- Pediatric Endocrinology
Clinical Associate Professor, Pediatrics - Endocrinology and Diabetes
Board Certification, American Board of Preventative Medicine, Clinical Informatics (2021)
Board Certification: American Board of Pediatrics, Pediatric Endocrinology (2015)
Board Certification: American Board of Pediatrics, Pediatrics (2014)
Fellowship, University of California - San Francisco, Pediatric Endocrinology (2015)
Internship, University of California - San Francisco, Pediatrics (2011)
Residency, University of California - San Francisco, Pediatrics (2012)
Medical Education: Georgetown University School of Medicine Registrar (2010) DC
Lower HbA1c targets are associated with better metabolic control.
European journal of pediatrics
Previous studies have suggested that clear HbA1c target setting by the diabetes team is associated with HbA1c outcomes in adolescents. The aim of this study was to evaluate whether this finding is consistent in a larger cohort of children from centers participating in the SWEET international diabetes registry. A questionnaire was sent out to 76 SWEET centers, of which responses from 53 pediatric centers were included (70%). Descriptive outcomes were presented as median with lower and upper quartile. The association between the centers' target HbA1c and mean outcome HbA1c was calculated using linear regression adjusted for age, diabetes duration, sex, and gross domestic product. Median age of the children in the studied centers (n = 35,483) was 13.3 [12.6-14.6] years (49% female). Of the 53 centers, 13.2% reported an HbA1c target between 6.0 and 6.5%, 32.1% had a target between ≥ 6.0 and 7.0%, 18.9% between ≥ 7.0 and 7.5%, and 3.8% between ≥ 7.5 and 8.5%. No specific target value was reported by 32.1% of all centers. Median HbA1c across all centers was 7.9 [7.6-8.3] %. Adjusted regression analysis showed a positive association between HbA1c outcome and target HbA1c (p = 0.005).Conclusions: This international study demonstrated that a lower target for HbA1c was associated with better metabolic control. It is unclear whether low target values result in better metabolic control, or lower HbA1c values actually result in more ambitious target values. This target setting could contribute to the differences in HbA1c values between centers and could be an approach for improving metabolic outcomes. What is Known: • Target setting of HbA1c is important in children and adolescents with type 1 diabetes. • The optimal therapeutic approach of children with type 1 diabetes requires a trained multidisciplinary team. What is New: • Lower HbA1c targets are associated with better metabolic control. • No associations between the composition of the diabetes teams and metabolic control could be demonstrated.
View details for DOI 10.1007/s00431-020-03891-2
View details for PubMedID 33415466
"I was ready for it at the beginning": Parent experiences with early introduction of continuous glucose monitoring following their child's Type 1 diabetes diagnosis.
Diabetic medicine : a journal of the British Diabetic Association
To capture the experience of parents of youth with recent onset Type 1 diabetes who initiated use of continuous glucose monitoring (CGM) technology soon after diagnosis, which is a new practice.Focus groups and individual interviews were conducted with parents of youth with Type 1 diabetes who had early initiation of CGM as part of a new clinical protocol. Interviewers used a semi-structured interview guide to elicit feedback and experiences with starting CGM within 30 days of diagnosis, and the benefits and barriers they experienced when adjusting to this technology. Groups and interviews were audio-recorded, transcribed, and analyzed using content analysis.Participants were 16 parents (age 44.13±8.43 years; 75% female; 56.25% non-Hispanic White) of youth (age 12.38±4.15 years; 50% female; 50% non-Hispanic White; diabetes duration 10.35±3.89 months) who initiated CGM 11.31±7.33 days after diabetes diagnosis. Overall, parents reported high levels of satisfaction with starting CGM within a month of diagnosis and described a high level of reliance on the technology to help manage their child's diabetes. All participants recommended early CGM initiation for future families and were committed to continue using the technology for the foreseeable future, provided that insurance covered it.Parents experienced CGM initiation shortly after their child's Type 1 diabetes diagnosis as a highly beneficial and essential part of adjusting to living with diabetes.
View details for DOI 10.1111/dme.14567
View details for PubMedID 33772862
Thiamine-Responsive Megaloblastic Anemia-Related Diabetes: Long-Term Clinical Outcomes in 23 Pediatric Patients From the DPV and SWEET Registries.
Canadian journal of diabetes
OBJECTIVES: To describe clinical presentation and long-term outcomes in a large cohort of children diagnosed with thiamine-responsive megaloblastic anemia (TRMA)-related diabetes.METHODS: Data from the Diabetes Patienten Verlaufsdokumentation (DPV) and Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference (SWEET) registries were used to identify cases. Complementary information was collected through a chart review of each case. Descriptive analyses with medians and interquartile ranges and numbers (proportions) were tabulated.RESULTS: We identified 23 cases (52% male) in the 2 registries. Eighteen (78%) had genetic confirmation of TRMA. Median age at diabetes onset was 1.4 (quartiles 0.8 to 3.6) years and median age at initiation of thiamine treatment was 5.9 (2.4 to 12.4) years. At their most recent visit, patients' median age was 14.3 (8.1 to 17.5) years, glycated hemoglobin level was 6.9% (6.1% to 7.9%), insulin dose was 0.9 (0.4 to 1.2) units/kg per day and thiamine dose was 200 (100 to 300) mg/day. Three patients were not treated with insulin or antidiabetic drugs. There was no difference in diabetes outcomes in patients with initiation of thiamine ≤1 year after diabetes onset compared to patients with initiation of thiamine >1 year after diabetes onset.CONCLUSIONS: This is the longest case series of pediatric TRMA-related diabetes reported to date. Diabetes onset often occurs several years before initiation of thiamine supplementation. Early initiation of thiamine (within 1 year of diabetes onset) was not linked to improved diabetes outcome. However, the role of thiamine in pancreatic function needs further assessment. Patients with TRMA-related diabetes maintained good glycemic control even after 9 years (median) of follow up.
View details for DOI 10.1016/j.jcjd.2020.11.006
View details for PubMedID 33388275
Multimethod, multidataset analysis reveals paradoxical relationships between sociodemographic factors, Hispanic ethnicity and diabetes.
BMJ open diabetes research & care
2020; 8 (2)
INTRODUCTION: Population-level and individual-level analyses have strengths and limitations as do 'blackbox' machine learning (ML) and traditional, interpretable models. Diabetes mellitus (DM) is a leading cause of morbidity and mortality with complex sociodemographic dynamics that have not been analyzed in a way that leverages population-level and individual-level data as well as traditional epidemiological and ML models. We analyzed complementary individual-level and county-level datasets with both regression and ML methods to study the association between sociodemographic factors and DM.RESEARCH DESIGN AND METHODS: County-level DM prevalence, demographics, and socioeconomic status (SES) factors were extracted from the 2018 Robert Wood Johnson Foundation County Health Rankings and merged with US Census data. Analogous individual-level data were extracted from 2007 to 2016 National Health and Nutrition Examination Survey studies and corrected for oversampling with survey weights. We used multivariate linear (logistic) regression and ML regression (classification) models for county (individual) data. Regression and ML models were compared using measures of explained variation (area under the receiver operating characteristic curve (AUC) and R2).RESULTS: Among the 3138 counties assessed, the mean DM prevalence was 11.4% (range: 3.0%-21.1%). Among the 12824 individuals assessed, 1688 met DM criteria (13.2% unweighted; 10.2% weighted). Age, gender, race/ethnicity, income, and education were associated with DM at the county and individual levels. Higher county Hispanic ethnic density was negatively associated with county DM prevalence, while Hispanic ethnicity was positively associated with individual DM. ML outperformed regression in both datasets (mean R2 of 0.679 vs 0.610, respectively (p<0.001) for county-level data; mean AUC of 0.737 vs 0.727 (p<0.0427) for individual-level data).CONCLUSIONS: Hispanic individuals are at higher risk of DM, while counties with larger Hispanic populations have lower DM prevalence. Analyses of population-level and individual-level data with multiple methods may afford more confidence in results and identify areas for further study.
View details for DOI 10.1136/bmjdrc-2020-001725
View details for PubMedID 33229378
Uninterrupted Continuous Glucose Monitoring Access is Associated with a Decrease in HbA1c in Youth with Type 1 Diabetes and Public Insurance.
OBJECTIVE: Continuous glucose monitor (CGM) use is associated with improved glucose control. We describe the effect of continued and interrupted CGM use on hemoglobin A1c (HbA1c) in youth with public insurance.METHODS: We reviewed 956 visits from 264 youth with type 1 diabetes (T1D) and public insurance. Demographic data, HbA1c and two-week CGM data were collected. Youth were classified as never user, consistent user, insurance discontinuer, and self-discontinuer. Visits were categorized as never-user visit, visit before CGM start, visit after CGM start, visit with continued CGM use, visit with initial loss of CGM, visit with continued loss of CGM, and visit where CGM is regained after loss. Multivariate regression adjusting for age, sex, race, diabetes duration, initial HbA1c, and BMI were used to calculate adjusted mean and delta HbA1c.RESULTS: Adjusted mean HbA1c was lowest for the consistent user group (HbA1c 8.6%;[95%CI 7.9,9.3]). Delta HbA1c (calculated from visit before CGM start) was lower for visit after CGM start (-0.39%;[95%CI -0.78,-0.02]) and visit with continued CGM use (-0.29%;[95%CI -0.61,0.02]) whereas it was higher for visit with initial loss of CGM (0.40%;[95%CI -0.06,0.86]), visit with continued loss of CGM (0.46%;[95%CI 0.06,0.85]), and visit where CGM is regained after loss (0.57%;[95%CI 0.06,1.10]).CONCLUSIONS: Youth with public insurance using CGM have improved HbA1c, but only when CGM use is uninterrupted. Interruptions in use, primarily due to gaps in insurance coverage of CGM, were associated with increased HbA1c. These data support both initial and ongoing coverage of CGM for youth with T1D and public insurance. This article is protected by copyright. All rights reserved.
View details for DOI 10.1111/pedi.13082
View details for PubMedID 32681582
Effect of Continuous Glucose Monitoring on Glycemic Control in Adolescents and Young Adults With Type 1 Diabetes: A Randomized Clinical Trial.
2020; 323 (23): 2388–96
Importance: Adolescents and young adults with type 1 diabetes exhibit the worst glycemic control among individuals with type 1 diabetes across the lifespan. Although continuous glucose monitoring (CGM) has been shown to improve glycemic control in adults, its benefit in adolescents and young adults has not been demonstrated.Objective: To determine the effect of CGM on glycemic control in adolescents and young adults with type 1 diabetes.Design, Setting, and Participants: Randomized clinical trial conducted between January 2018 and May 2019 at 14 endocrinology practices in the US including 153 individuals aged 14 to 24 years with type 1 diabetes and screening hemoglobin A1c (HbA1c) of 7.5% to 10.9%.Interventions: Participants were randomized 1:1 to undergo CGM (CGM group; n=74) or usual care using a blood glucose meter for glucose monitoring (blood glucose monitoring [BGM] group; n=79).Main Outcomes and Measures: The primary outcome was change in HbA1c from baseline to 26 weeks. There were 20 secondary outcomes, including additional HbA1c outcomes, CGM glucose metrics, and patient-reported outcomes with adjustment for multiple comparisons to control for the false discovery rate.Results: Among the 153 participants (mean [SD] age, 17  years; 76 [50%] were female; mean [SD] diabetes duration, 9  years), 142 (93%) completed the study. In the CGM group, 68% of participants used CGM at least 5 days per week in month 6. Mean HbA1c was 8.9% at baseline and 8.5% at 26 weeks in the CGM group and 8.9% at both baseline and 26 weeks in the BGM group (adjusted between-group difference, -0.37% [95% CI, -0.66% to -0.08%]; P=.01). Of 20 prespecified secondary outcomes, there were statistically significant differences in 3 of 7 binary HbA1c outcomes, 8 of 9 CGM metrics, and 1 of 4 patient-reported outcomes. The most commonly reported adverse events in the CGM and BGM groups were severe hypoglycemia (3 participants with an event in the CGM group and 2 in the BGM group), hyperglycemia/ketosis (1 participant with an event in CGM group and 4 in the BGM group), and diabetic ketoacidosis (3 participants with an event in the CGM group and 1 in the BGM group).Conclusions and Relevance: Among adolescents and young adults with type 1 diabetes, continuous glucose monitoring compared with standard blood glucose monitoring resulted in a small but statistically significant improvement in glycemic control over 26 weeks. Further research is needed to understand the clinical importance of the findings.Trial Registration: ClinicalTrials.gov Identifier: NCT03263494.
View details for DOI 10.1001/jama.2020.6940
View details for PubMedID 32543683
- Novel De Novo INS P.T97P Variant Presenting with Severe Neonatal DKA AMER DIABETES ASSOC. 2020
- The Association between Time-in-Range, Mean Glucose, and Incidence of Hypoglycemia in Youth with Newly Diagnosed T1D AMER DIABETES ASSOC. 2020
- A Telemedicine-CGM Recommendation System for Personalized Population Health Management AMER DIABETES ASSOC. 2020
- Early Introduction of Continuous Glucose Monitoring Is Well Accepted by Youth and Parents AMER DIABETES ASSOC. 2020
- Newly Diagnosed Pediatric Patients with Type 1 Diabetes Show Steady Decline in Glucose Time-in-Range (TIR) over 1 Year: Pilot Study AMER DIABETES ASSOC. 2020
- Early CGM Initiation Improves HbA1c in T1D Youth over the First 15 Months AMER DIABETES ASSOC. 2020
- Clinically Significant Hypoglycemia Is Rare in Youth with T1D during Partial Clinical Remission AMER DIABETES ASSOC. 2020
UNMET TECHNOLOGY NEEDS IN MINORITY PEOPLE IN NORTH AND SOUTH AMERICA
MARY ANN LIEBERT, INC. 2020: A10
View details for Web of Science ID 000514025300046
HBA1C TARGET SETTING IS ASSOCIATED WITH METABOLIC CONTROL
MARY ANN LIEBERT, INC. 2020: A237
View details for Web of Science ID 000514025300602
- Longitudinal Changes in Continuous Glucose Monitoring Use Among Individuals With Type 1 Diabetes: International Comparison in the German and Austrian DPV and U.S. T1D Exchange Registries. Diabetes care 2020; 43 (1): e1–e2
Improving Clinical Outcomes in Newly Diagnosed Pediatric Type 1 Diabetes: Teamwork, Targets, Technology, and Tight Control-The 4T Study.
Frontiers in endocrinology
2020; 11: 360
Many youth with type 1 diabetes (T1D) do not achieve hemoglobin A1c (HbA1c) targets. The mean HbA1c of youth in the USA is higher than much of the developed world. Mean HbA1c in other nations has been successfully modified following benchmarking and quality improvement methods. In this review, we describe the novel 4T approach-teamwork, targets, technology, and tight control-to diabetes management in youth with new-onset T1D. In this program, the diabetes care team (physicians, nurse practitioners, certified diabetes educators, dieticians, social workers, psychologists, and exercise physiologists) work closely to deliver diabetes education from diagnosis. Part of the education curriculum involves early integration of technology, specifically continuous glucose monitoring (CGM), and developing a curriculum around using the CGM to maintain tight control and optimize quality of life.
View details for DOI 10.3389/fendo.2020.00360
View details for PubMedID 32733375
View details for PubMedCentralID PMC7363838
- ISPAD Annual Conference 2018 Highlights PEDIATRIC DIABETES 2019; 20 (4): 375–79
Cinacalcet therapy in an infant with an R185Q calcium-sensing receptor mutation causing hyperparathyroidism: a case report and review of the literature.
Journal of pediatric endocrinology & metabolism : JPEM
Background Neonatal severe hyperparathyroidism (NSHPT) is commonly treated with either parathyroidectomy or pharmacologic agents with varying efficacy and numerous side effects. Reports of using cinacalcet for NSHPT have increased, however, the effective dose for pediatric patients from the onset of symptoms through infancy has not been established. Case presentation We describe the clinical course of a newborn with a de novo R185Q mutation in the calcium-sensing receptor (CASR) gene, causing NSHPT. The infant received cinacalcet from the first days of life until 1 year of age. Conclusions Cinacalcet therapy effectively controlled the patient's serum calcium, phosphorus, and parathyroid hormone (PTH) levels without side effects.
View details for PubMedID 30730839
Hemoglobin A1c Trajectory in Pediatric Patients with Newly Diagnosed Type 1 Diabetes.
Diabetes technology & therapeutics
Despite advances in diabetes technology and treatment, a majority of children and adolescents with type 1 diabetes (T1D) fail to meet hemoglobin A1c (HbA1c) targets. Among high-income nations, the United States has one of the highest mean HbA1c values. We tracked the HbA1c values of 261 patients diagnosed with T1D in our practice over a 2.5-year period to identify inflection points in the HbA1c trajectory. The HbA1c declined until 5 months postdiagnosis. There was a rise in the HbA1c between the fifth and sixth month postdiagnosis. The HbA1c continued to steadily rise and by 18 months postdiagnosis, the mean HbA1c was 8.2%, which is also our clinic mean. Understanding the HbA1c trajectory early in the course of diabetes has helped to identify opportunities for intensification of diabetes management to flatten the trajectory of HbA1c and improve clinical outcomes.
View details for DOI 10.1089/dia.2019.0065
View details for PubMedID 31180244
- CGM Initiation Soon After Type 1 Diabetes Diagnosis Results in Sustained CGM Use and Wear Time. Diabetes care 2019
Diabetes Technology Society Report on the FDA Digital Health Software Precertification Program Meeting.
Journal of diabetes science and technology
Diabetes Technology Society (DTS) convened a meeting about the US Food and Drug Administration (FDA) Digital Health Software Precertification Program on August 28, 2018. Forty-eight attendees participated from clinical and academic endocrinology (both adult and pediatric), nursing, behavioral health, engineering, and law, as well as representatives of FDA, National Institutes of Health (NIH), National Telecommunications and Information Administration (NTIA), and industry. The meeting was intended to provide ideas to FDA about their plan to launch a Digital Health Software Precertification Program. Attendees discussed the four components of the plan: (1) excellence appraisal and certification, (2) review pathway determination, (3) streamlined premarket review process, and (4) real-world performance. The format included (1) introductory remarks, (2) a program overview presentation from FDA, (3) roundtable working sessions focused on each of the Software Precertification Program's four components, (4) presentations reflecting the discussions, (5) questions to and answers from FDA, and (6) concluding remarks. The meeting provided useful information to the diabetes technology community and thoughtful feedback to FDA.
View details for PubMedID 30394807
Sustained Continuous Glucose Monitor Use in Low-Income Youth with Type 1 Diabetes Following Insurance Coverage Supports Expansion of Continuous Glucose Monitor Coverage for All.
Diabetes technology & therapeutics
View details for PubMedID 30020810
- Sustained Continuous Glucose Monitor Use in Low-Income Youth with Type 1 Diabetes Following Insurance Coverage Supports Expansion of Continuous Glucose Monitor Coverage for All DIABETES TECHNOLOGY & THERAPEUTICS 2018; 20 (9): 632–34
Diabetes technology: improving care, improving patient-reported outcomes and preventing complications in young people with Type 1 diabetes.
Diabetic medicine : a journal of the British Diabetic Association
With the evolution of diabetes technology, those living with Type 1 diabetes are given a wider arsenal of tools with which to achieve glycaemic control and improve patient-reported outcomes. Furthermore, the use of these technologies may help reduce the risk of acute complications, such as severe hypoglycaemia and diabetic ketoacidosis, as well as long-term macro- and microvascular complications. In addition, diabetes technology can have a beneficial impact on psychosocial health by reducing the burden of diabetes. Unfortunately, diabetes goals are often unmet and people with Type 1 diabetes too frequently experience acute and long-term complications of this condition, in addition to often having less than ideal psychosocial outcomes. Increasing realization of the importance of patient-reported outcomes is leading to diabetes care delivery becoming more patient-centred. Diabetes technology in the form of medical devices, digital health and big data analytics have the potential to improve clinical care and psychosocial support, resulting in lower rates of acute and chronic complications, decreased burden of diabetes care, and improved quality of life. This article is protected by copyright. All rights reserved.
View details for PubMedID 29356074
Evidence-based Mobile Medical Applications in Diabetes.
Endocrinology and metabolism clinics of North America
2016; 45 (4): 943-965
This article reviews mobile medical applications that are commercially available in the United States or European Union (EU) and are (1) associated with published data of clinical outcomes in the peer-reviewed literature during the past 5 years, (2) cleared by the US Food and Drug Administration (FDA) in the United States, or (3) a recipient of a CE (Conformité Européenne) mark by the EU. Many of these applications have been shown to positively affect outcomes in the short term, but long-term studies are needed. Until more data are available, consumers and professionals can consider guidance based on FDA/CE status.
View details for DOI 10.1016/j.ecl.2016.06.001
View details for PubMedID 27823614
Performance of Cleared Blood Glucose Monitors.
Journal of diabetes science and technology
2015; 9 (4): 895-910
Cleared blood glucose monitor (BGM) systems do not always perform as accurately for users as they did to become cleared. We performed a literature review of recent publications between 2010 and 2014 that present data about the frequency of inaccurate performance using ISO 15197 2003 and ISO 15197 2013 as target standards. We performed an additional literature review of publications that present data about the clinical and economic risks of inaccurate BGMs for making treatment decisions or calibrating continuous glucose monitors (CGMs). We found 11 publications describing performance of 98 unique BGM systems. 53 of these 98 (54%) systems met ISO 15197 2003 and 31 of the 98 (32%) tested systems met ISO 15197 2013 analytical accuracy standards in all studies in which they were evaluated. Of the tested systems, 33 were identified by us as FDA-cleared. Among these FDA-cleared BGM systems, 24 out of 32 (75%) met ISO 15197 2003 and 15 out of 31 (48.3%) met ISO 15197 2013 in all studies in which they were evaluated. Among the non-FDA-cleared BGM systems, 29 of 65 (45%) met ISO 15197 2003 and 15 out of 65 (23%) met ISO 15197 2013 in all studies in which they were evaluated. It is more likely that an FDA-cleared BGM system, compared to a non-FDA-cleared BGM system, will perform according to ISO 15197 2003 (χ(2) = 6.2, df = 3, P = 0.04) and ISO 15197 2013 (χ(2) = 11.4, df = 3, P = 0.003). We identified 7 articles about clinical risks and 3 articles about economic risks of inaccurate BGMs. We conclude that a significant proportion of cleared BGMs do not perform at the level for which they were cleared or according to international standards of accuracy. Such poor performance leads to adverse clinical and economic consequences.
View details for DOI 10.1177/1932296815584797
View details for PubMedID 25990294
Retinoic acid mediates regulation of network formation by COUP-TFII and VE-cadherin expression by TGFbeta receptor kinase in breast cancer cells.
2010; 5 (4)
Tumor development, growth, and metastasis depend on the provision of an adequate vascular supply. This can be due to regulated angiogenesis, recruitment of circulating endothelial progenitors, and/or vascular transdifferentiation. Our previous studies showed that retinoic acid (RA) treatment converts a subset of breast cancer cells into cells with significant endothelial genotypic and phenotypic elements including marked induction of VE-cadherin, which was responsible for some but not all morphological changes. The present study demonstrates that of the endothelial-related genes induced by RA treatment, only a few were affected by knockdown of VE-cadherin, ruling it out as a regulator of the RA-induced endothelial genotypic switch. In contrast, knockdown of the RA-induced gene COUP-TFII prevented the formation of networks in Matrigel but had no effect on VE-cadherin induction or cell fusion. Two pan-kinase inhibitors markedly blocked RA-induced VE-cadherin expression and cell fusion. However, RA treatment resulted in a marked and broad reduction in tyrosine kinase activity. Several genes in the TGFbeta signaling pathway were induced by RA, and specific inhibition of the TGFbeta type I receptor blocked both RA-induced VE-cadherin expression and cell fusion. Together these data indicate a role for the TGFbeta pathway and COUP-TFII in mediating the endothelial transdifferentiating properties of RA.
View details for DOI 10.1371/journal.pone.0010023
View details for PubMedID 20386594
Role of Sox-9, ER81 and VE-Cadherin in Retinoic Acid-Mediated Trans-Differentiation of Breast Cancer Cells
2008; 3 (7)
Many aspects of development, tumor growth and metastasis depend upon the provision of an adequate vasculature. This can be a result of regulated angiogenesis, recruitment of circulating endothelial progenitors and/or vascular trans-differentiation. The present study demonstrates that treatment of SKBR-3 breast cancer cells with retinoic acid (RA), an important regulator of embryogenesis, cancer and other diseases, stimulates the formation of networks in Matrigel. RA-treatment of SKBR-3 cells co-cultured with human umbilical vein endothelial cells resulted in the formation of mixed structures. RA induces expression of many endothelial genes including vascular endothelial (VE) cadherin. VE-cadherin was also induced by RA in a number of other breast cancer cells. We show that RA-induced VE-cadherin is responsible for the RA-induced morphological changes. RA rapidly induced the expression of Sox-9 and ER81, which in turn form a complex on the VE-cadherin promoter and are required to mediate the transcriptional regulation of VE-cadherin by RA. These data indicate that RA may promote the expression of endothelial genes resulting in endothelial-like differentiation, or provide a mechanism whereby circulating endothelial progenitor cells could be incorporated into a growing organ or tumor.
View details for DOI 10.1371/journal.pone.0002714
View details for Web of Science ID 000264057200057
View details for PubMedID 18628953
Regulation of MDCK cell-substratum adhesion by RhoA and myosin light chain kinase after ATP depletion
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
2004; 286 (3): C693-C707
The attachment of epithelial cells to the extracellular matrix substratum is essential for their differentiation and polarization. Despite this, the precise adhesion mechanism and its regulation are poorly understood. In the kidney, an ischemic insult causes renal tubular epithelial cells to detach from the basement membrane, even though they remain viable. To understand this phenomenon, and to probe the regulation of epithelial cell attachment, we used a model system consisting of newly adherent Madin-Darby canine kidney (MDCK) cells subjected to ATP depletion to mimic ischemic injury. We found that MDCK cells detach from collagen I after 60 min of ATP depletion but reattach when resupplied with glucose. Detachment is not caused by degradation or endocytosis of beta(1)-integrins, which mediate attachment to collagen I. Basal actin filaments and paxillin-containing adhesion complexes are disrupted by ATP depletion and quickly reform on glucose repletion. However, partial preservation of basal actin by overexpression of constitutively active RhoA does not significantly affect cell detachment. Furthermore, Y-27632, an inhibitor of the RhoA effector Rho-kinase, does not prevent reattachment of cells on glucose addition, even though reformation of central stress fibers and large adhesion complexes is blocked. In contrast, reattachment of ATP-depleted cells and detachment of cells not previously subjected to ATP depletion are prevented by ML-7, an inhibitor of myosin light chain kinase (MLCK). We conclude that initial adherence of MDCK cells to a collagen I substratum is mediated by peripheral actin filaments and adhesion complexes regulated by MLCK but not by stress fibers and adhesion complexes controlled by RhoA.
View details for DOI 10.1152/ajpcell.00124.2003
View details for Web of Science ID 000188707600027
View details for PubMedID 14644769