Faculty Bibliography
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231
Anti-Mullerian hormone and endometrial cancer: a multi-cohort study
BACKGROUND: The Mullerian ducts are the embryological precursors of the female reproductive tract, including the uterus; anti-Mullerian hormone (AMH) has a key role in the regulation of foetal sexual differentiation. Anti-Mullerian hormone inhibits endometrial tumour growth in experimental models by stimulating apoptosis and cell cycle arrest. To date, there are no prospective epidemiologic data on circulating AMH and endometrial cancer risk. METHODS: We investigated this association among women premenopausal at blood collection in a multicohort study including participants from eight studies located in the United States, Europe, and China. We identified 329 endometrial cancer cases and 339 matched controls. Anti-Mullerian hormone concentrations in blood were quantified using an enzyme-linked immunosorbent assay. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) across tertiles and for a doubling of AMH concentrations (ORlog2). Subgroup analyses were performed by ages at blood donation and diagnosis, oral contraceptive use, and tumour characteristics. RESULTS: Anti-Mullerian hormone was not associated with the risk of endometrial cancer overall (ORlog2: 1.07 (0.99-1.17)), or with any of the examined subgroups. CONCLUSIONS: Although experimental models implicate AMH in endometrial cancer growth inhibition, our findings do not support a role for circulating AMH in the aetiology of endometrial cancer.British Journal of Cancer advance online publication 5 September 2017; doi:10.1038/bjc.2017.299 www.bjcancer.com.
PMCID:5672934
PMID: 28873086
ISSN: 1532-1827
CID: 2688732
Exposure to benzophenone-3 and reproductive toxicity: A systematic review of human and animal studies
Hydroxy-4-methoxybenzophenone, also known as benzophenone-3 (BP-3), is a commonly used ultraviolet filter in skincare and as a food additive. Large concentrations of similar phenolic compounds have been detected in urine, amniotic fluid, and placental tissue, thereby raising questions about its impact on reproduction. The objective of this paper was to investigate the reproductive toxicity of BP-3 in humans and animals. In humans, studies showed that high levels of BP-3 exposure could be linked to an increase in male birth weight but a decline in female birth weight and male gestational age. In fish, BP-3 exposure resulted in a decline in egg production, hatching, and testosterone, along with a down-regulation of steroidogenic genes. In rats, a decrease in epididymal sperm density and a prolonged estrous cycle for females was observed. These positive associations may be attributed to an altered estrogen and testosterone balance as a result of endocrine disrupting effects of BP-3. However, the current body of literature is limited by non-uniform exposure and outcome measurements in studies both across and within species and future studies will need to be conducted in a standardized fashion to allow for a more significant contribution to the literature that allows for better comparison across studies.
PMID: 28844799
ISSN: 1873-1708
CID: 2679882
Androgens are differentially associated with ovarian cancer subtypes in the Ovarian Cancer Cohort Consortium
Invasive epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The etiology of EOC remains elusive; however, experimental and epidemiologic data suggest a role for hormone-related exposures in ovarian carcinogenesis and risk factor differences by histologic phenotypes and developmental pathways. Research on pre-diagnosis androgen concentrations and EOC risk has yielded inconclusive results, and analyses incorporating EOC subtypes are sparse. We conducted a pooled analysis of 7 nested case-control studies in the Ovarian Cancer Cohort Consortium to investigate the association between pre-diagnosis circulating androgens (testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS)), sex hormone binding globulin (SHBG), and EOC risk by tumor characteristics (i.e. histology, grade, and stage). The final study population included 1,331 EOC cases and 3,017 matched controls. Multivariable conditional logistic regression was used to assess risk associations in pooled individual data. Testosterone was positively associated with EOC risk (all subtypes combined, Odds Ratio (OR)log2=1.12 [95% Confidence Interval (CI) 1.02-1.24]); other endogenous androgens and SHBG were not associated with overall risk. Higher concentrations of testosterone and androstenedione associated with an increased risk in endometrioid and mucinous tumors (e.g., testosterone, endometrioid tumors, ORlog2=1.40 [1.03-1.91]), but not serous or clear cell. An inverse association was observed between androstenedione and high grade serous tumors (ORlog2=0.76 [0.60-0.96]). Our analyses provide further evidence for a role of hormone-related pathways in EOC risk, with differences in associations between androgens and histologic subtypes of EOC.
PMCID:5512110
PMID: 28381542
ISSN: 1538-7445
CID: 2521542
Reduction of Annexin A5 Anticoagulant Ratio Identifies Antiphospholipid Antibody-Positive Patients with Adverse Clinical Outcomes
BACKGROUND: Annexin A5 (A5) is a potent anticoagulant protein that shields anionic phospholipids from availability for coagulation reactions. Previous studies showed that antibodies from patients with antiphospholipid (aPL) syndrome (APS) interfere with A5 crystallization and anticoagulant activity. OBJECTIVE: The purpose of this study was to investigate whether reduction of the Annexin A5 Anticoagulant Ratio (A5R) assay (i.e. 'A5 resistance') is associated with adverse clinical events in aPL antibody-positive patients. PATIENTS/METHODS: In an initial discovery phase group of 679 patient samples from a 'real world' tertiary care hospital population who were tested for A5R. This was followed by a validation phase cohort of 71 asymptomatic patients with aPL antibodies and no prior history for an adverse clinical event whose baseline samples were tested for A5R then subsequently observed for up to 4 years. RESULTS: In the discovery phase group, we found a reduction of A5R in aPL antibody-positive patients with thrombosis and/or pregnancy complications compared to aPL antibody-negative patients and controls. In addition, reduced A5R values in both the discovery and validation phase cohorts correlated with the extent of multipositivity for standard APS tests, which has also been shown to be associated with risk for adverse clinical outcomes. CONCLUSION: Reduction of A5R levels was associated with a multipositivity profile in aPL antibody-positive patients within both groups and with the development of adverse clinical events
PMID: 28393472
ISSN: 1538-7836
CID: 2528092
Expression of Ezrin and Estrogen Receptors During Cervical Carcinogenesis
RATIONALE: Development of cervical squamous carcinoma (CXCA) is accompanied by changes in estrogen receptors (ERs, ERalpha and ERbeta) and ezrin expression; however, reports have been conflicting. Using histologically documented staging of cervical biopsies, we determined ezrin and ER relationships during CXCA development. METHODS: Immunoreactive (ir) ezrin, ir-ERalpha, and ir-ERbeta were studied in normal epithelium, carcinoma in situ/cervical intraepithelial neoplasia (CIN) 1 to 3, and local invasion or metastatic CXCA. Results were compared using H scoring. Cultures of Caski metastatic CXCA cells were treated with estradiol and/or tamoxifen and studied for ER-driven ir-ezrin and the morphologic response. RESULTS: Koilocytosis was present and indicated viral presence. The ezrin H score increased from CIN1 to CIN3, reaching significant differences from normal by CIN3 (P = .004) and 2x normal in metastatic CXCA. Estrogen receptor alpha and ERbeta H scores fell, reaching significance by CIN3 (ERalpha, P = .0001; ERbeta, P = .024). During estradiol treatment, ezrin in Caski cells increased and localized to the periphery, in ruffles and processes. The selective ER modulator tamoxifen blocked the estradiol-induced changes. CONCLUSIONS: During cervical carcinogenesis, the usual relationship between estrogen and ezrin induction is abridged. This is consistent with the effects of human papilloma virus viral proteins such as E6 and E7 that upregulate SIX1, a protein that induces ezrin. Cervical carcinogenesis is progressive but arrests at the preinvasive stage for varying lengths of time. These studies suggest that changes in ezrin may be associated with the development of the invasive phenotype and penetration of the basement membrane. They also raise the possibility that inhibiting ezrin expression could be a target for the prevention of invasive CXCA.
PMID: 27688241
ISSN: 1933-7205
CID: 2262782
Demographic, lifestyle, and other factors in relation to antimullerian hormone levels in mostly late premenopausal women
OBJECTIVE: To identify reproductive, lifestyle, hormonal, and other correlates of circulating antimullerian hormone (AMH) concentrations in mostly late premenopausal women. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): A total of 671 premenopausal women not known to have cancer. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Concentrations of AMH were measured in a single laboratory using the picoAMH ELISA. Multivariable-adjusted median (and interquartile range) AMH concentrations were calculated using quantile regression for several potential correlates. RESULT(S): Older women had significantly lower AMH concentrations (>/=40 [n = 444] vs. <35 years [n = 64], multivariable-adjusted median 0.73 ng/mL vs. 2.52 ng/mL). Concentrations of AMH were also significantly lower among women with earlier age at menarche (<12 [n = 96] vs. >/=14 years [n = 200]: 0.90 ng/mL vs. 1.12 ng/mL) and among current users of oral contraceptives (n = 27) compared with never or former users (n = 468) (0.36 ng/mL vs. 1.15 ng/mL). Race, body mass index, education, height, smoking status, parity, and menstrual cycle phase were not significantly associated with AMH concentrations. There were no significant associations between AMH concentrations and androgen or sex hormone-binding globulin concentrations or with factors related to blood collection (e.g., sample type, time, season, and year of blood collection). CONCLUSION(S): Among premenopausal women, lower AMH concentrations are associated with older age, a younger age at menarche, and currently using oral contraceptives, suggesting these factors are related to a lower number or decreased secretory activity of ovarian follicles.
PMCID:5426228
PMID: 28366409
ISSN: 1556-5653
CID: 2519352
Australian & New Zealand journal of obstetrics & gynaecology. 2017:57(1):99-104.DOI: 10.1111/ajo.12580
Placenta praevia and the risk of adverse outcomes during second trimester abortion: A retrospective cohort study
BACKGROUND: There are few reports in the literature of the risks associated with second trimester abortion in women with placenta praevia (PP). We hypothesise that PP increases the risk of complications. AIMS: We sought to determine if PP is associated with a higher risk of blood loss and blood transfusion at the time of dilation and evacuation (D&E). MATERIALS AND METHODS: The records of 612 consecutive women undergoing abortion at 15-24 weeks of gestation were reviewed. Participant characteristics, need for blood transfusion, estimated blood loss (EBL) during the abortion and other complications were compared between women with and without ultrasound-documented PP. RESULTS: Eighty-seven of 612 (14.2%, 95% CI 11.5-17.2%) women had ultrasound-documented PP. The rate of blood transfusion was 3.4 and 1.3% in the group with PP and without PP, respectively (adjusted relative risk (RR = 2.8, 95% CI 0.7-11.3). An estimated blood loss of 500 cc or greater during the D&E procedure was observed in 12.6% of women in the PP group compared with 4.2% of women in the group without PP (adjusted RR 3.1, 95% CI 1.4-6.8, P = 0.004). CONCLUSIONS: Second-trimester abortion in women with PP is associated with a higher risk of blood loss of 500 cc or greater. Our study represents a larger sample size of patients with PP undergoing second-trimester abortion than previously reported in the literature. Women with PP may have a higher estimated blood loss and may require access to blood transfusion.
PMID: 28251636
ISSN: 1479-828x
CID: 2471192
Factors associated with cesarean delivery rates: a single-institution experience
BACKGROUND: The aim of this study was to identify factors associated with variability in Cesarean delivery (CD) rates amongst providers at a single institution. METHODS: A retrospective cohort analysis was carried out on all births at NYU Langone Medical Center from 2005-2013. Data was collected for subjects and linked to diagnosis codes for singleton and twin deliveries. Descriptive characteristics were generated for all deliveries, and inferential analysis was performed including multiple covariates for singleton deliveries in the 2010-2013 cohort, including both univariate and multivariate regression analyses to identify factors associated with higher CD rates. RESULTS: 37,692 deliveries were identified at our institution during the study period, performed by 88 unique providers. The mean CD rate was 29.6%, with a range for individual physicians from 9.9% to 75.6%. In multivariate regression analysis, CD rate was directly correlated with average patient age, physician male gender, proportion of high-risk deliveries, and Maternal-Fetal Medicine specialty, and it was inversely correlated with total number of deliveries by physician and forceps delivery rate. There was no significant difference in CD rates between group and solo practices. Within the same group practice, each member's CD rate was strongly correlated with the average CD rate of the group. CONCLUSION: Our study demonstrates the wide range of CD rates for providers practicing within the same institution and reiterates the association of CD rates with patient age, high-risk pregnancy, and provider volume. Among operative vaginal deliveries, forceps delivery rate was associated with lower CD rates whereas vacuum delivery rate was not. Despite these findings, practice patterns within individual practices appear to contribute significantly to the wide range of CD rates.
PMCID:5401466
PMID: 28439421
ISSN: 2054-958x
CID: 2542452
Serum biomarkers of polyomavirus infection and risk of lung cancer in never smokers
BACKGROUND: Lung cancer in never smokers is a significant contributor of cancer mortality worldwide. In this analysis, we explored the role of nine human polyomaviruses, including JC virus (JCV), BK virus (BKV) and Merkel cell virus (MCV), in lung cancer development in never smokers as there are data to support that polyomaviruses are potentially carcinogenic in the human lung. METHODS: We used multiplex serology to detect serum antibodies to polyomaviruses in a nested case-control design combining lung cancer cases and controls from four cohort studies - NYU Women's Health Study (NYU-WHS), Janus Serum Bank, Shanghai Women's Health Study and Singapore Chinese Health Study (SCHS). RESULTS: The final analyses included 511 cases and 508 controls. Seroprevalence for each polyomavirus showed significant heterogeneity by study, but overall there were no statistically significant differences between cases and controls. In total, 69.1% of the cases and 68.7% of the controls were seropositive for JCV VP1 antibody. Seropositivity for BKV was higher at 89.0% in cases and 89.8% in controls and lower for MCV at 59.3% in cases and 61.6% in controls. Similar results were obtained after adding an additional retrospective case-control study (Xuanwei study) to the analysis. CONCLUSIONS: Our results do not support the hypothesis that seropositivity for polyomaviruses is associated with increased lung cancer risk in never smokers. Future research to evaluate relationship between polyomavirus infection and lung carcinogenesis should focus more on evaluating the presence of virus or viral nucleic acids (DNA or RNA) in lung tumour samples.British Journal of Cancer advance online publication, 15 September 2016; doi:10.1038/bjc.2016.285 www.bjcancer.com.
PMCID:5117783
PMID: 27632373
ISSN: 1532-1827
CID: 2247082
Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21
Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10-15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10-9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10-8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10-8). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10-4-2.0x10-3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
PMCID:5340084
PMID: 27579533
ISSN: 1949-2553
CID: 2232522
