS MS findings.SM-22α, a marker for myofibroblasts, was identified as a biomarker of SUI. Differential protein profiling by SELDI-TOF MS is a powerful and reliable tool for urogynecological research as it allows us to study an array of proteins simultaneously using small tissue samples.

  View details for DOI 10.1111/j.1447-0756.2011.01690.x

  View details for Web of Science ID 000298882800014

  View details for PubMedID 22136672

  View details for PubMedCentralID PMC3253185

• Alterations in Connective Tissue Metabolism in Stress Incontinence and Prolapse JOURNAL OF UROLOGY Chen, B., Yeh, J. 2011; 186 (5): 1768-1772

  Abstract

  We describe current knowledge about collagen/elastin and extracellular matrix metabolism in the genitourinary tract with special emphasis on stress urinary incontinence. We also explored the influence of genetics and reproductive hormones on extracellular matrix metabolism.We performed a MEDLINE® search from 1995 to February 2011 using the key words stress urinary incontinence, pelvic organ prolapse, extracellular matrix, collagen, elastin, matrix metalloproteinase, collagenase, tissue inhibitors of matrix metalloproteinase, elastin metabolism, elastase, connective tissue, supportive tissue, mechanical stress, biomechanical properties, selective estrogen receptor modulators, transforming growth factor-β and wound healing.The literature searched produced data on 4 areas of significance for extracellular matrix metabolism in patients with stress urinary incontinence and prolapse, including collagen, elastin and transforming growth factor-β. Data on collagen metabolism continue to support the hypothesis of increased turnover involving matrix metalloproteinases and serine proteases in pelvic tissues of affected individuals. Elastin metabolism studies suggest increased degradation but also abnormal elastin fiber synthesis. Epidemiological data indicate a genetic predisposition to abnormal extracellular matrix in affected individuals while human tissue and animal models reveal differential expression of candidate genes involved in structural proteins. Transforming growth factor-β pathways have been documented to be involved in stress urinary incontinence in human tissues and animal models. Finally, these extracellular matrix metabolisms are modulated by reproductive hormones and selective estrogen receptor modulators.Pelvic tissue from women with stress urinary incontinence and pelvic organ prolapse show a genetic predisposition to abnormal extracellular matrix remodeling, which is modulated by reproductive hormones, trauma, mechanical stress load and aging. This progressive remodeling contributes to stress urinary incontinence/pelvic organ prolapse by altering normal tissue architecture and mechanical properties.

  View details for DOI 10.1016/j.juro.2011.06.054

  View details for Web of Science ID 000296022200008

  View details for PubMedID 21944102

• Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy A Randomized Controlled Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LaCroix, A. Z., Chlebowski, R. T., Manson, J. E., Aragaki, A. K., Johnson, K. C., Martin, L., Margolis, K. L., Stefanick, M. L., Brzyski, R., Curb, J. D., Howard, B. V., Lewis, C. E., Wactawski-Wende, J. 2011; 305 (13): 1305-1314

  Abstract

  The Women's Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported.To examine health outcomes associated with randomization to treatment with conjugated equine estrogens (CEE) among women with prior hysterectomy after a mean of 10.7 years of follow-up through August 2009.The intervention phase was a double-blind, placebo-controlled, randomized clinical trial of 0.625 mg/d of CEE compared with placebo in 10,739 US postmenopausal women aged 50 to 79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7645 surviving participants (78%) who provided written consent.The primary outcomes were coronary heart disease (CHD) and invasive breast cancer. A global index of risks and benefits included these primary outcomes plus stroke, pulmonary embolism, colorectal cancer, hip fracture, and death.The postintervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00; 95% CI, 0.84-1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27; 95% CI, 0.88-1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62-0.95). Health outcomes were more favorable for younger compared with older women for CHD (P = .05 for interaction), total myocardial infarction (P = .007 for interaction), colorectal cancer (P = .04 for interaction), total mortality (P = .04 for interaction), and global index of chronic diseases (P = .009 for interaction).Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted.clinicaltrials.gov Identifier: NCT00000611.

  View details for Web of Science ID 000289162400019

  View details for PubMedID 21467283

• Visualization of pelvic floor reflex and voluntary contractions. Studies in health technology and informatics Constantinou, C. E., Korenblum, D., Chen, B. 2011; 163: 138-143

  Abstract

  Visualization of the geometric deformation and associated displacement patterns of tubular abdominal organs to mechanical stimuli provides a quantitative measure that is useful in modeling their elastic properties. The origin of the stimulus may be the result of direct and voluntary muscle contraction or in response to a triggered reflex activity. Using trans-perineal 2D ultrasound imaging we examined the characteristics of deformation and displacement of these organs in response to voluntary activity, contraction, straining, and fast reflex responses to stimuli such as coughing. The relative time sequence in movement was examined by serially segmenting the outline of these structures and mapping their temporal characteristics.

  View details for PubMedID 21335777

• THE EFFECT OF DONOR AGE ON INDUCED PLURIPOTENT STEM CELLS FROM WOMEN WITH PELVIC FLOOR DISORDERS 8th Annual Winter Meeting of the Society-for-Urodynamics-and-Female-Urology Wen, Y., Gujar, P., Jarvis, R., Baer, T., Pera, R. R., Chen, B. WILEY-BLACKWELL PUBLISHING, INC. 2011: 239–40

  View details for Web of Science ID 000286997900082

• Expression of Apoptotic Factors in Vaginal Tissues From Women With Urogenital Prolapse NEUROUROLOGY AND URODYNAMICS Wen, Y., Ho, J. Y., Polan, M. L., Chen, B. 2011; 30 (8): 1627-1632

  Abstract

  Increased apoptotic activity in pelvic tissues may contribute to development of pelvic floor disorders. We evaluated expression of apoptotic factors (Bcl-2 family) in vaginal tissues from women with pelvic organ prolapse (POP) and how these factors correlate with severity of prolapse.mRNA and protein expression of anti-apoptotic and pro-apoptotic factors in vaginal tissues from subjects and controls were determined by real-time PCR and Western blot. Severity of prolapse was staged using POP-Q criteria.Differential expression of Bcl-2 family factors was observed in protein rather than in gene expression. During the secretory phase, the anti-apoptotic (Bcl-2, Bcl-xl) and pro-apoptotic protein (Bax) were upregulated in controls compared to cases (P < 0.05). The ratios of Bcl-2/Bax and Bcl-2/Bad, which determine cellular sensitivity to induction of apoptosis, were higher in controls versus cases. Higher ratios indicate reduced cellular sensitivity to apoptosis. Protein expression of Bax and Bad was higher in women with severe compared to mild prolapse (P < 0.05).Increased expression of Bad, Bax, and decreased ratios of Bcl-2/Bax, Bcl-2/Bad suggest increased apoptotic activity or sensitivity to induction of apoptosis in vaginal tissues of women with POP.

  View details for DOI 10.1002/nau.21127

  View details for Web of Science ID 000296425200046

  View details for PubMedID 21674599

• Estrogen Plus Progestin and Breast Cancer Incidence and Mortality in Postmenopausal Women JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Chlebowski, R. T., Anderson, G. L., Gass, M., Lane, D. S., Aragaki, A. K., Kuller, L. H., Manson, J. E., Stefanick, M. L., Ockene, J., Sarto, G. E., Johnson, K. C., Wactawski-Wende, J., Ravdin, P. M., Schenken, R., Hendrix, S. L., Rajkovic, A., Rohan, T. E., Yasmeen, S., Prentice, R. L. 2010; 304 (15): 1684-1692

  Abstract

  In the Women's Health Initiative randomized, placebo-controlled trial of estrogen plus progestin, after a mean intervention time of 5.6 (SD, 1.3) years (range, 3.7-8.6 years) and a mean follow-up of 7.9 (SD, 1.4) years, breast cancer incidence was increased among women who received combined hormone therapy. Breast cancer mortality among participants in the trial has not been previously reported.To determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (SD, 2.7) years, through August 14, 2009.A total of 16,608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were randomly assigned to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo pill. After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12,788 (83%) of the surviving participants.Invasive breast cancer incidence and breast cancer mortality.In intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow-up on March 31, 2005, estrogen plus progestin was associated with more invasive breast cancers compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46; P = .004). Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03). There were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04; P = .049) as well as more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P = .045) among women who received estrogen plus progestin compared with women in the placebo group.Estrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive. Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin.clinicaltrials.gov Identifier: NCT00000611.

  View details for Web of Science ID 000283129700022

  View details for PubMedID 20959578

• Preputial Epidermoid Cyst: An Atypical Case of Acquired Pseudoclitoromegaly JOURNAL OF LOWER GENITAL TRACT DISEASE Paulus, Y. M., Wong, A. E., Chen, B., Jacobson, M. T. 2010; 14 (4): 382-386

  Abstract

  Clitoromegaly and pseudoclitoromegaly are rare conditions with both congenital and acquired causes. Acquired causes of adult onset have most frequently been reported to occur in the setting of female genital cutting or neurofibromatosis.Case report.We describe the management of a 47-year-old postmenopausal woman who presented with a 1-year history of a progressive and painful enlargement of her clitoris. Surgical resection revealed an epidermoid, or follicular infundibular, cyst of the prepuce.A review of the etiology underlying acquired clitoromegaly and pseudoclitoromegaly is presented. Previously published cases of pseudoclitoromegaly secondary to cysts are reviewed, all of which were congenital or secondary to female genital cutting, abscesses, or puberty. We report the first case of a postmenopausal woman with no previous history of female genital cutting or infection with a preputial epidermoid cyst. Local cysts or tumors should be considered in the differential diagnosis as causes of pseudoclitoromegaly.

  View details for DOI 10.1097/LGT.0b013e3181d85da9

  View details for Web of Science ID 000282482600017

  View details for PubMedID 20885168

• Radiofrequency Treatment of Vaginal Laxity after Vaginal Delivery: Nonsurgical Vaginal Tightening JOURNAL OF SEXUAL MEDICINE Millheiser, L. S., Pauls, R. N., Herbst, S. J., Chen, B. H. 2010; 7 (9): 3088-3095

  Abstract

  All women who have given birth vaginally experience stretching of their vaginal tissue. Long-term physical and psychological consequences may occur, including loss of sensation and sexual dissatisfaction. One significant issue is the laxity of the vaginal introitus.To evaluate safety and tolerability of nonsurgical radiofrequency (RF) thermal therapy for treatment of laxity of the vaginal introitus after vaginal delivery. We also explored the utility of self-report questionnaires in assessing subjective effectiveness of this device.Pilot study to treat 24 women (25-44 years) once using reverse gradient RF energy (75-90 joules/cm(2) ), delivered through the vaginal mucosa. Post-treatment assessments were at 10 days, 1, 3, and 6 months.Pelvic examinations and adverse event reports to assess safety. The author modified Female Sexual Function Index (mv-FSFI) and Female Sexual Distress Scale-Revised (FSDS-R), Vaginal Laxity and Sexual Satisfaction Questionnaires (designed for this study) to evaluate both safety and effectiveness, and the Global Response Assessment to assess treatment responses.No adverse events were reported; no topical anesthetics were required. Self-reported vaginal tightness improved in 67% of subjects at one month post-treatment; in 87% at 6 months (P<0.001). Mean sexual function scores improved: mv-FSFI total score before treatment was 27.6 ± 3.6, increasing to 32.0 ± 3.0 at 6 months (P < 0.001); FSDS-R score before treatment was 13.6 ± 8.7, declining to 4.3 ± 5.0 at month 6 post-treatment (P < 0.001). Twelve of 24 women who expressed diminished sexual satisfaction following their delivery; all reported sustained improvements on SSQ at 6 months after treatment (P = 0.002).The RF treatment was well tolerated and showed an excellent 6-month safety profile in this pilot study. Responses to the questionnaires suggest subjective improvement in self-reported vaginal tightness, sexual function and decreased sexual distress. These findings warrant further study.

  View details for DOI 10.1111/j.1743-6109.2010.01910.x

  View details for PubMedID 20584127

• Transforming growth interacting factor expression in leiomyoma compared with myometrium FERTILITY AND STERILITY Yen-Ping, J., Man, W. C., Wen, Y., Polan, M. L., Ho, E. S., Chen, B. 2010; 94 (3): 1078-1083

  Abstract

  To investigate the expression of transforming growth interacting factor (TGIF), a Smad transcriptional corepressor, in leiomyoma and matched myometrial tissue samples and the effect of TGIF overexpression in myometrial cells.Experimental study.Tertiary university hospital.Uterine leiomyoma and myometrial tissues from 16 patients.None.The distribution of TGIF in leiomyoma and myometrial tissues by immunohistochemistry stain, mRNA, and protein expression levels by real-time quantitative polymerase chain-reaction (QPCR) and Western blot. Transcriptional regulation of TGIF in myometrial cells with overexpressed TGIF.Although TGIF is present in the smooth muscle cells of the leiomyoma and the myometrium, it is not found in the extracellular matrix. The TGIF mRNA and protein expressions were statistically significantly higher in the leiomyoma compared with the matched, unaffected myometrial tissues in both phases of the menstrual cycle. There were no differences in mRNA or protein expression throughout the menstrual cycle. Overexpression of TGIF protein in myometrial cells statistically significantly suppressed up-regulation of plasminogen activator inhibitor (PAI-1) induced by TGF-beta1 treatment.Expression of TGIF is increased in leiomyoma compared with myometrium. This increase in TGIF expression is not affected by endogenous ovarian hormones. Thus, TGIF is a potential repressor of TGF-beta pathways in myometrial cells.

  View details for DOI 10.1016/j.fertnstert.2009.05.001

  View details for Web of Science ID 000280407900038

  View details for PubMedID 19524896

  View details for PubMedCentralID PMC2888713

• Identification of Protein Marker in Vaginal Wall Tissues of Women with Stress Urinary Incontinence by Protein Chip Array 57th Annual Meeting of the Society-for-Gynecologic-Investigation Wen, Y., Whitin, J., Yu, T., Cohen, H., Polan, M. L., Chen, B. SAGE PUBLICATIONS INC. 2010: 275A–275A

  View details for Web of Science ID 000275558601205

• The Relationship between Extracellular Matrix Proteins and the Severity of Prolpase in Women with Pelvic Organ Prolapse: A Preliminary Study Wen, Y., Polan, M. L., Chen, B. SAGE PUBLICATIONS INC. 2010: 275A

  View details for Web of Science ID 000275558601204

• Imaging-Based Computation of the Dynamics of Pelvic Floor Deformation and Strain Visualization Analysis 6th International Symposium on Visual Computing Constantinou, C. E., McLean, L., Kuhl, E., Chen, B. SPRINGER-VERLAG BERLIN. 2010: 604–612

  View details for Web of Science ID 000290358400062

• Is lysyl oxidase-like protein-1, alpha-1 antitrypsin, and neutrophil elastase site specific in pelvic organ prolapse? INTERNATIONAL UROGYNECOLOGY JOURNAL Man, W. C., Ho, J. Y., Wen, Y., Sokol, E. R., Polan, M. L., Chen, B. 2009; 20 (12): 1423-1429

  Abstract

  We investigated whether the expression of alpha-1 antitrypsin (ATT), neutrophil elastase (NE), and lysyl oxidase-like protein 1 (LOXL-1) vary within the vagina in subjects with pelvic organ prolapse (POP).Biopsies were obtained from the anterior and posterior vaginal wall of 22 women with POP (> or =stage 2 by POP-Q). The subjects were grouped by the most prominent defect: cystocele, cystocele plus uterine prolapse, and rectocele. Comparative real-time PCR, Western blotting, and NE enzyme activity assay were performed.The ratio of anterior and posterior vaginal wall ATT, NE, and LOXL-1 expression varied between individuals within the same defect group.ATT, NE, and LOXl-1 expression was variable among different biopsy sites in the vagina. No consistent pattern was present when the subjects were grouped by the most prominent defect. We recommend careful consideration of biopsy sites in future studies on POP to enhance reproducibility of data.

  View details for DOI 10.1007/s00192-009-0905-y

  View details for PubMedID 19763368

• Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial LANCET Chlebowski, R. T., Schwartz, A. G., Wakelee, H., Anderson, G. L., Stefanick, M. L., Manson, J. E., Rodabough, R. J., Chien, J. W., Wactawski-Wende, J., Gass, M., Kotchen, J. M., Johnson, K. C., O'Sullivan, M. J., Ockene, J. K., Chen, C., Hubbell, F. A. 2009; 374 (9697): 1243-1251

  Abstract

  In the post-intervention period of the Women's Health Initiative (WHI) trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo. Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period.The WHI study was a randomised, double-blind, placebo-controlled trial undertaken in 40 centres in the USA. 16 608 postmenopausal women aged 50-79 years with an intact uterus were randomly assigned by a computerised, stratified, permuted block algorithm to receive a once-daily tablet of 0.625 mg conjugated equine oestrogen plus 2.5 mg medroxyprogesterone acetate (n=8506) or matching placebo (n=8102). We assessed incidence and mortality rates for all lung cancer, small-cell lung cancer, and non-small-cell lung cancer by use of data from treatment and post-intervention follow-up periods. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00000611.After a mean of 5.6 years (SD 1.3) of treatment and 2.4 years (0.4) of additional follow-up, 109 women in the combined hormone therapy group had been diagnosed with lung cancer compared with 85 in the placebo group (incidence per year 0.16%vs 0.13%; hazard ratio [HR] 1.23, 95% CI 0.92-1.63, p=0.16). 96 women assigned to combined therapy had non-small-cell lung cancer compared with 72 assigned to placebo (0.14%vs 0.11%; HR 1.28, 0.94-1.73, p=0.12). More women died from lung cancer in the combined hormone therapy group than in the placebo group (73 vs 40 deaths; 0.11%vs 0.06%; HR 1.71, 1.16-2.52, p=0.01), mainly as a result of a higher number of deaths from non-small-cell lung cancer in the combined therapy group (62 vs 31 deaths; 0.09%vs 0.05%; HR 1.87, 1.22-2.88, p=0.004). Incidence and mortality rates of small-cell lung cancer were similar between groups.Although treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, it increased the number of deaths from lung cancer, in particular deaths from non-small-cell lung cancer. These findings should be incorporated into risk-benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer.National Heart, Lung and Blood Institute, National Institutes of Health.

  View details for DOI 10.1016/S0140-6736(09)61526-9

  View details for Web of Science ID 000270852500030

  View details for PubMedID 19767090

• Retained Products of Conception Spectrum of Color Doppler Findings JOURNAL OF ULTRASOUND IN MEDICINE Kamaya, A., Petrovitch, I., Chen, B., Frederick, C. E., Jeffrey, R. B. 2009; 28 (8): 1031-1041

  Abstract

  The purpose of this study was to characterize color Doppler imaging features of retained products of conception (RPOC) with gray scale correlation.Clinically suspected cases of RPOC between January 2005 and February 2008 were reviewed. Patient data and relevant color Doppler and gray scale features were recorded.A total of 269 patients referred for sonographic evaluation for RPOC were identified. Thirty-five patients had confirmed pathologic diagnoses, 28 of whom had RPOC. In those with RPOC, 5 (18%) were avascular (type 0); 6 (21%) had minimal vascularity (type 1); 12 (43%) had moderate vascularity (type 2); and 5 (18%) had marked vascularity (type 3). Peak systolic velocities ranged from 10 to 108 cm/s (average, 36.1 cm/s). Resistive indices in arterial waveforms ranged from 0.33 to 0.7 (average, 0.5). Five (45%) of the patients with type 0 vascularity had RPOC; 6 (86%) of those with type 1 had RPOC; and 17 (100%) of those with types 2 and 3 had RPOC. An echogenic mass had a moderate positive predictive value (80%) but low sensitivity (29%) for RPOC.Color Doppler evaluation of the endometrium is helpful in determining the presence of RPOC. Endometrial vascularity is highly correlated with RPOC, whereas the lack of vascularity can be seen in both intrauterine clots and avascular RPOC.

  View details for Web of Science ID 000268556800008

  View details for PubMedID 19643786

• Relaxin increases elastase activity and protease inhibitors in smooth muscle cells from the myometrium compared with cells from leiomyomas FERTILITY AND STERILITY Chen, B., Wen, Y., Yu, X. Y., Polan, M. L. 2009; 91 (4): 1351-1354

  Abstract

  We investigated the effect of relaxin on extracellular matrix remodeling in cultured myometrial compared with leiomyoma smooth muscle cells. Relaxin increases elastase activity and protease inhibitor expressions in myometrial smooth muscle cells, but no effect was observed in leiomyoma cells.

  View details for DOI 10.1016/j.fertnstert.2008.03.043

  View details for Web of Science ID 000265132600018

  View details for PubMedID 18554597

  View details for PubMedCentralID PMC2728012

• Emergency Gynecologic Imaging SEMINARS IN ULTRASOUND CT AND MRI Kamaya, A., Shin, L., Chen, B., Desser, T. S. 2008; 29 (5): 353-368

  Abstract

  Acute pelvic pain in the female patient can have myriad presentations and, depending on the diagnosis, profound consequences. In the pregnant patient with pelvic pain or bleeding, an ectopic pregnancy must be first excluded. Ultrasound is important in determining the size and location of the ectopic pregnancy, and presence of bleeding, which in turn helps guide treatment decisions. Subchorionic or subplacental bleeds in an intrauterine pregnancy may also present with vaginal bleeding with consequences dependent on gestational age and size of bleed. In the postpartum female suspected to have retained products of conception, sonographic findings may vary from a thickened endometrial stripe to an echogenic mass with associated marked vascularity, often mimicking an arterial-venous malformation. In the nonpregnant patient, early diagnosis and treatment of ovarian torsion can preserve ovarian function. Other causes of peritoneal irritation may also cause acute pelvic pain including a ruptured hemorrhagic cyst or ruptured endometrioma. When pelvic inflammatory disease is suspected, imaging is used to evaluate for serious associated complications including the presence of a tuboovarian abscess or peritonitis. While leiomyomas of the uterus are largely asymptomatic, a leiomyoma that undergoes necrosis, torsion or prolapse through the cervix may be associated with acute severe pain or bleeding. The imaging features of these and other important clinical entities in the female pelvis will be presented.

  View details for DOI 10.1053/j.sult.2008.06.006

  View details for PubMedID 18853841

• Conjugated equine estrogens and colorectal cancer incidence and survival: The women's health initiative randomized clinical trial CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ritenbaugh, C., Stanford, J. L., Wu, L., Shikany, J. M., Schoen, R. E., Stefanick, M. L., Taylor, V., Garland, C., Frank, G., Lane, D., Mason, E., Mcneeley, S. G., Ascensao, J., Chlebowski, R. T. 2008; 17 (10): 2609-2618

  Abstract

  In separate Women's Health Initiative randomized trials, combined hormone therapy with estrogen plus progestin reduced colorectal cancer incidence but estrogen alone in women with hysterectomy did not. We now analyze features of the colorectal cancers that developed and examine the survival of women following colorectal cancer diagnosis in the latter trial.10,739 postmenopausal women who were 50 to 79 years of age and had undergone hysterectomy were randomized to conjugated equine estrogens (0.625 mg/d) or matching placebo. Colorectal cancer incidence was a component of the monitoring global index of the study but was not a primary study endpoint. Colorectal cancers were verified by central medical record and pathology report review. Bowel exam frequency was not protocol defined, but information on their use was collected.After a median 7.1 years, there were 58 invasive colorectal cancers in the hormone group and 53 in the placebo group [hazard ratio, 1.12; 95% confidence interval (95% CI), 0.77-1.63]. Tumor size, stage, and grade were comparable in the two randomization groups. Bowel exam frequency was also comparable in the two groups. The cumulative mortality following colorectal cancer diagnosis among women in the conjugated equine estrogen group was 34% compared with 30% in the placebo group (hazard ratio, 1.34; 95% CI, 0.58-3.19).In contrast to the preponderance of observational studies, conjugated equine estrogens in a randomized clinical trial did not reduce colorectal cancer incidence nor improve survival after diagnosis.

  View details for DOI 10.1158/1055-9965.EPI-08-0385

  View details for Web of Science ID 000260051000013

  View details for PubMedID 18829444

  View details for PubMedCentralID PMC2937217

• Effect of relaxin on TGF-beta 1 expression in cultured vaginal fibroblasts from women with stress urinary incontinence REPRODUCTIVE SCIENCES Wen, Y., Zhao, Y., Polan, M. L., Chen, B. 2008; 15 (3): 312-320

  Abstract

  The objective of this study is to compare relaxin's effect on transforming growth factor (TGF)- beta1 and latent TGF-beta1-binding protein (LTBP-1) in vaginal fibroblasts from women with stress urinary incontinence (SUI) to continent women (controls) in both phases of the menstrual cycle. Fibroblasts were treated with relaxin. TGF-beta1 levels were measured by enzyme-linked immunosorbent assay. LTBP-1 expression was evaluated by Western blot. In the proliferative phase, total TGF-beta1 level in the supernatant, cells, and extracellular matrix (ECM) of SUI fibroblasts decreased with increasing relaxin concentration (P < .05). Active TGF-beta1 levels increased at a low concentration of relaxin (P < .05) in the supernatant but decreased in the ECM of SUI fibroblasts at high concentration (P < .05). In the secretory phase, total TGF-beta1 levels decreased with relaxin treatment (P < .05) in the supernatant, cells and ECM of both women with SUI and controls. Relaxin decreased the levels of total and active TGF-beta1 in the ECM isolated from SUI vaginal fibroblasts.

  View details for DOI 10.1177/1933719108315299

  View details for Web of Science ID 000255410900012

  View details for PubMedID 18421026

• Is alpha 2-macroglobulin important in female stress urinary incontinence? HUMAN REPRODUCTION Wen, Y., Man, W. C., Sokol, E. R., Polan, M. L., Chen, B. H. 2008; 23 (2): 387-393

  Abstract

  Loss of mechanical stability of the urethra and bladder is thought to be important in the development of stress urinary incontinence (SUI). The vaginal wall is the main supporting tissue for pelvic organs and changes in components of supporting tissues are known to be involved in the pathophysiology of SUI.We evaluated changes in expression of alpha2-macroglobulin (alpha2-M), a protease inhibitor, in vaginal wall tissues from premenopausal women (aged 42-45 years) with SUI (n = 28) compared with menstrual cycle-matched continent women (controls, n = 29). The distribution of alpha2-M in vaginal wall tissues and fibroblasts was analysed by immunohistochemistry and immunofluorescence. Expression levels of alpha2-M mRNA and protein was determined by relative real-time quantitative PCR and enzyme-linked immunosorbent assay, respectively. Protease inhibition was measured to assess bioactivity.Vaginal wall tissues do express alpha2-M. Expression of alpha2-M mRNA and protein was significantly higher in tissues from controls compared to women with SUI in both proliferative and secretory phases (P < 0.05). Protease inhibitory activity of alpha2-M was significantly higher in tissues from controls compared to women with SUI in the secretory phase (P < 0.05), but we found no difference in the proliferative phase between groups. alpha2-M protein level was lower in the proliferative phase than the secretory phase in both controls and SUI patients, while for alpha2-M mRNA this was found only in controls.Decreased expression of alpha2-M mRNA and protein and protease inhibitory activity in the vaginal wall tissues of women with SUI may contribute to the development of SUI.

  View details for DOI 10.1093/humrep/dem370

  View details for PubMedID 18077315

• Expression of CD9 in frozen-thawed mouse oocytes: preliminary experience FERTILITY AND STERILITY Wen, Y., Quintero, R., Chen, B., Shu, Y., Polan, M. L., Behr, B. 2007; 88 (2): 526-529

  Abstract

  CD9 mRNA and protein expression levels in mouse slow frozen-rapid thawed oocytes were compared with those in fresh oocytes by using comparative quantitative real time reverse transcription-PCR and semiquantitative Western blot, respectively. The expression levels of both CD9 mRNA and protein in the frozen oocytes were significantly lower than those found in the fresh oocytes.

  View details for DOI 10.1016/j.fertnstert.2006.11.130

  View details for Web of Science ID 000248716000044

  View details for PubMedID 17307168

• Differences in mRNA and protein expression of small proteoglycans in vaginal wall tissue from women with and without stress urinary incontinence HUMAN REPRODUCTION Wen, Y., Zhao, Y. Y., Li, S., Polan, M. L., Chen, B. H. 2007; 22 (6): 1718-1724

  Abstract

  To investigate changes in mRNA and protein levels of biglycan (BGN), decorin (DCN) and fibromodulin (FMOD) in vaginal wall tissue from women with stress urinary incontinence (SUI) compared to menstrual-cycle matched continent women.We determined mRNA expressions of BGN, DCN and FMOD by quantitative real-time PCR. They were localized in vaginal wall tissue by immunohistochemistry. We performed western blot analysis to examine protein expression.BGN, DCN and FMOD co-localized with collagen and elastin in the extracellular matrix (ECM) of vaginal wall tissue from both groups. The mRNA expression of FMOD was significantly lower in cases versus controls in the proliferative phase (P = 0.03). DCN mRNA expression in cases was higher in the proliferative (P = 0.05) and secretory phases (P = 0.02) versus controls. BGN mRNA expression showed no significant differences in either phase. Protein expression of FMOD in cases was lower in the proliferative phase versus controls (six out of nine pairs), whereas DCN and BGN protein expression in the secretory phase in cases was higher (seven out of nine pairs).BGN, DCN and FMOD expressions in vaginal wall tissue differ in women with SUI and are hormonally modulated. Differences in small proteoglycans may contribute to the altered pelvic floor connective tissues found in these women.

  View details for DOI 10.1093/humrep/dem039

  View details for Web of Science ID 000247470700033

  View details for PubMedID 17395685

• Increased expression of latent TGF-beta binding protein-1 and fibrillin-1 in human uterine leiomyomata. Molecular human reproduction Zhao, Y., Wen, Y., Polan, M. L., Qiao, J., Chen, B. H. 2007; 13 (5): 343-349

  Abstract

  We compared latent TGF-ss binding protein-1 (LTBP-1) and fibrillin-1 (FBN-1) expression in leiomyomata and myometrium, correlated with leiomyomata size. We studied in vivo and in vitro effects of ovarian steroids using matched leiomyomata and myometrium samples from both phases of the menstrual cycle. Leiomyomata were divided into small (or=6 cm) groups. We validated LTBP-1 and FBN-1 expression using QPCR, western blot and immunohistochemistry. LTBP-1 and FBN-1 mRNA and protein expressions were higher in the medium-sized group compared with myometrium in the proliferative phase (P = 0.01; P = 0.01). FBN-1 mRNA expression was higher in the secretory phase (P = 0.01). LTBP-1 mRNA and protein expression was higher in the medium group compared with the small and large groups in the proliferative phase (P = 0.04; P = 0.04). No differences between groups were seen in FBN-1 expression in either phase. 17Beta-estradiol (E2) increased mRNA and protein expression of LTBP-1 and FBN-1 in cultured leiomyoma smooth muscle cells (LSMC) (P < 0.05). No change in FBN-1 and LTBP-1 expression was observed when cells were treated with E2 plus progesterone. Estrogen may be involved in LTBP-1 and FBN-1 expression in leiomyomata. Extracellular matrix metabolism may be different in medium-sized leiomyoma.

  View details for PubMedID 17360930

• Increased expression of latent TGF-beta binding protein-1 and fibrillin-1 in human uterine leiomyomata MOLECULAR HUMAN REPRODUCTION Zhao, Y., Wen, Y., Polan, M. L., Qiao, J., Chen, B. H. 2007; 13 (5-6): 343-349

  Abstract

  We compared latent TGF-ss binding protein-1 (LTBP-1) and fibrillin-1 (FBN-1) expression in leiomyomata and myometrium, correlated with leiomyomata size. We studied in vivo and in vitro effects of ovarian steroids using matched leiomyomata and myometrium samples from both phases of the menstrual cycle. Leiomyomata were divided into small (or=6 cm) groups. We validated LTBP-1 and FBN-1 expression using QPCR, western blot and immunohistochemistry. LTBP-1 and FBN-1 mRNA and protein expressions were higher in the medium-sized group compared with myometrium in the proliferative phase (P = 0.01; P = 0.01). FBN-1 mRNA expression was higher in the secretory phase (P = 0.01). LTBP-1 mRNA and protein expression was higher in the medium group compared with the small and large groups in the proliferative phase (P = 0.04; P = 0.04). No differences between groups were seen in FBN-1 expression in either phase. 17Beta-estradiol (E2) increased mRNA and protein expression of LTBP-1 and FBN-1 in cultured leiomyoma smooth muscle cells (LSMC) (P < 0.05). No change in FBN-1 and LTBP-1 expression was observed when cells were treated with E2 plus progesterone. Estrogen may be involved in LTBP-1 and FBN-1 expression in leiomyomata. Extracellular matrix metabolism may be different in medium-sized leiomyoma.

  View details for DOI 10.1093/molehr/gam007

  View details for Web of Science ID 000247348500007

• Acupuncture for postmenopausal hot flashes MATURITAS Nir, Y., Huang, M. I., Schnyer, R., Chen, B., Manber, R. 2007; 56 (4): 383-395

  Abstract

  To determine whether individually tailored acupuncture is an effective treatment option for reducing postmenopausal hot flashes and improving quality of life.In a randomized, placebo-controlled pilot study, 29 postmenopausal participants averaging at least seven moderate to severe hot flashes per 24h, with a baseline estradiol concentration of less than 50 pg/mL and a normal TSH level, were randomized to receive 7 weeks (nine treatment sessions) of either active acupuncture or placebo acupuncture (placebo needles that did not penetrate the skin at sham acupuncture points). Participants recorded hot flashes in logs that were reported daily. Global indices of the severity and frequency of hot flashes were derived from the participants' daily logs.Participants receiving the active treatment had a greater reduction in hot flash severity (24.5+/-30.7%) compared to those receiving placebo (4.4+/-17.1%, P=0.042). Within group repeated measures analyses of variance revealed a significant reduction in hot flash severity in the active (P=0.042), but not in the placebo treatment group (P=0.15). Although there was no significant group difference in the reduction of hot flash frequency between the active (42.4+/-32.2%) and placebo groups (32.0+/-26.5%; P>or=0.352), within group repeated measures analyses of variance revealed that the reduction was statistically significant in both groups (P

  View details for DOI 10.1016/j.maturitas.2006.11.001

  View details for Web of Science ID 000245757900006

  View details for PubMedID 17182200

• The role of neutrophil elastase in elastin metabolism of pelvic tissues from women with stress urinary incontinence NEUROUROLOGY AND URODYNAMICS Chen, B., Wen, Y., Yu, X., Polan, M. L. 2007; 26 (2): 274-279

  Abstract

  Altered elastin metabolism is implicated in pelvic floor disorders. We studied neutrophil elastase (NE) and matrix metalloproteinase (MMP) activities in vaginal tissues from premenopausal women with stress urinary incontinence (SUI).Elastase and NE activities in vaginal tissues were assessed. Protein and mRNA expressions were determined by RT-PCR and Western blot. Total elastin and collagen contents were evaluated. To compare the relative elastolytic effect of NE and MMP-2, we used their respective antibodies to immunoprecipitate these proteins from vaginal fibroblast extracts prior to assessing elastase activity.Elastase activity in vaginal wall tissues was significantly higher in the secretory compared to the proliferative phase. NE mRNA and protein expressions were similar between control and SUI tissues from the secretory phase. However, NE activity in the SUI tissues was higher compared to control tissues. The mRNA expression of alpha-1 antitrypsin (ATT) was higher in control tissues from the proliferative phase compared to those from the secretory phase, while no difference was observed in SUI tissues between either phase. Protein expression of the active form of ATT was decreased in SUI tissues compared to controls during the secretory phase. Anti-NE antibody reduced total elastase activity by 60-70%, compared to less than 20% reduction with anti-MMP-2 antibody.During the secretory phase, elastolytic activity is increased in pelvic tissues from women with SUI, through an increase in NE activity and a concurrent decrease in ATT expression. The serine protease, NE, appears to be a more significant modulator of elastase activity compared to MMP-2.

  View details for DOI 10.1002/nau.20347

  View details for Web of Science ID 000245557300023

  View details for PubMedID 17089373

• Severe vaginal pain caused by a neuroma in the rectovaginal septum after posterior colporrhaphy OBSTETRICS AND GYNECOLOGY Millheiser, L. S., Chen, B. 2006; 108 (3): 809-811

  Abstract

  Traumatic vaginal neuromas are a rarely documented finding in the setting of vaginal pain after posterior colporrhaphy. They arise as a result of trauma or surgery and are often mistaken for scar tissue.After a total vaginal hysterectomy and posterior colporrhaphy, a 32-year-old woman presented with debilitating vaginal pain, presumed to be secondary to scar tissue formation. Excision of the tissue from the rectovaginal septum revealed a traumatic neuroma. After the removal of the neuroma, the patient's vaginal pain resolved.Traumatic neuromas may be a cause of significant point tenderness and thickened tissue after vaginal surgery or repair of obstetric lacerations. If conservative treatment methods have failed, surgical excision of the neuroma can be considered.

  View details for Web of Science ID 000247038500042

  View details for PubMedID 17018512

• A randomized controlled pilot study of acupuncture for postmenopausal hot flashes: effect on nocturnal hot flashes and sleep quality FERTILITY AND STERILITY Huang, M. I., Nir, Y., Chen, B., Schnyer, R., Manber, R. 2006; 86 (3): 700-710

  Abstract

  To assess the effectiveness of acupuncture on postmenopausal nocturnal hot flashes and sleep.Prospective randomized placebo-controlled study.Stanford University School of Medicine and private acupuncture offices.Active or placebo acupuncture was administered for nine sessions over seven weeks.Severity and frequency of nocturnal hot flashes from daily diaries and Pittsburgh Sleep Quality Index (PSQI).Twenty-nine postmenopausal women experiencing at least seven moderate to severe hot flashes daily, with E(2) <18 pg/mL and FSH 30.0-110.0 IU/L.Nocturnal hot-flash severity significantly decreased in the active acupuncture group (28%) compared with the placebo group (6%), P=.017. The frequency of nocturnal hot flashes also decreased in the active group (47%, P=.001), though it was not significantly different from the placebo group (24%, P=.170; effect size = 0.65). Treatment did not differentially influence sleep; however, correlations between improvements in PSQI and reductions in nocturnal hot flash severity and frequency were significant (P<.026).Acupuncture significantly reduced the severity of nocturnal hot flashes compared with placebo. Given the strength of correlations between improvements in sleep and reductions in nocturnal hot flashes, further exploration is merited.

  View details for DOI 10.1016/j.fertnstert.2006.02.100

  View details for Web of Science ID 000240998000036

  View details for PubMedID 16952511

• Do extracellular matrix protein expressions change with cyclic reproductive hormones in pelvic connective tissue from women with stress urinary incontinence? HUMAN REPRODUCTION Wen, Y., Polan, M. L., Chen, B. 2006; 21 (5): 1266-1273

  Abstract

  To evaluate differential expression of transforming growth factor (TGF-beta1), latent transforming factor-binding proteins (LTBP-1, LTBP-2) and elastin microfibril components (fibrillin-1 and fibrillin-2) in vaginal tissue from women with stress urinary incontinence (SUI).In this case-control study, vaginal tissue from women in both phases of the menstrual cycle was obtained. Messenger RNA (mRNA) expressions of LTBP-1, LTBP-2, fibrillin-1, fibrillin-2 and TGF-beta1 were determined by relative real-time quantification PCR. Tissue localization was analysed by immunohistochemistry, and semiquantitative protein expression was evaluated by Western blot analysis.Vaginal wall fibroblasts synthesized all proteins tested. LTBP-1, LTBP-2 and TGF-beta1 co-localized with elastin microfibrils, fibrillin-1 and fibrillin-2 in the extracellular matrix. LTBP-1 mRNA and protein expressions were higher in control versus women affected with SUI in the proliferative phase (P = 0.04), while in the secretory phase, mRNA expression in cases was higher (P = 0.04). Fibrillin-1 mRNA was higher in women affected by SUI versus controls in both phases, but no statistical differences in fibrillin-1 protein expression were observed between the two groups in either phase. LTBP-2 and TGF-beta1 mRNA expressions showed the same trends as LTBP-1.LTBP-1, LTBP-2, TGF-beta1, fibrillin-1, and fibrillin-2 expressions are hormonally regulated in vaginal wall fibroblasts and differ in women affected by SUI when compared to controls. These data suggest a mechanism to regulate TGF-beta1 activity in pelvic connective tissue.

  View details for DOI 10.1093/humrep/dei485

  View details for Web of Science ID 000236818600026

  View details for PubMedID 16452154

• Female urinary incontinence in China: experiences and perspectives. Health care for women international Komorowski, L., Chen, B. 2006; 27 (2): 169-181

  Abstract

  We sought to understand the perceptions and experiences of Chinese women living with urinary incontinence (UI), a problem that has not yet been characterized in China. We conducted the study using semistructured interviews with 15 women, aged 24-81, diagnosed with UI at the Obstetrics and Gynecology Clinic of Fuzhou General Hospital, Fujian, China. We conducted and analyzed the interviews according to the Interpretative Phenomenological Analysis model. The five core themes we derived from the participants' responses were uncertainty about UI, self-blame, avoidance, emotional isolation, and desire for treatment. The negative impacts of UI we documented, such as limiting exercise and causing embarrassment, demonstrated that UI is a problem for the affected women in China. Our study was limited by the small sample size and the need for additional reliability/validity measures, but we believe it presented a strong foundation and justification for more rigorous research into UI in China.

  View details for PubMedID 16484160

• Metastatic mantle cell lymphoma presenting as a vaginal mass - A case report GYNECOLOGIC AND OBSTETRIC INVESTIGATION Bujor, A., Chen, B. 2006; 62 (4): 217-219

  Abstract

  Vaginal masses are an uncommon finding in well-woman gynecologic examinations. The differential diagnosis includes cysts, leiomyomata, ectopic ureteroceles, infected granuloma, and malignancy.A 74-year-old woman with a history of mantle cell lymphoma was referred for vaginal prolapse. Examination revealed a vaginal mass, with MRI confirming 3 masses. Fine needle aspiration confirmed metastatic mantle cell lymphoma which later regressed with radiation therapy.Although vaginal masses are often rare and incidental findings during routine gynecologic examinations, a comprehensive differential diagnosis is required to avoid delays in treatment. Fine needle aspiration should be included as part of the arsenal of diagnostic tools because of its low cost and the ease with which it can be performed in a clinical setting.

  View details for DOI 10.1159/000094006

  View details for Web of Science ID 000241776600005

  View details for PubMedID 16785735

• Microarray analysis of differentially expressed genes in vaginal tissues from women with stress urinary incontinence compared with asymptomatic women HUMAN REPRODUCTION Chen, B., Wen, Y., Zhang, Z. M., Guo, Y. Q., Warrington, J. A., Polan, M. L. 2006; 21 (1): 22-29

  Abstract

  The pathophysiology of pelvic floor dysfunction resulting in stress urinary incontinence (SUI) in women is complex. Evidence suggests that there is also a genetic predisposition towards SUI. We sought to identify differentially expressed genes involved in extracellular matrix (ECM) metabolism in vaginal tissues from women with SUI in the secretory phase of menses compared with asymptomatic women.Tissue samples were taken from the periurethral vaginal wall of five pairs of premenopausal, age-matched SUI and continent women and subjected to microarray analysis using the GeneChip Human Genome U133 oligonucleotide chip set.Extensive statistical analyses generated a list of 79 differentially expressed genes. Elafin, keratin 16, collagen type XVII and plakophilin 1 were consistently identified as up-regulated ECM genes. Elafin, a serine protease inhibitor involved in the elastin degradation pathway and wound healing, was expressed in pelvic fibroblasts and confirmed by Western blot, quantitative competitive PCR and immunofluorescence cell staining.Genes involved in elastin metabolism were differentially expressed in vaginal tissue from women with SUI, suggesting that elastin remodelling may be important in the molecular aetiology of SUI.

  View details for DOI 10.1093/humrep/dei276

  View details for Web of Science ID 000233846700003

  View details for PubMedID 16126751

• Elastin metabolism in pelvic tissues: Is it modulated by reproductive hormones? Joint Annual Meeting of the American-Urogynecologic-Society/Society-of-Gynecologic-Surgeons Chen, B., Wen, Y., Yu, X. Y., Polan, M. L. MOSBY-ELSEVIER. 2005: 1605–13

  Abstract

  The purpose of this study was to investigate the effect of relaxin on extracellular matrix protein expression in pelvic fibroblasts that were cultured from women with stress urinary incontinence compared with asymptomatic control subjects.Periurethral vaginal wall fibroblasts from premenopausal women with stress urinary incontinence and continent women (in both the proliferative and secretory phase of the menstrual cycle) were stimulated with increasing concentrations of relaxin (0-500 ng/mL). The supernatant was sampled for matrix metalloproteinase-2 and -9 by zymography. Tissue inhibitors of metalloproteinase-1 and -2 and alpha-1 antitrypsin were evaluated with Western blot. Total elastase activity was measured by generation of free amino groups from succinylated elastin. Increasing concentrations of alpha-1 antitrypsin were added to cell lysate to evaluate total elastase activity inhibition.Proliferative-phase stress urinary incontinence fibroblasts demonstrated an increase in matrix metalloproteinase-2 and no change in matrix metalloproteinase-9 and tissue inhibitors of metalloproteinase-1 and -2 expressions with increasing relaxin concentrations. Cells from control subjects showed increased expression of matrix metalloproteinase-2 and -9, but no change in tissue inhibitors of metalloproteinases. Secretory-phase stress urinary incontinence fibroblasts showed no response in matrix metalloproteinase or tissue inhibitors of metalloproteinase expressions with relaxin stimulation. Secretory-phase control fibroblasts reacted by increasing matrix metalloproteinase-2 and -9 and tissue inhibitors of metalloproteinase-2. With respect to total elastase activity and alpha-1 antitrypsin expression, increasing doses of relaxin appear to increase elastolytic activity in stress urinary incontinence cells by decreasing the expression of alpha-1 antitrypsin in proliferative phase cells or increasing the total elastase activity in secretory phase cells. Fibroblast total elastase activity was inhibited by increasing concentrations of alpha-1 antitrypsin.Elastase activity appears to be increased in relaxin-stimulated stress urinary incontinence fibroblasts by either decreased inhibitor (alpha-1 antitrypsin) production or increased elastase activity.

  View details for DOI 10.1016/j.ajog.2004.11.027

  View details for Web of Science ID 000229384100057

  View details for PubMedID 15902165

• Elastolytic activity in women with stress urinary incontinence and pelvic organ prolapse NEUROUROLOGY AND URODYNAMICS Chen, B., Wen, Y., Polan, M. L. 2004; 23 (2): 119-126

  Abstract

  Weakening of pelvic supportive tissues is thought to be a contributing etiology in female pelvic floor disorders such as stress urinary incontinence and/or pelvic organ prolapse (SUI/POP). Since elastin modulates the mechanical properties of supportive tissues, we examined elastase activity in vaginal tissue from women with pelvic floor dysfunction compared to asymptomatic controls, by comparing overall elastase activity, human neutrophil elastase, cathepsin K, and alpha-1 antitrypsin (a serine protease inhibitor) mRNA and protein levels.Full-thickness peri-urethral vaginal wall tissues were collected from age and menstrual-phase matched SUI/POP and control women at the time of pelvic surgery. Elastolytic activity in the homogenized tissue was determined by the generation of amino groups from succinylated elastin. To quantify mRNA levels of each protein, quantitative competitive-PCR and confirmatory Western blot analyses were performed on the samples for human neutrophil elastase, cathepsin K, and alpha-1 antitrypsin.The mean elastolytic activity in vaginal tissues from the SUI/POP group was similar to that in the control group. With respect to the proteolytic enzymes, neither human neutrophil elastase nor cathepsin K differed between the two groups. However, alpha-1 antitrypsin mRNA and protein levels were significantly decreased in tissues from affected women.A significant decrease in alpha-1 antitrypsin expression was seen in tissues from women with SUI/POP compared to controls. This data suggest that altered elastin metabolism may contribute to the connective tissue alterations observed in pelvic floor dysfunction. Future investigations are warranted to help define the role of elastin turnover in pelvic floor dysfunction.

  View details for DOI 10.1002/nau.20012

  View details for Web of Science ID 000220085600008

  View details for PubMedID 14983422

• Basic science and translational research in female pelvic floor disorders: Proceedings of an NIH-sponsored meeting NEUROUROLOGY AND URODYNAMICS Weber, A. M., Buchsbaum, G. M., Chen, B., Clark, A. L., Damaser, M. S., Daneshgari, F., Davis, G., DeLancey, J., Kenton, K., Weidner, A. C., Word, R. A. 2004; 23 (4): 288-301

  Abstract

  To report the findings of a multidisciplinary group of scientists focusing on issues in basic science and translational research related to female pelvic floor disorders, and to produce recommendations for a research agenda for investigators studying female pelvic floor disorders.A National Institutes of Health (NIH)-sponsored meeting was held on November 14-15, 2002, bringing together scientists in diverse fields including obstetrics, gynecology, urogynecology, urology, gastroenterology, biomechanical engineering, neuroscience, endocrinology, and molecular biology. Recent and ongoing studies were presented and discussed, key gaps in knowledge were identified, and recommendations were made for research that would have the highest impact in making advances in the field of female pelvic floor disorders.The meeting included presentations and discussion on the use of animal models to better understand physiology and pathophysiology; neuromuscular injury (such as at childbirth) as a possible pathogenetic factor and mechanisms for recovery of function after injury; the use of biomechanical concepts and imaging to better understand the relationship between structure and function; and molecular and biochemical mechanisms that may underlie the development of female pelvic floor disorders.While the findings of current research will help elucidate the pathophysiologic pathways leading to the development of female pelvic floor disorders, much more research is needed for full understanding that will result in better care for patients through specific rather than empiric therapy, and lead to the potential for prevention on primary and secondary levels.

  View details for DOI 10.1002/nau.20048

  View details for Web of Science ID 000222481100002

  View details for PubMedID 15227643

• Bench to bedside: clinical opportunities for microarray analysis FERTILITY AND STERILITY Polan, M. L., Warrington, J. A., Chen, B., Mahadevappa, M., Wang, H. B., Wen, Y. 2003; 80 (2): 291-292

  View details for DOI 10.1016/S0015-0282(03)00727-1

  View details for PubMedID 12909488

• Distinctive proliferative phase differences in gene expression in human myometrium and leiomyomata FERTILITY AND STERILITY Wang, H. B., Mahadevappa, M., Yamamoto, K., Wen, Y., Chen, B., Warrington, J. A., Polan, M. L. 2003; 80 (2): 266-276

  Abstract

  To gain a comprehensive view of the gene expression and regulation involved in uterine leiomyomata and matched normal myometrium using oligonucleotide microarray-based hybridization analysis.Retrospective analyses of tissue obtained in a prospective randomized clinical study.Academic institution.Seven patients with leiomyomata scheduled for surgery during the proliferative phase.Seven paired samples of leiomyomata and adjacent myometrium were obtained from patients undergoing hysterectomy.The total RNA extracted from leiomyomata and myometrium was used for gene expression profiling of 6800 human genes using high-density oligonucleotide microarrays. In addition, reverse transcriptase-semiquantitative polymerase chain reaction and immunohistochemistry were used to validate tumor-specific gene expression.A comparison of expression patterns in each paired sample revealed 68 genes significantly up- or down-regulated in each paired tissue sample, of which 23 genes showed increased expression and 45 showed decreased expression in leiomyomata compared with normal myometrium. Cluster analysis supported the relevance of these candidate genes for distinguishing between normal myometrium and leiomyomata biologic activity.Expression profiling of uterine leiomyomata using high-density oligonucleotide microarrays yields signature patterns that reflect the distinctive differences between normal human myometrium and leiomyomata during the proliferative phase. These observations suggest that a number of genes are involved in the tumorigenesis of leiomyomata.

  View details for DOI 10.1016/S0015-0282(03)00730-1

  View details for PubMedID 12909484

• Menstrual phase-dependent gene expression differences in periurethral vaginal tissue from women with stress incontinence 23rd Annual Meeting of the American-Urogynecologic-Society Chen, B., Wen, Y., Zhang, Z. M., Wang, H. B., Warrington, J. A., Polan, M. L. MOSBY-ELSEVIER. 2003: 89–97

  Abstract

  The mechanical stability of the genitourinary tract is dependent on intact collagen fibers that support the bladder neck, urethra, and pelvic organs. We hypothesize that genetic differences in collagen metabolism may contribute to stress urinary incontinence. Because sex hormones have substantial influence on the female lower urinary tract throughout adult life, we investigated the gene expression of vaginal tissue of women with stress incontinence compared with women with no stress incontinence in the proliferative phase of the menstrual cycle.Quantitative competitive polymerase chain reaction was used to verify that the gene expressions were similar between periurethral vaginal tissue and pelvic ligamentous tissue. Labeled complementary RNA was obtained from periurethral vaginal tissue in five pairs of age- and menstrual phase-matched, premenopausal women with and without stress urinary incontinence. The vaginal tissues were then hybridized on HuGeneFL arrays that contained probes representing 6800 full-length human genes. The Student t test and Mann-Whitney ranking were used independently to select candidates with probability values <.05. Hierarchical clustering analysis was performed on the selected candidates to assess the ability of these genes to discriminate between normal and affected individuals.Tissue inhibitor of metalloproteinases-1 and estrogen receptor-alpha messenger RNA expressions were found to be similar between uterosacral ligament and periurethral vaginal tissue in six participants. Of the 90 candidate genes that were identified, 62 genes were up-regulated and 28 were down-regulated in the stress urinary incontinence group. Genes that were involved in extracellular matrix activity in the up-regulated group include transforming growth factor-beta3, laminin, and collagen type VI. Down-regulated genes that may participate in collagen metabolism include laminin-related protein, collagen XVII, serine/threonine protein kinase, type II interleukin-1 receptor, and platelet-derived growth factor-associated protein.In this preliminary study, we identified differential gene expressions that may contribute to extracellular matrix remodeling in pelvic tissue from women with stress urinary incontinence in the proliferative phase versus continent control subjects. The alteration in expression of these candidate genes suggests that they should be targets for further investigation.

  View details for DOI 10.1067/mob.2003.373

  View details for PubMedID 12861144

• Differences in estrogen modulation of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-1 expression in cultured fibroblasts from continent and incontinent women 23rd Annual Meeting of the American-Urogynecologic-Society Chen, B., Wen, Y., Wang, H., Polan, M. L. MOSBY-ELSEVIER. 2003: 59–65

  Abstract

  The purpose of this study was to investigate the effect of increasing estrogen concentrations on metalloproteinase and tissue inhibitors of metalloproteinase protein expressions in cultured pelvic fibroblasts that were obtained from continent and incontinent women.Periurethral vaginal wall tissues were taken from four stress incontinent and three continent premenopausal women who underwent gynecologic surgery for benign indications. Protein was extracted from these tissues, and Western blot analysis was performed to document that fibroblasts from continent and incontinent women differed with respect to metalloproteinase and tissue inhibitors of metalloproteinase production. One age-matched tissue pair was prepared for fibroblast culture. Cells were cultured with increasing concentrations of estradiol (0-500 pg/mL). Extracellular metalloproteinase and tissue inhibitors of metalloproteinase were assessed semiquantitatively with Western blotting.Periurethral vaginal tissues from incontinent women expressed less tissue inhibitors of metalloproteinase when compared with tissue from the control subjects; there was no difference in the expression of cleaved, active metalloproteinase protein. Tissue inhibitors of metalloproteinase expression from fibroblasts of continent women significantly increased with increasing estradiol concentrations (0-100 pg/mL, P <.05). No significant dose response was seen in fibroblasts from an incontinent woman. Metalloproteinase expression was not altered by increasing estradiol concentrations in fibroblasts from either continent or incontinent women.This preliminary in vitro study suggested that, in fibroblasts that were derived from the continent woman, tissue inhibitors of metalloproteinase protein production increases with increasing estrogen levels and that, in stress incontinent fibroblasts, no similar increase occurs. Neither group demonstrated a change in metalloproteinase production in response to varying estrogen levels, which suggests that estrogen may inhibit collagen degradation in continent women by increasing tissue inhibitors of metalloproteinase production but exerts a reduced inhibitory effect on collagenolysis in women with stress urinary incontinence.

  View details for DOI 10.1067/mob.2003.378

  View details for PubMedID 12861139

• Abdominal myomectomy versus uterine fibroid embolization in the treatment of symptomatic uterine leiomyomas AMERICAN JOURNAL OF ROENTGENOLOGY Razavi, M. K., Hwang, G., Jahed, A., Modanloo, S., Chen, B. 2003; 180 (6): 1571-1575

  Abstract

  The purpose of this study was to compare treatment efficacy and complications of abdominal myomectomy with those of uterine fibroid embolization in women with symptomatic uterine fibroids.We analyzed the outcomes of 111 consecutive patients who underwent abdominal myomectomy (n = 44) or fibroid embolization (n = 67) over a 30-month period. The mean ages of the two groups were 37.7 years (range, 28-48 years) and 44.2 years (range, 31-56 years), respectively. A questionnaire and review of medical records assessed all procedure-related complications and changes in symptoms. Length of hospital stay, time until resumption of daily activities, and pain medication requirements after the procedure were also analyzed.Follow-up times for the myomectomy and embolization groups were 14.6 and 14.3 months, respectively. The respective observed success rates in abdominal myomectomy and uterine fibroid embolization patients were 64% versus 92% for menorrhagia (p < 0.05), 54% versus 74% for pain (not significant), and 91% versus 76% for mass effect (p < 0.05). The complication rates were 25% (abdominal myomectomy) and 11% (uterine fibroid embolization) (p < 0.05). The respective secondary end points for the two procedures were 2.9 versus 0 days mean hospital stay, 8.7 versus 5.1 days of narcotics use, and 36 versus 8 days until resumption of normal activities. These differences were all statistically significant.Uterine fibroid embolization is a less invasive and safer treatment option in women with symptomatic leiomyomas than myomectomy. Menorrhagia may be better controlled with embolization, and myomectomy may be a better option in patients with mass effect. Both procedures were equally effective in controlling pain.

  View details for Web of Science ID 000183149200013

  View details for PubMedID 12760922

• Collagen metabolism and turnover in women with stress urinary incontience and pelvic prolapse INTERNATIONAL UROGYNECOLOGY JOURNAL Chen, B. H., Wen, Y., Li, H., Polan, M. L. 2002; 13 (2): 80-87

  Abstract

  The aim of this study was to investigate quantitative mRNA expression of matrix metalloproteinases MMP-1, MMP-2, MMP-9, and their inhibitors, the tissue inhibitors of metalloproteinases TIMP-1, TIMP-2 and TIMP-3, in vaginal wall tissue from women with stress urinary incontinence compared to continent controls. Vaginal wall tissues were obtained from 7 women with stress urinary incontinence/severe pelvic prolapse and 15 continent controls. RNA was then extracted and quantified. Quantitative competitive reverse transcription (QC-RT-PCR) was carried out with oligonucleotide primers to quantify MMP-1, MMP-2, MMP-9, TIMP-1, TIMP-2 and TIMP-3 mRNA expression. Stress continent women demonstrated a significant decrease in TIMP-1 and mRNA expression (P = 0.03). There was no difference in TIMP-2, TIMP-3, MMP-2 or MMP-9 mRNA expression between stress incontinent women and controls. However, MMP-1 mRNA expression was significantly increased (P = 0.05) in the incontinent group and the MMP-1/TIMP-1 ratio (P = 0.04) was consistent with increased collagen degradation in the stress incontinence. Stress incontinent women demonstrated an increase in MMP-1 mRNA expression and a decrease in the inhibitor TIMP-1 mRNA expression. Both these findings are consistent with increased collagen breakdown as a pathologic etiology of incontinence.

  View details for Web of Science ID 000175825400004

  View details for PubMedID 12054187

• Virtual endoscopy using perspective volume-rendered three-dimensional sonographic Data: Technique and clinical applications AMERICAN JOURNAL OF ROENTGENOLOGY Yuh, E. L., Jeffrey, R. B., Birdwell, R. L., Chen, B. H., Napel, S. 1999; 172 (5): 1193-1197

  Abstract

  We present a technique for obtaining three-dimensional external and virtual endoscopy views of organs using perspective volume-rendered gray-scale and Doppler sonographic data, and we explore potential clinical applications in the carotid artery, the female pelvis, and the bladder.Using the proposed methods, radiologists will find it possible to create virtual endoscopy and external perspective views using sonographic data. The technique works well for revealing the interior of fluid-filled structures and cavities. However, expected improvements in computer performance and integration with existing sonographic equipment will be necessary for the technique to become practical in the clinical environment.

  View details for Web of Science ID 000079919700005

  View details for PubMedID 10227488

• Dysfunctional uterine bleeding WESTERN JOURNAL OF MEDICINE Chen, B. H., Giudice, L. C. 1998; 169 (5): 280-284

  Abstract

  Abnormal uterine bleeding is a common, debilitating condition. Dysfunctional uterine bleeding (DUB) is the diagnosis given to women with abnormal uterine bleeding in whom no clear etiology can be identified. DUB has been observed in both ovulatory and anovulatory cycles. Medical treatments include nonsteroidal anti-inflammatory drugs, oral contraceptive pills, progestins, danazol (a synthetic androgen), GnRH agonists, and antifibrinolytic drugs. The drawback to medical therapy, in addition to side effects, is that the benefit lasts only while the patient takes the medication. Surgical options have concentrated mainly on endometrial ablation and hysterectomy, and it is unclear whether one is superior to the other in terms of long-term outcome and patient satisfaction. Newer and less invasive ablation techniques, such as thermal balloon ablation, offer more treatment alternatives.

  View details for Web of Science ID 000077010900004

  View details for PubMedID 9830356