Bo Yu, MD

All Publications

• Identification of fallopian tube microbiota and its association with ovarian cancer. eLife Yu, B., Liu, C., Proll, S. C., Manhardt, E., Liang, S., Srinivasan, S., Swisher, E., Fredricks, D. N. 2024; 12

  Abstract

  Investigating the human fallopian tube (FT) microbiota has significant implications for understanding the pathogenesis of ovarian cancer (OC). In this large prospective study, we collected swabs intraoperatively from the FT and other surgical sites as controls to profile the microbiota in the FT and to assess its relationship with OC. Eighty-one OC and 106 non-cancer patients were enrolled and 1001 swabs were processed for 16S rRNA gene PCR and sequencing. We identified 84 bacterial species that may represent the FT microbiota and found a clear shift in the microbiota of the OC patients when compared to the non-cancer patients. Of the top 20 species that were most prevalent in the FT of OC patients, 60% were bacteria that predominantly reside in the gastrointestinal tract, while 30% normally reside in the mouth. Serous carcinoma had higher prevalence of almost all 84 FT bacterial species compared to the other OC subtypes. The clear shift in the FT microbiota in OC patients establishes the scientific foundation for future investigation into the role of these bacteria in the pathogenesis of OC.

  View details for DOI 10.7554/eLife.89830

  View details for PubMedID 38451065

• Vaginal Bacteria Elicit Acute Inflammatory Response in Fallopian Tube Organoids. Reproductive sciences (Thousand Oaks, Calif.) Yu, B., McCartney, S., Strenk, S., Valint, D. J., Liu, C., Haggerty, C. L., Fredricks, D. N. 2023

  Abstract

  To facilitate in vitro mechanistic studies in pelvic inflammatory disease and subsequent tubal factor infertility, we sought to establish patient tissue derived fallopian tube (FT) organoids and to study their inflammatory response to acute vaginal bacterial infection. FT tissues were obtained from four patients after salpingectomy for benign gynecological diseases. We introduced acute infection in the FT organoid culture system by inoculating the organoid culture media with two common vaginal bacterial species, Lactobacillus crispatus and Fannyhessea vaginae. The inflammatory response elicited in the organoids after acute bacterial infection was analyzed by the expression profile of 249 inflammatory genes. Compared to the negative controls that were not cultured with any bacteria, the organoids cultured with either bacterial species showed multiple differentially expressed inflammatory genes. Marked differences were noted between the Lactobacillus crispatus infected organoids and those infected by Fannyhessea vaginae. Genes from the C-X-C motif chemokine ligand (CXCL) family were highly upregulated in Fannyhessea vaginae infected organoids. Flow cytometry showed that immune cells quickly disappeared during the organoid culture, indicating the inflammatory response observed with bacterial culture was generated by the epithelial cells in the organoids. In summary, we have shown that patient tissue derived FT organoids respond to acute bacterial infection with upregulation of inflammatory genes specific to different vaginal bacterial species. FT organoids is a useful in vitro model system to study the host-pathogen interaction during bacterial infection.

  View details for DOI 10.1007/s43032-023-01350-5

  View details for PubMedID 37726587

  View details for PubMedCentralID 5587694

• The developmental competence of human metaphase I oocytes with delayed maturation in vitro. Fertility and sterility Moon, J. H., Zhao, Q., Zhang, J., Reddy, V., Han, J., Cheng, Y., Zhang, N., Dasig, J., Nel-Themaat, L., Behr, B., Yu, B. 2022

  Abstract

  To evaluate if metaphase I (MI) oocytes completing maturation in vitro to metaphase II ("MI-MII oocytes") have similar developmental competence as the sibling metaphase II (MII) oocytes that reached maturity in vivo.Retrospective cohort study.A total of 1124 intracytoplasmic sperm injection (ICSI) cycles from 800 patients at a single academic center between April 2016 and Dec 2020 with at least one MII oocyte immediately after retrieval and at least one sibling "MI-MII oocyte" that was retrieved as MI and matured to MII in culture before ICSI were included in the study.A total of 7865 MII and 2369 sibling MI-MII retrieved from the same individuals were compared for fertilization and blastocyst formation rates. For patients undergoing single euploid blastocyst transfers (n=406), the clinical pregnancy, spontaneous pregnancy loss rate and live birth rate were compared between the two groups.The fertilization rate was significantly higher in MII oocytes than delayed matured MI-MII oocytes (75.9% vs 56.1%, p<0.001). Similarly, the blastocyst formation rate was higher in embryos derived from MII oocytes as compared to those from MI-MII oocytes (53.8% vs 23.9%; p<0.001). The percentage of euploid embryos derived from MII oocytes was significantly higher than those from MI-MII oocytes (49.2% vs 34.7%; p<0.001). Paired comparison of sibling oocytes within the same cycle showed higher developmental competence of the MII oocytes than MI-MII oocytes. However, the pregnancy, spontaneous pregnancy loss and live birth rate after a single euploid blastocyst transfer showed no statistically significant difference between the two groups (65.7% vs 74.1%: 6.4% vs 5.0%: 61.5% vs 70.0%, respectively, MII vs MI-MII group, p>0.05).Compared to oocytes that matured in vivo and were retrieved as MII, the oocytes that were retrieved as MI and matured to MII in vitro before ICSI showed lower developmental competence, including lower fertilization, blastocyst formation, and euploidy rates. However, euploid blastocysts from either cohort resulted in similar live birth rates, indicating the MI oocytes with delayed maturation can still be useful even though the overall developmental competence was lower than their in vivo matured counterparts.

  View details for DOI 10.1016/j.fertnstert.2022.12.033

  View details for PubMedID 36567036

• Single-cell analysis of transcriptome and DNA methylome in human oocyte maturation. PloS one Yu, B. n., Doni Jayavelu, N. n., Battle, S. L., Mar, J. C., Schimmel, T. n., Cohen, J. n., Hawkins, R. D. 2020; 15 (11): e0241698

  Abstract

  Oocyte maturation is a coordinated process that is tightly linked to reproductive potential. A better understanding of gene regulation during human oocyte maturation will not only answer an important question in biology, but also facilitate the development of in vitro maturation technology as a fertility treatment. We generated single-cell transcriptome and used our previously published single-cell methylome data from human oocytes at different maturation stages to investigate how genes are regulated during oocyte maturation, focusing on the potential regulatory role of non-CpG methylation. DNMT3B, a gene encoding a key non-CpG methylation enzyme, is one of the 1,077 genes upregulated in mature oocytes, which may be at least partially responsible for the increased non-CpG methylation as oocytes mature. Non-CpG differentially methylated regions (DMRs) between mature and immature oocytes have multiple binding motifs for transcription factors, some of which bind with DNMT3B and may be important regulators of oocyte maturation through non-CpG methylation. Over 98% of non-CpG DMRs locate in transposable elements, and these DMRs are correlated with expression changes of the nearby genes. Taken together, this data indicates that global non-CpG hypermethylation during oocyte maturation may play an active role in gene expression regulation, potentially through the interaction with transcription factors.

  View details for DOI 10.1371/journal.pone.0241698

  View details for PubMedID 33152014

  View details for PubMedCentralID PMC7643955

• Superovulation alters global DNA methylation in early mouse embryo development. Epigenetics Yu, B. n., Smith, T. H., Battle, S. L., Ferrell, S. n., Hawkins, R. D. 2019; 14 (8): 780–90

  Abstract

  Assisted reproductive technologies are known to alter the developmental environment of gametes and early embryos during the most dynamic period of establishing the epigenome. This may result in the introduction of errors during active DNA methylation reprogramming. Controlled ovarian hyperstimulation, or superovulation, is a ubiquitously used intervention which has been demonstrated to alter the methylation of certain imprinted genes. The objective of this study was to investigate whether ovarian hyperstimulation results in genome-wide DNA methylation changes in mouse early embryos. Ovarian hyperstimulation was induced by treating mice with either low doses (5 IU) or high doses (10 IU) of PMSG and hCG. Natural mating (NM) control mice received no treatment. Zygotes and 8-cell embryos were collected from each group and DNA methylomes were generated by whole-genome bisulfite sequencing. In the NM group, mean CpG methylation levels slightly decreased from zygote to 8-cell stage, whereas a large decrease in mean CpG methylation level was observed in both superovulated groups. A separate analysis of the mean CpG methylation levels within each developmental stage confirmed that significant genome-wide erasure of CpG methylation from the zygote to 8-cell stage only occurred in the superovulation groups. Our results suggest that superovulation alters the genome-wide DNA methylation erasure process in mouse early pre-implantation embryos. It is not clear whether these changes are transient or persistent. Further studies are ongoing to investigate the impact of ovarian hyperstimulation on DNA methylation re-establishment in later stages of embryo development.

  View details for DOI 10.1080/15592294.2019.1615353

  View details for PubMedID 31060426

  View details for PubMedCentralID PMC6615540

• Genome-wide, Single-Cell DNA Methylomics Reveals Increased Non-CpG Methylation during Human Oocyte Maturation. Stem cell reports Yu, B., Dong, X., Gravina, S., Kartal, Ö., Schimmel, T., Cohen, J., Tortoriello, D., Zody, R., Hawkins, R. D., Vijg, J. 2017; 9 (1): 397-407

  Abstract

  The establishment of DNA methylation patterns in oocytes is a highly dynamic process marking gene-regulatory events during fertilization, embryonic development, and adulthood. However, after epigenetic reprogramming in primordial germ cells, how and when DNA methylation is re-established in developing human oocytes remains to be characterized. Here, using single-cell whole-genome bisulfite sequencing, we describe DNA methylation patterns in three different maturation stages of human oocytes. We found that while broad-scale patterns of CpG methylation have been largely established by the immature germinal vesicle stage, localized changes continue into later development. Non-CpG methylation, on the other hand, undergoes a large-scale, generalized remodeling through the final stage of maturation, with the net overall result being the accumulation of methylation as oocytes mature. The role of the genome-wide, non-CpG methylation remodeling in the final stage of oocyte maturation deserves further investigation.

  View details for DOI 10.1016/j.stemcr.2017.05.026

  View details for PubMedID 28648898

  View details for PubMedCentralID PMC5511109

• DNA methylome and transcriptome sequencing in human ovarian granulosa cells links age-related changes in gene expression to gene body methylation and 3'-end GC density. Oncotarget Yu, B., Russanova, V. R., Gravina, S., Hartley, S., Mullikin, J. C., Ignezweski, A., Graham, J., Segars, J. H., DeCherney, A. H., Howard, B. H. 2015; 6 (6): 3627-43

  Abstract

  Diminished ovarian function occurs early and is a primary cause for age-related decline in female fertility; however, its underlying mechanism remains unclear. This study investigated the roles that genome and epigenome structure play in age-related changes in gene expression and ovarian function, using human ovarian granulosa cells as an experimental system. DNA methylomes were compared between two groups of women with distinct age-related differences in ovarian functions, using both Methylated DNA Capture followed by Next Generation Sequencing (MethylCap-seq) and Reduced Representation Bisulfite Sequencing (RRBS); their transcriptomes were investigated using mRNA-seq. Significant, non-random changes in transcriptome and DNA methylome features are observed in human ovarian granulosa cells as women age and their ovarian functions deteriorate. The strongest correlations between methylation and the age-related changes in gene expression are not confined to the promoter region; rather, high densities of hypomethylated CpG-rich regions spanning the gene body are preferentially associated with gene down-regulation. This association is further enhanced where CpG regions are localized near the 3'-end of the gene. Such features characterize several genes crucial in age-related decline in ovarian function, most notably the AMH (Anti-Müllerian Hormone) gene. The genome-wide correlation between the density of hypomethylated intragenic and 3'-end regions and gene expression suggests previously unexplored mechanisms linking epigenome structure to age-related physiology and pathology.

  View details for DOI 10.18632/oncotarget.2875

  View details for PubMedID 25682867

  View details for PubMedCentralID PMC4414142

• Changes in markers of ovarian reserve and endocrine function in young women with breast cancer undergoing adjuvant chemotherapy. Cancer Yu, B., Douglas, N., Ferin, M. J., Nakhuda, G. S., Crew, K., Lobo, R. A., Hershman, D. L. 2010; 116 (9): 2099-105

  Abstract

  Premenopausal women undergoing chemotherapy are at risk for amenorrhea and impaired fertility. The objective of the current study was to assess levels of mullerian inhibitory substance (MIS), estradiol (E2), follicle-stimulating hormone (FSH), and menstrual status, in women undergoing chemotherapy.A nested prospective cohort study was conducted in women aged <40 years with breast cancer (BC) who were undergoing adjuvant chemotherapy (n = 26). Serum MIS, FSH, and E2 were measured before chemotherapy (baseline) and at Weeks 6, 12, 36, and 52. Controls were 134 age-matched women with known fertility. Hormone levels were compared between the cases and controls at baseline. Differences between amenorrhea and age subgroups were tested using the nonparametric Wilcoxon 2-sample test using a 2-sided alpha of 0.05.Subjects with BC and age-matched controls had similar baseline MIS levels (median, 0.94 ng/mL vs 0.86 ng/mL;, P > .05). Serum MIS decreased significantly at 6 weeks and remained suppressed for 52 weeks. E2 levels decreased, and FSH levels increased during chemotherapy; however, at 52 weeks, the levels returned to baseline. At 52 weeks, only 1 patient had MIS above the lower normal range, 15 had return of menstrual function, 11 had premenopausal levels of FSH, and 13 had follicular phase levels of E2. In women aged <35 years, 25% remained amenorrheic, whereas in women aged >35 years, 50% were amenorrheic. Amenorrheic and menstruating women were found to have similar MIS values at baseline and follow-up.In young women with BC, chemotherapy decreases MIS rapidly and dramatically. Rapid reductions in MIS do not appear to be predictive of subsequent menstrual function. Ovarian reserve and endocrine function may be affected differently by chemotherapy.

  View details for DOI 10.1002/cncr.25037

  View details for PubMedID 20187091

  View details for PubMedCentralID PMC3625425

• DISCORDANT NON-INVASIVE PGT-A RESULTS AND CLINICAL OUTCOME Curnow, E., Ryan, G. L., Yu, B. ELSEVIER SCIENCE INC. 2023: E276

  View details for Web of Science ID 001084670200654

• Vaginal bacteria elicit acute inflammatory response in fallopian tube organoids: a model for pelvic inflammatory disease. Research square Yu, B., McCartney, S., Strenk, S., Valint, D., Liu, C., Haggerty, C., Fredricks, D. N. 2023

  Abstract

  Objective: To facilitate in vitro mechanistic studies in pelvic inflammatory disease (PID) and subsequent tubal factor infertility, as well as ovarian carcinogenesis, we sought to establish patient tissue derived fallopian tube (FT) organoids and to study their inflammatory response to acute vaginal bacterial infection. Design: Experimental study. Setting: Academic medical and researchcenter. Patients: FT tissues were obtained from four patients after salpingectomy for benign gynecological diseases. Interventions: We introduced acute infection in the FT organoid culture system by inoculating the organoid culture media with two common vaginal bacterial species, Lactobacillus crispatus and Fannyhesseavaginae . Main Outcome Measures: The inflammatory response elicited in the organoids after acute bacterial infection was analyzed by the expression profile of 249 inflammatory genes. Results: Compared to the negative controls that were not cultured with any bacteria, the organoids cultured with either bacterial species showed multiple differentially expressed inflammatory genes. Marked differences were noted between the Lactobacillus crispatus infected organoids and those infected by Fannyhessea vaginae . Genes from the C-X-C motif chemokine ligand (CXCL) family were highly upregulated in F. vaginae infected organoids. Flow cytometry showed that immune cells quickly disappeared during the organoid culture, indicating the inflammatory response observed with bacterial culture was generated by the epithelial cells in the organoids. Conclusion : Patient tissue derived FT organoids respond to acute bacterial infection with upregulation of inflammatory genes specific to different vaginal bacterial species. FT organoids is a useful model system to study the host-pathogen interaction during bacterial infection which may facilitate mechanistic investigations in PID and its contribution to tubal factor infertility and ovarian carcinogenesis.

  View details for DOI 10.21203/rs.3.rs-2891189/v1

  View details for PubMedID 37293093

  View details for PubMedCentralID PMC10246240

• Congenital male genital malformations and paternal health: an analysis of US claims data. Andrology Yu, B., Zhang, C. A., Chen, T., Mulloy, E., Shaw, G. M., Eisenberg, M. L. 2023

  Abstract

  OBJECTIVE: To investigate the potential association between paternal health and male genital malformations in the offspring.MATERIALS AND METHODS: We analyzed data from 2007 to 2016 derived from the IBM MarketScan Research database, which reports on reimbursed private healthcare claims in the United States. The association between paternal comorbidities (defined as individual and combined measures) and genital malformations in male offspring was analyzed.RESULTS: Of 376,362 male births, 22% of fathers had at least one component of the metabolic syndrome (MetS ≥1) prior to conception. Totals of 2880 cases of cryptorchidism (0.77%) and 2651 cases of hypospadias (0.70%) were identified at birth. While 0.76% of sons born to fathers with no MetS components were diagnosed with cryptorchidism, 0.82% of sons with fathers with multiple MetS components had cryptorchidism. Similarly, 0.69% vs 0.88% of sons had hypospadias when fathers had 0 or 2+ components of MetS. After adjusting for maternal and paternal factors, the odds of a son diagnosed with hypospadias increased with two or more paternal MetS components (Odds ratio [95% confidence interval]: 1.27 [1.10 - 1.47]). Specific components of paternal MetS were not generally more associated with a son's genital malformations. When we performed a subgroup analysis where genital malformations were defined based on surgical correction, the association with hypospadias persisted.CONCLUSIONS: Fathers with multiple components of the metabolic syndrome in the preconception period were observed to be at increased risks for having sons born with hypospadias. The results support the association between a man's andrological and overall health. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/andr.13404

  View details for PubMedID 36727635

• Pregnancy outcomes in women with sickle cell disease in California. American journal of hematology Adesina, O. O., Brunson, A., Fisch, S. C., Yu, B., Mahajan, A., Willen, S. M., Keegan, T. H., Wun, T. 2023

  Abstract

  Adverse pregnancy outcomes occur frequently in women with sickle cell disease (SCD) across the globe. In the United States, Black women experience disproportionately worse maternal health outcomes than all other racial groups. To better understand how social determinants of health impact SCD maternal morbidity, we used California's Department of Health Care Access and Information data (1991-2019) to estimate the cumulative incidence of pregnancy outcomes in Black women with and without SCD-adjusted for age, insurance status, and Distressed Community Index (DCI) scores. Black pregnant women with SCD were more likely to deliver at a younger age, use government insurance, and live in at-risk or distressed neighborhoods, compared to those without SCD. They also experienced higher stillbirths (26.8, 95% confidence interval [CI]: 17.5-36.1 vs. 12.4 [CI: 12.1-12.7], per 1,000 births) and inpatient maternal mortality (344.5 [CI: 337.6-682.2] vs. 6.1 [CI: 2.3-8.4], per 100,000 live births). Multivariate logistic regression models showed Black pregnant women with SCD had significantly higher odds ratios (OR) for sepsis (OR 14.89, CI: 10.81, 20.52), venous thromboembolism (OR 13.60, CI: 9.16, 20.20), and postpartum hemorrhage (OR 2.25, CI 1,79-2.82), with peak onset in the 2nd trimester, 3rd trimester, and 6weeks postpartum, respectively. Despite adjusting for sociodemographic factors, Black women with SCD still experienced significantly worse pregnancy outcomes than those without SCD. We need additional studies to determine if early introduction to reproductive health education, continuation of SCD-modifying therapies during pregnancy, and increasing access to multidisciplinary perinatal care can reduce morbidity in pregnant women with SCD. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ajh.26818

  View details for PubMedID 36594168

• The Reproductive Competence of Human Metaphase I Oocytes with Delayed Maturation In Vitro Nguyen, E., Moon, J. H., Nel-Themaat, L., Lathi, R., Yu, B. SPRINGER HEIDELBERG. 2023: 43A-44A

  View details for Web of Science ID 001043029500005

• Establishing Upper Genital Tract Organoids to Model Pathogenesis of Cancers and Infectious Diseases Nguyen, E., Fredricks, D., Swisher, E., Yu, B. SPRINGER HEIDELBERG. 2023: 145A-146A

  View details for Web of Science ID 001043029500256

• Comprehensive Profiling of the Fallopian Tube Microbiome Nguyen, E., Liu, C., Proll, S., Srinivasan, S., Yu, B. SPRINGER HEIDELBERG. 2023: 208A

  View details for Web of Science ID 001043029500413

• Preconception paternal comorbidities and offspring birth defects: Analysis of a large national data set. Birth defects research Yu, B., Zhang, C. A., Li, S., Chen, T., Mulloy, E., Shaw, G. M., Eisenberg, M. L. 2022

  Abstract

  BACKGROUND: Despite the fact that the father contributes half the genome to a child, associations between paternal factors and birth defects are poorly understood.OBJECTIVES: To investigate the association between preconception paternal health and birth defects in the offspring.MATERIALS AND METHODS: We conducted analysis of a national cohort study utilizing the IBM Marketscan Research Database, which includes data on reimbursed private healthcare claims in the United States from 2007 to 2016. The potential association between paternal comorbidities, as measured by the components of metabolic syndrome (MetS), and any birth defect in the offspring was analyzed.RESULTS: Of the 712,774 live births identified, 21.2% of children were born to fathers with at least one component of the metabolic syndrome (MetS ≥1) prior to conception. Compared to infants born to fathers with no components of the metabolic syndrome, a modestly higher percentage of infants with cardiac birth defects were born to fathers with more components of MetS (MetS=1, OR [95% CI]: 1.07 [1.01-1.13]; MetS ≥2, 1.17 [1.08-1.26], in comparison to MetS=0) after adjusting for maternal and paternal factors. Similarly, a higher percentage of infants with respiratory defects were born to fathers with two or more components of metabolic syndrome (MetS ≥2, OR [95% CI]: 1.45 [1.22-1.71]).DISCUSSION AND CONCLUSION: In this private insurance claims-based study, we found that fathers with metabolic syndrome-related diseases before conception were at increased risk for having a child affected by birth defects, especially cardiac and respiratory defects, and this association was not influenced by paternal age or assessed maternal factors.

  View details for DOI 10.1002/bdr2.2082

  View details for PubMedID 36106720

• Pregnancy Outcomes in Women with Sickle Cell Disease in California: A Retrospective Cohort Study Fisch, S. C., Brunson, A. M., Mahajan, A., Keegan, T., Yu, B., Wun, T., Adesina, O. O. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-151715

  View details for Web of Science ID 000736398802031

• Severe ovarian hyperstimulation syndrome associated with long-acting GnRH agonist in oncofertility patients. Journal of assisted reproduction and genetics Christ, J., Herndon, C. N., Yu, B. 2021

  Abstract

  To report three cases of severe ovarian hyperstimulation syndrome (OHSS) among oncofertility patients receiving a long-acting GnRH agonist for ovarian suppression after controlled ovarian hyperstimulation (COH) with a GnRH antagonist protocol METHODS: Chart abstraction was completed for three patients at a single academic medical center. Patients included were undergoing fertility preservation prior to gonadotoxic chemotherapy. All patients underwent COH with GnRH antagonist protocol and embryo cryopreservation immediately followed by ovarian suppression with long-acting GnRH agonist. Main outcome measure was development of OHSS.Despite using GnRH agonist trigger and freezing all embryos, patients developed ascites, intermittent hyponatremia and hemoconcentration consistent with severe early-onset OHSS after receiving long-acting GnRH agonist immediately following oocyte retrieval for ovarian preservation.Risk of severe OHSS may be increased when a long-acting GnRH agonist is used for ovarian suppression immediately following oocyte retrieval. A delay in initiating long-acting GnRH agonist after oocyte retrieval in patients at high risk for developing OHSS should be considered.

  View details for DOI 10.1007/s10815-020-02051-7

  View details for PubMedID 33471229

• Dissociation of Pubertal Development Abnormality and Gonadal Dysfunction in Childhood Cancer Survivors JOURNAL OF ADOLESCENT AND YOUNG ADULT ONCOLOGY Yu, B., Fritz, R., Vega, M., Merino, M. 2020; 9 (4): 490–95

  Abstract

  Purpose: To determine the relationship between pubertal development and postpubertal gonadal function in childhood cancer survivors. Methods: Childhood cancer survivors (≥10 years of age) who received follow-up care in a pediatric oncology group in an academic medical center during the period from January 1, 1985, to July 1, 2010 were included in this case series. Their pubertal development and gonadal function were evaluated. Results: The cohort consists of 39 males (age 10-21 years) and 35 females (age 10-29 years) with a variety of cancer diagnosis and treatments. The average age at diagnosis was ∼7.5 years. The average age at the time of the study was 16 and 16.7 years in males and females, respectively, representing a mean follow-up interval of ∼9 years. Despite the fact that 60% of survivors received cyclophosphamide equivalents and 16.2% received cranial radiation or brain tumor resection, the majority of survivors (68%) presented with both normal puberty and normal gonadal functions at the time of follow-up. In 27% of survivors, puberty development did not predict gonadal function in early adulthood: 20% of survivors had normal puberty, but abnormal gonadal function; 7% of survivors had abnormal puberty, but gonadal function remained normal as young adults. Conclusions: Most childhood cancer survivors had normal puberty and gonadal function despite a variety of cancer treatment modalities. However, normal puberty did not predict normal gonadal function later in life in many survivors. Therefore, close follow-up with gonadal function in adolescent and early adulthood years is essential.

  View details for DOI 10.1089/jayao.2019.0138

  View details for Web of Science ID 000524993500001

  View details for PubMedID 32186962

  View details for PubMedCentralID PMC7415869

• Gonadotropin-Releasing Hormone (GnRH) Agonists for Fertility Preservation: Is POEMS the Final Verse? Journal of the National Cancer Institute Yu, B., Davidson, N. E. 2019; 111 (2): 107-108

  View details for DOI 10.1093/jnci/djy188

  View details for PubMedID 30371813

  View details for PubMedCentralID PMC6376902

• The impact of using donor sperm in assisted reproductive technology cycles on perinatal outcomes. Fertility and sterility Yu, B., Fritz, R., Xie, X., Negassa, A., Jindal, S., Vega, M., Buyuk, E. 2018; 110 (7): 1285-1289

  Abstract

  To assess the impact of using donor sperm in assisted reproductive technology (ART) cycles on perinatal outcomes.Historical cohort study.US national database from the Society of Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 2012 to 2013.Patients undergoing the first fresh autologous ART cycle using either donor or partner sperm.None.Miscarriage, preterm birth, low birthweight rates.A total of 134,710 fresh autologous ART cycles were evaluated from the SART CORS database. Following exclusion criteria and after restricting to the first cycle, 2,123 donor sperm and 42,799 partner sperm ART cycles were included in the final analyses. After adjusting for all confounding variables (including maternal age, race, body mass index, smoking status, gravidity, history of preterm birth, highest follicle stimulating hormone count, blastocyst transfer percentage, total embryo transferred, and etiology of infertility), no statistically significant differences in miscarriage rates, preterm births, very preterm births, low birthweight, and very low birthweight were observed. Birthweight was significantly lower in the partner sperm group than in the donor sperm group (3,292 ± 601 and 3,233 ± 592 g in donor and partner sperm groups, respectively, adjusted P value 0.003); however, this small absolute difference (adjusted effect estimate 42 g, 95% CI 14.7-70.9) does not carry clinical significance.The use of donor sperm in fresh autologous ART cycles was not associated with increased miscarriage, preterm births, or low birthweights, as compared to cycles using partner sperm. This information can be used in patient counseling to reassure patients using donor sperm in ART cycles.

  View details for DOI 10.1016/j.fertnstert.2018.08.012

  View details for PubMedID 30503127

  View details for PubMedCentralID PMC7605214

• Comparison of perinatal outcomes following frozen embryo transfer cycles using autologous versus donor oocytes in women 40 to 43 years old: analysis of SART CORS data. Journal of assisted reproduction and genetics Yu, B., Vega, M., Zaghi, S., Fritz, R., Jindal, S., Buyuk, E. 2018; 35 (11): 2025-2029

  Abstract

  To study the differences in perinatal outcomes after frozen embryo transfer cycles using autologous or donor oocytes in women of advanced maternal age.Historical cohort study.US national database from the Society of Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 2009 to 2013.Women at 40-43 years of age undergoing autologous frozen embryo transfers (a-FET) or donor oocyte frozen embryo transfers (d-FET) resulting in singleton pregnancies that were entered in the SART CORS database from 2009 to 2013.a-FET resulted in 4402 singleton live births whereas d-FET resulted in 2703 singleton live births. d-FET resulted in a higher risk of preterm births (< 37 weeks), with adjusted odds ratio (aOR) 1.33 (95% CI 1.02-1.75), but similar risk of small for gestational age (SGA), with aOR 1.75 (95% CI 0.85-3.7), when compared to a-FET. However, when only single blastocyst transfer cycles are considered, d-FET and a-FET showed no difference in preterm births or other adverse perinatal outcomes.Singletons resulting from d-FET are at increased risk for perinatal morbidity. However, the risk was diminished in single blastocyst transfer cycles. Our study supports the current American Society for Reproductive Medicine (ASRM) guidelines of transferring a single blastocyst in d-FET cycles.

  View details for DOI 10.1007/s10815-018-1287-1

  View details for PubMedID 30128819

  View details for PubMedCentralID PMC6240548

• Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome. Genome biology Gravina, S., Dong, X., Yu, B., Vijg, J. 2016; 17 (1): 150

  Abstract

  Transmission fidelity of CpG DNA methylation patterns is not foolproof, with error rates from less than 1 to well over 10 % per CpG site, dependent on preservation of the methylated or unmethylated state and the type of sequence. This suggests a fairly high chance of errors. However, the consequences of such errors in terms of cell-to-cell variation have never been demonstrated by experimentally measuring intra-tissue heterogeneity in an adult organism.We employ single-cell DNA methylomics to analyze heterogeneity of genome-wide 5-methylcytosine (5mC) patterns within mouse liver. Our results indicate a surprisingly high level of heterogeneity, corresponding to an average epivariation frequency of approximately 3.3 %, with regions containing H3K4me1 being the most variable and promoters and CpG islands the most stable. Our data also indicate that the level of 5mC heterogeneity is dependent on genomic features. We find that non-functional sites such as repeat elements and introns are mostly unstable and potentially functional sites such as gene promoters are mostly stable.By employing a protocol for whole-genome bisulfite sequencing of single cells, we show that the liver epigenome is highly unstable with an epivariation frequency in DNA methylation patterns of at least two orders of magnitude higher than somatic mutation frequencies.

  View details for DOI 10.1186/s13059-016-1011-3

  View details for PubMedID 27380908

  View details for PubMedCentralID PMC4934005

• Cost-effectiveness analysis comparing continuation of assisted reproductive technology with conversion to intrauterine insemination in patients with low follicle numbers. Fertility and sterility Yu, B., Mumford, S., Royster, G. D., Segars, J., Armstrong, A. Y. 2014; 102 (2): 435-9

  Abstract

  To compare the cost effectiveness of proceeding with oocyte retrieval vs. converting to intrauterine insemination (IUI) in patients with ≤4 mature follicles during assisted reproductive technology (ART) cycles.Probabilistic decision analysis. The cost effectiveness of completing ART cycles in poor responders was compared to that for converting the cycles to IUI.Not applicable.Not applicable.Cost-effectiveness analysis.Cost effectiveness, which was defined as the average direct medical costs per ongoing pregnancy.In patients with 1-3 mature follicles, completing ART was more cost effective if the cost of a single ART cycle was between $10,000 and $25,000. For patients with 4 mature follicles, if an ART cycle cost<$18,025, it was more cost effective to continue with oocyte retrieval than to convert to IUI.In patients with ≤4 mature follicles following ovarian stimulation in ART cycles, it was on average more cost effective to proceed with oocyte retrieval rather than convert to IUI. However, important factors, such as age, prior ART failures, other fertility factors, and medications used in each individual case need to be considered before this analysis model can be adapted by individual practices.

  View details for DOI 10.1016/j.fertnstert.2014.05.015

  View details for PubMedID 24951366

  View details for PubMedCentralID PMC4119511

• The prevalence of genuine empty follicle syndrome. Fertility and sterility Mesen, T. B., Yu, B., Richter, K. S., Widra, E., DeCherney, A. H., Segars, J. H. 2011; 96 (6): 1375-7

  Abstract

  To describe the prevalence of "genuine" empty follicle syndrome (EFS) and "false" EFS at assisted reproductive technology (ART).Retrospective cohort.Large private fertility center.A total of 12,359 patients who underwent ART between 2004 and 2009.None.The failure to recover an oocyte during oocyte retrieval at ART, with and without a detectable serum β-hCG on the day of retrieval.Two cases of genuine EFS and nine cases of false EFS were identified in the cohort examined. The prevalence of genuine EFS was 0.016%, and the prevalence of false EFS was 0.072%. Only two out of 11 cases of EFS were considered genuine.Genuine EFS is a rare occurrence. Because this syndrome tends to recur with dismal pregnancy rates at ART, continued identification and further investigation of the syndrome are needed.

  View details for DOI 10.1016/j.fertnstert.2011.09.047

  View details for PubMedID 22130102

  View details for PubMedCentralID PMC3576020

• Subclinical elevations of thyroid-stimulating hormone and assisted reproductive technology outcomes. Fertility and sterility Michalakis, K. G., Mesen, T. B., Brayboy, L. M., Yu, B., Richter, K. S., Levy, M., Widra, E., Segars, J. H. 2011; 95 (8): 2634-7

  Abstract

  The prevalence of moderately elevated TSH levels consistent with subclinical hypothyroidism (2.5-4.0 μIU/mL) was 23% in a cohort of 1,231 women pursuing assisted reproductive technologies. Preconception elevated levels of TSH were associated with diminished ovarian reserve but were not associated with adverse assisted reproductive technology or pregnancy outcomes.

  View details for DOI 10.1016/j.fertnstert.2011.02.056

  View details for PubMedID 21457968

  View details for PubMedCentralID PMC3124612

• The role of peripheral gonadotropin-releasing hormone receptors in female reproduction. Fertility and sterility Yu, B., Ruman, J., Christman, G. 2011; 95 (2): 465-73

  Abstract

  To review the physiologic functions and clinical significance of peripheral GnRH receptors.Literature review. All peer-reviewed journal articles published before 2010 on peripheral GnRH receptors were searched for in the Pubmed database, and relevant findings were summarized.Peripheral GnRH/GnRH receptor systems may serve as regulators of hCG synthesis and implantation, and play crucial roles in antiproliferation and apoptosis. Currently, GnRH agonists have been used in cancer treatment and ovary protection during chemotherapy, taking advantage of the local direct effect mediated by peripheral GnRH receptors.The ubiquitous GnRH/GnRH receptor system in human tissues has been shown to have some important physiologic functions. Further research to clarify functions of these peripheral GnRH receptors may lead to discovery of new therapeutic options.

  View details for DOI 10.1016/j.fertnstert.2010.08.045

  View details for PubMedID 20888559

• A systematic, multidisciplinary approach to address the reproductive needs of HIV-seropositive women. Reproductive biomedicine online Douglas, N. C., Wang, J. G., Yu, B., Gaddipati, S., Guarnaccia, M. M., Sauer, M. V. 2009; 19 (2): 257-63

  Abstract

  Nearly 130,000 American women are human immunodeficiency virus (HIV) seropositive. The present study sought to establish a comprehensive programme to address their fertility needs in order to minimize infectious, medical and reproductive risks to prospective patients. Forty women, aged 27-42 years, were evaluated. HIV was diagnosed 7.2 +/- 0.7 years prior to their seeking care, and most women (n = 38) were on highly active antiretroviral therapy. Their prenatal CD4 counts were 712.2 +/- 56 cells/mm(3) (range 327-1881) and HIV-1 concentrations were undetectable in all cases prior to initiating treatment. HIV-seropositive women were statistically identical to their age-matched HIV-seronegative counterparts with respect to the IVF clinical outcome parameters measured. Throughout the pregnancies, maternal HIV-1 RNA concentrations remained undetectable and CD4 counts were stable. All infants, tested at birth and at 3 and 6 months of age, remained HIV negative. This is the first report of an institutional paradigm in the USA dedicated to evaluate and treat HIV-seropositive women. Using a multidisciplinary approach to care, HIV-seropositive women may be successfully managed in a programme of assisted reproduction.

  View details for DOI 10.1016/s1472-6483(10)60082-x

  View details for PubMedID 19712564

• Uterine artery embolization as an adjunctive measure to decrease blood loss prior to evacuating a cervical pregnancy. Archives of gynecology and obstetrics Yu, B., Douglas, N. C., Guarnaccia, M. M., Sauer, M. V. 2009; 279 (5): 721-4

  Abstract

  Cervical ectopic pregnancy accounts for less than 1% of all ectopic gestations. The most effective, fertility sparing treatment of a cervical ectopic pregnancy is still unclear due to limited reported experience.The diagnosis and management of a 32-year-old with a cervical ectopic pregnancy after in vitro fertilization and embryo transfer is described. The patient had multiple risk factors, including Asherman's syndrome following an abdominal myomectomy and three uterine curettages, for a cervical ectopic pregnancy. Due to her desire for future childbearing, conservative management strategies were chosen. This patient was successfully treated with uterine artery embolization followed by immediate dilation and evacuation of the pregnancy.This report demonstrates that UAE followed by immediate evacuation of a cervical ectopic pregnancy effectively terminates a viable gestation with minimal blood loss while maintaining fertility capacity.

  View details for DOI 10.1007/s00404-008-0775-4

  View details for PubMedID 18791728

• Efficacy of native and hyperglycosylated follicle-stimulating hormone analogs for promoting fertility in female mice. Fertility and sterility Trousdale, R. K., Yu, B., Pollak, S. V., Husami, N., Vidali, A., Lustbader, J. W. 2009; 91 (1): 265-70

  Abstract

  To compare the efficacy of recombinant human FSH (rhFSH) with rhFSH with four additional O-linked carbohydrates (rhFSH-CTP), rhFSH with four additional N-linked carbohydrates (rhFSH-N4), and the current gold standard for rodent ovarian stimulation, pregnant mare serum gonadotropin (PMSG), on fertility parameters in mice.Animal study.Academic research center.Adult C57Bl/6J female mice.Ovarian stimulation with 5 IU of rhFSH, rhFSH-CTP, rhFSH-N4, or PMSG. Forty-six hours later, 5 IU of hCG was injected to promote ovulation and females were mated overnight.Eggs retrieved after ovulation, in vitro embryo development, delivery rate, and litter size.The hyperglycosylated FSH analogs, rhFSH-CTP and rhFSH-N4, enhanced ovulation and embryo maturation significantly better than rhFSH. RhFSH-N4 produced more eggs (28.5 +/- 1.9 per mouse) and embryos (17.8 +/- 1.6) compared with rhFSH-CTP (18.3 +/- 1.2 and 9.0 +/- 1.0, respectively). Treatment with rhFSH, rhFSH-N4, and PMSG produced statistically equivalent delivery rates and litter sizes. The delivery rate was surprisingly lower with rhFSH-CTP (14%) compared with PMSG (33%).Compared with rhFSH, treatment with hyperglycosylated rhFSH-CTP and rhFSH-N4 led to superior rates of ovulated eggs and subsequent in vitro embryo development. RhFSH-N4 was equivalent to PMSG, while all of the fertility parameters studied were lower with rhFSH-CTP than with PMSG therapy.

  View details for DOI 10.1016/j.fertnstert.2007.11.013

  View details for PubMedID 18249396

  View details for PubMedCentralID PMC2748679

• Management of chyle fistula utilizing thoracoscopic ligation of the thoracic duct. ORL; journal for oto-rhino-laryngology and its related specialties Gunnlaugsson, C. B., Iannettoni, M. D., Yu, B., Chepeha, D. B., Teknos, T. N. 2004; 66 (3): 148-54

  Abstract

  To document the treatment of refractory chyle leaks using thoracoscopic thoracic duct ligation and provide systematic guidelines to manage chyle leaks.The medical records of 2 patients with chyle leaks are reviewed, followed by a review of the literature on chyle leaks and their thoracoscopic management.Initial treatment of chyle fistula is aimed at conservative medical management. Persistent high-output fistulas (>500 cm(3)) should be considered for neck reexploration as conservative management is likely to fail. Thoracoscopic thoracic duct ligation provides a safe and efficient means of treating chyle leaks refractory to repeated surgical and medical intervention. It should also be considered as a primary surgical intervention for patients with: (1) chyle output exceeding 500 cm(3)/day where prior intraoperative attempts at ligation have failed, (2) severe metabolic and nutritional complications, (3) coexisting chylothorax with respiratory compromise, and (4) low-output fistulas (<500 cm(3)/day) of long duration (>14 days).

  View details for DOI 10.1159/000079335

  View details for PubMedID 15316236

• Therapeutic effects of tumor reactive CD4+ cells generated from tumor-primed lymph nodes using anti-CD3/anti-CD28 monoclonal antibodies. Journal of immunotherapy (Hagerstown, Md. : 1997) Li, Q., Yu, B., Grover, A. C., Zeng, X., Chang, A. E. 2002; 25 (4): 304-13

  Abstract

  T-cell activation involves multiple signaling pathways. In this report, we conducted in vitro and in vivo immune function analysis of tumor-draining lymph node (TDLN) cells after anti-CD3/anti-CD28 activation versus anti-CD3 activation alone in a murine tumor model. In cytokine release assays, the doubly activated TDLN cells secreted significantly greater amounts of IFN-gamma and GM-CSF in response to specific tumor antigen compared with anti-CD3 activated cells. In adoptive immunotherapy, the doubly activated TDLN cells were more effective in mediating regression of 3-day pulmonary metastases compared with anti-CD3 activated cells. Although there was predominant proliferation of CD8+ cells after either activation procedure, the mean-fold expansion of CD4+ cells was significantly greater after anti-CD3/anti-CD28 activation than anti-CD3 activation alone. Using magnetic bead-enriched T-cell subsets, we found that either CD4+ or CD8+ doubly activated TDLN cells could independently mediate tumor regression. Furthermore, the doubly activated CD4+ cells were more effective than CD8+ cells in adoptive immunotherapy on a per-cell basis. The antitumor activity mediated by CD4+ or CD8+ cells could be significantly enhanced with the exogenous administration of IL-2. CD28 co-stimulation of tumor-primed lymphoid cells promotes the generation of potent tumor reactive effector cells, particularly CD4+ T cells, with antitumor activity in adoptive immunotherapy.

  View details for DOI 10.1097/00002371-200207000-00002

  View details for PubMedID 12142553