BACKGROUND Endometriosis, defined as the presence of ectopic endometrial stroma and epithelium, affects approximately 10% of reproductive-age women and can cause pelvic pain and infertility. Endometriotic lesions are considered to be benign inflammatory lesions but have cancerlike features such as local invasion and resistance to apoptosis. METHODS We analyzed deeply infiltrating endometriotic lesions from 27 patients by means of exomewide sequencing (24 patients) or cancer-driver targeted sequencing (3 patients). Mutations were validated with the use of digital genomic methods in micro-dissected epithelium and stroma. Epithelial and stromal components of lesions from an additional 12 patients were analyzed by means of a droplet digital polymerase-chain-reaction (PCR) assay for recurrent activating KRAS mutations. RESULTS Exome sequencing revealed somatic mutations in 19 of 24 patients (79%). Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis. The likelihood of driver genes being affected at this rate in the absence of selection was estimated at P = 0.001 (binomial test). Targeted sequencing and a droplet digital PCR assay identified KRAS mutations in 2 of 3 patients and 3 of 12 patients, respectively, with mutations in the epithelium but not the stroma. One patient harbored two different KRAS mutations, c.35G→T and c.35G→C, and another carried identical KRAS c.35G→A mutations in three distinct lesions. CONCLUSIONS We found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions.
Objective To estimate the total annual societal cost of uterine fibroids in the United States, based on direct and indirect costs, including associated obstetric complications. Study Design A systematic review of the literature was conducted to estimate the number of women seeking treatment for symptomatic fibroids annually, the costs of medical and surgical treatment, work lost and obstetric complications attributable to fibroids. Total annual costs were converted to 2010 U.S. dollars. A sensitivity analysis was performed. Results The estimated annual direct costs (surgery, hospital admissions, outpatient visits, medications) were $4.1 to $9.4 billion. Estimated lost work costs ranged from $1.55 to $17.2 billion annually. Obstetric outcomes attributed to fibroids resulted in a cost of $238 million to $7.76 billion annually. Uterine fibroids were estimated to cost the US $5.9 to $34.4 billion annually. Conclusions Obstetric complications associated with fibroids contributed significantly to their economic burden. Lost work costs may account for the largest proportion of societal costs due to fibroids.
H‐2RIIBP (RXR beta) is a member of the nuclear hormone receptor superfamily that activates transcription of MHC class I genes in response to retinoic acid (RA). Using chemical cross‐linking, co‐immunoprecipitation, gel mobility shift and streptavidin‐biotin DNA precipitation assays, we show that H‐2RIIBP formed heterodimers with thyroid hormone (T3) and RA receptors (T3R alpha and RAR alpha). H‐2RIIBP heterodimer formation required a conserved sub‐domain of its C‐terminal region, occurred independently of target DNA and was much more efficient than either T3R alpha/RAR alpha heterodimer or H‐2RIIBP homodimer formation. Heterodimers displayed enhanced binding to target DNA elements and contacted DNA in a manner distinct from that of homodimers. A functional role for heterodimers in vivo was demonstrated by synergistic enhancement of MHC class I transcription following co‐transfection of H‐2RIIBP with T3R alpha or RAR alpha. We provide biochemical evidence that H‐2RIIBP formed heterodimers with several naturally occurring nuclear proteins. The results suggest that H‐2RIIBP, by virtue of its ability to heterodimerize, enhances combinatorial diversity and versatility in gene regulation mediated by nuclear hormone receptors.
Objective: To summarize current understanding of the effects of novel and prior coronaviruses on human reproduction, specifically male and female gametes, and in pregnancy. Design: Review of English publications in PubMed and Embase to April 6, 2020. Method(s): Articles were screened for reports including coronavirus, reproduction, pathophysiology, and pregnancy. Intervention(s): None. Main Outcome Measure(s): Reproductive outcomes, effects on gametes, pregnancy outcomes, and neonatal complications. Result(s): Seventy-nine reports formed the basis of the review. Coronavirus binding to cells involves the S1 domain of the spike protein to receptors present in reproductive tissues, including angiotensin-converting enzyme-2 (ACE2), CD26, Ezrin, and cyclophilins. Severe Acute Respiratory Syndrome Coronavirus 1 (SARS-CoV-1) may cause severe orchitis leading to germ cell destruction in males. Reports indicate decreased sperm concentration and motility for 72-90 days following Coronavirus Disease 2019 (COVID-19) infection. Gonadotropin-dependent expression of ACE2 was found in human ovaries, but it is unclear whether SARS-Coronavirus 2 (CoV-2) adversely affects female gametogenesis. Evidence suggests that COVID-19 infection has a lower maternal case fatality rate than SARS or Middle East respiratory syndrome (MERS), but anecdotal reports suggest that infected, asymptomatic women may develop respiratory symptoms postpartum. Coronavirus Disease 2019 infections in pregnancy are associated with preterm delivery. Postpartum neonatal transmission from mother to child has been reported. Conclusion(s): Coronavirus Disease 2019 infection may affect adversely some pregnant women and their offspring. Additional studies are needed to assess effects of SARS-CoV-2 infection on male and female fertility. (Fertil Steril Ò 2020;113:1140-9. Ó2020 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo.
Objective To review currently available literature on the association between imprinting disorders (Beckwith-Wiedemann syndrome [BWS], Angleman syndrome [AS] and retinoblastoma) and assisted reproductive technologies (ART) in humans. Design Publications related to imprinting/epigenetic disorders including BWS, AS and retinoblastoma with ART and articles publishing outcome of ART, including IVF and ICSI, from July 1978 to February 2008 were identified using PubMed, Medline and EMBASE. Result(s) Considerable evidence in animal studies has demonstrated alteration in gene imprinting of embryos cultured in vitro. Publications from Europe, America and Australia have suggested an association between ART and BWS. Importantly, more than 90% of BWS in children born after ART had imprinting defects, compared to 40–50% of BWS in children conceived without ART. Moreover, there have been other reports suggesting an association between AS and ART. The majority of children with AS born after ART had an imprinting defect as the underlying etiology, specifically loss of methylation of the maternal allele. There was a single report suggesting an increased incidence of retinoblastoma in children conceived with ART. Conclusion(s) Because the absolute incidence of imprinting disorders is very small (< 1:12,000 births), routine screening for imprinting disorders in children conceived with ART is not recommended. Additional large cohort studies of children born after ART are needed to determine whether there is a genuine association between ART and imprinting disorders.
Arrays offer large-scale screening of mRNA expression, which will help us differentiate between the genes and metabolic pathways necessary for leiomyoma growth and those regulating myometrial contractions.
This article will discuss some recent insights based on our microarray studies that have emphasized the role the extracellular matrix, transforming growth factor beta, and collagen structure in fibroid formation. These studies led to appreciation of molecular similarities between fibroids and keloids. Collectively, these observations suggest a model of fibroid development based on an abnormal response to tissue repair, resulting in disordered healing and formation of an altered extracellular matrix.
Uterine leiomyomas are prevalent estrogen-responsive clonal tumors, but the specific genetic alterations that contribute to their development have not been elucidated. To identify genes involved in the formation of leiomyomas, we used global expression profiling to compare clonal tumors with normal myometrium. Contrary to expectation, genes involved in estrogen action were not differentially expressed between leiomyoma and normal myometrium. Genes encoding extracellular-matrix proteins were prominently featured, suggesting their involvement in formation of a myofibroblast phenotype. Analysis of the extracellular matrix in the leiomyomas revealed a disordered collagen fibril orientation. Expression of the collagen-binding protein dermatopontin was found to be consistently decreased in leiomyoma by both reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time RT-PCR (mean underexpression = 9.41-fold) regardless of leiomyoma size, leiomyoma location, patient race, and patient age. This expression pattern was observed in 11 subjects and a total of 23 leiomyoma:myometrium pairs. Decreased expression of dermatopontin was also associated with keloid formation, a fibrotic disease that shares epidemiologic similarities with leiomyoma. Immunohistochemical studies of leiomyomas and keloids demonstrated reduced levels of dermatopontin in both tissues. In addition, ultrastructural analysis revealed that the orientation of the collagen fibrils in the keloid tissues strongly resembled that in the leiomyomas. Reduction in dermatopontin was associated with an increase in transforming growth factor-beta3 (TGFB3) mRNA levels in leiomyomas, whereas other genes involved in dermatopontin signaling were not differentially expressed. These findings suggest that leiomyoma development involves a myofibroblast cell phenotype characterized by dysregulation of genes encoding extracellular-matrix proteins. In particular, decreased expression of dermatopontin represents a molecular link between the leiomyoma and keloid phenotypes.
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