Predictive model of IVF outcomes for polycystic ovarian morphology and polycystic ovary syndrome in GnRH antagonist protocol using AMH-MoM and ovarian sensitivity index.

AIM: To evaluate the relationship between AMH and ovarian response to controlled ovarian hyperstimulation in women with PCOM and PCOS. METHODS: A retrospective study was conducted on 559 patients who underwent the IVF-ET cycle between January 2018 and December 2022 at Gangnam Cha Hospital. Patients were divided into 3 groups matched for age and BMI: the PCOS group (n = 54), based on the new 2023 PCOS guideline; the PCOM group (n = 53); and the control group (n = 452) with normal ovaries. Serum AMH levels were converted to multiples of the median (MoM) for each corresponding age. The ovarian sensitivity index (OSI) was calculated as the number of retrieved oocytes divided by the total dose of recombinant FSH administered (per 1000 IU). RESULTS: There were significant differences in AMH-MoM value among women with PCOS [2.7 ± 1.3 (95% CI 2.3-3.0)], those with PCOM [2.0 ± 1.0 (95% CI 1.7-2.3)], and controls [0.8 ± 0.7 (95% CI 0.8-0.9)] (p < 0.001). The abortion rates in the normoovulatory, PCOM, and PCOS groups were 18.2%, 21.1%, and 25.0%, respectively. OSI and live birth rate were positively correlated with the AMH-MoM value in normoovulatory women (r = 0.389, p < 0.05, r = 0.122, p < 0.05), while no such correlation was observed in women with PCOM and PCOS. CONCLUSIONS: Ovarian response and live birth rate are possibly correlated with the AMH-MoM value in normoovulatory women, but not in women with PCOM and PCOS.

The Analysis of in vitro Fertilization Outcomes after Fertility-Preserving Therapy for Endometrial Hyperplasia or Carcinoma.

OBJECTIVES: This study aimed to evaluate the clinical efficacy of fertility-preserving therapy through in vitro fertilization (IVF) procedures in women who were pathologically diagnosed with endometrial hyperplasia or carcinoma. DESIGN: A retrospective cohort study on fertility-preserving therapy was conducted. Participants/Materials, Setting: A total of 82 women were enrolled who had simple endometrial hyperplasia (SH), complex hyperplasia (CH), complex atypical hyperplasia (CAH), and endometrioid endometrial carcinoma stage IA (EC IA) and underwent IVF at Gangnam CHA fertility center between January 2008 and December 2020. METHODS: The primary endpoints were oncologic outcomes and subsequent reproductive outcomes of patients who underwent fertility-preserving treatments analyzed by χ2 test or Fisher's exact test. RESULTS: Of the 82 patients, 33 had a cumulative clinical pregnancy (40.2%), and 25 had a cumulative live birth (30.5%) through IVF procedures following pathologic confirmation of complete remission or non-progressive status. The cumulative clinical pregnancy rates and live birth rates for SH were 50.0% and 30.0%, for CH were 37.8% and 28.9%, for CAH were 25.0% and 25.0%, and for EC were 38.5% and 38.5%, respectively. There were no significant differences in cumulative clinical pregnancy rates or live birth rates when comparing the four groups. There was a difference in endometrial thickness between medroxyprogesterone acetate (MPA) treatment group and intrauterine device (IUD) group (p = 0.036); however, there were no significant differences in clinical pregnancy rates among MPA, IUD, and MPA+IUD groups. LIMITATIONS: Because of the retrospective nature of the study, many factors relevant to the treatment decision were not strictly controlled. CONCLUSIONS: All endometrial hyperplasia and carcinoma groups had competent cumulative live birth rates by IVF procedures. There may be differences in endometrial thickness depending on the treatment methods, but this does not affect clinical pregnancy rates. Therefore, the fertility-preserving treatment for endometrial hyperplasia and carcinoma is a safe and feasible method that results in good IVF outcomes.

Correction: Demographic and Clinico-Epidemiological Features of Dengue Fever in Faisalabad, Pakistan.

[This corrects the article DOI: 10.1371/journal.pone.0267652.].

RNA sequencing-based transcriptome analysis of granulosa cells from follicular fluid: Genes involved in embryo quality during in vitro fertilization and embryo transfer.

BACKGROUND: Granulosa cells play an important role in folliculogenesis, however, the role of RNA transcripts of granulosa cells in assessing embryo quality remains unclear. Therefore, we aims to investigate that RNA transcripts of granulosa cells be used to assess the probability of the embryonic developmental capacity. METHODS: This prospective cohort study was attempted to figure out the probability of the embryonic developmental capacity using RNA sequencing of granulosa cells. Granulosa cells were collected from 48 samples in good-quality embryo group and 79 in only poor- quality embryo group from women undergoing in vitro fertilization and embryo transfer treatment. Three samples from each group were used for RNA sequencing. RESULTS: 226 differentially expressed genes (DEGs) were related to high developmental competence of embryos. Gene Ontology enrichment analysis indicated that these DEGs were primarily involved in biological processes, molecular functions, and cellular components. Additionally, pathway analysis revealed that these DEGs were enriched in 13 Kyoto Encyclopedia of Genes and Genomes pathways. Reverse transcription quantitative polymerase chain reaction verified the differential expression of the 13 selected DEGs. Among them,10 genes were differently expressed in the poor-quality embryo group compared to good-quality embryo group, including CSF1R, CTSH, SERPINA1, CYP27A1, ITGB2, IL1ß, TNF, TAB1, BCL2A1, and CCL4. CONCLUSIONS: RNA sequencing data provide the support or confute granulosa expressed genes as non-invasive biomarkers for identifying the embryonic developmental capacity.

Development and Validation of a Nursing Work Interruption Scale.

Work interruption disturbs nurses' flow of thinking, diminishes work efficiency, induces burnout, and causes errors that can threaten patients' lives. Therefore, it is important to identify the causes and measure the extent of work interruption. This study developed a self-report scale and established its validity and reliability for use in hospital settings. Through literature review and in-depth interviews with nurses, we identified two components and developed 25 preliminary items. These items were reviewed by nursing experts for content validity and pilot tested among 20 hospital nurses; subsequently, a 16-item preliminary instrument was finalized. A total of 359 questionnaires were included in the final analysis, and exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were performed. Two factors and 12 items were derived from two rounds of EFA, with a cumulative percentage of variance of 55.73%. Construct validity was established through CFA. The predictive validity and internal consistency reliability of the developed scale were also established. Thus, the 12-item Work Interruption Measurement Scale for Nurses comprising two domains (human and environmental factors) was developed. This scale can be useful in assessing work interruption experienced by nurses and for developing and assessing the effectiveness of interventions pertaining to nurses' work interruption.

Preimplantation genetic testing for aneuploidy: The management of mosaic embryos.

As the resolution and accuracy of diagnostic techniques for preimplantation genetic testing for aneuploidy (PGT-A) are improving, more mosaic embryos are being identified. Several studies have provided evidence that mosaic embryos have reproductive potential for implantation and healthy live birth. Notably, mosaic embryos with less than 50% aneuploidy have yielded a live birth rate similar to euploid embryos. This concept has led to a major shift in current PGT-A practice, but further evidence and theoretically relevant data are required. Proper guidelines for selecting mosaic embryos suitable for transfer will reduce the number of discarded embryos and increase the chances of successful embryo transfer. We present an updated review of clinical outcomes and practice recommendations for the transfer of mosaic embryos using PGT-A.

Freeze all-first versus biopsy-first: A retrospective analysis of frozen blastocyst transfer cycles with preimplantation genetic testing for aneuploidy.

Potential use of preimplantation genetic testing for aneuploidy (PGT-A) is increasing. Patients who have excess embryos cryopreserved at the blastocyst stage may desire PGT-A but there is little data available on options for these patients. We compared the efficacy and safety of the timing on the cryopreservation and trophectoderm(TE) biopsy for preimplantation genetic testing for aneuploidy (PGT-A) program associated with the better outcomes after frozen blastocyst transfer. Retrospective analysis of patients who underwent PGT-A cycles from January 2016 to December 2019 was carried out. 2684 blastocysts from cycles were subjected to TE biopsy for performing array comparative genomic hybridization test and Next-generation sequencing. All cycles were divided into two according to the timing of biopsy: biopsy-first (n = 211 cases/ 232 transfers) versus freeze all-first (n = 327 cases/ 415 transfers). In the biopsy-first group, embryos were cultured to expanded blastocyst and proceed to TE biopsy on day 5 or day 6 followed by cryopreservation. In the freeze all-first, blastocysts were vitrified and warmed before biopsy. Rates of clinical pregnancy (52.3% vs. 38.7%, P = 0.09) and ongoing pregnancy (44.3% vs. 34.5%, P = 0.07) in biopsy-first were significantly higher than those in freeze all-first. Biopsy-first showed comparable miscarriage rate with freeze all-first (15.2% (33/217) vs.11.1% (10/90), respectively). Rate ratio (RR) for clinical pregnancy was lower in freeze all-first group (adjusted RR = 0.78, 95% confidence interval: 0.65, 0.93). The RRs for miscarriage and live birth was also lower but it did not reach statistical significance. Our result supported performing TE biopsy of blastocyst for PGT-A before vitrification and warming. This finding would contribute to more evidence-based decision in PGT-A cycles.

High-risk endometrial cancer proteomic profiling reveals that FBXW7 mutation alters L1CAM and TGM2 protein levels.

BACKGROUND: FBXW7 is frequently somatically mutated in grade 3 endometrioid endometrial cancers (G3EECs) and serous endometrial cancers (SECs), which are high-risk cancers associated with poor outcomes and in need of novel treatment options. The aim of this study was to determine the proteomic effects of 3 FBXW7 mutations in high-risk endometrial cancers (ECs). METHODS: Clustered regularly interspaced short palindromic repeats (CRISPR) editing was used to generate 3 HEC-50B G3EEC derivative cell lines, each of which harbored 1 FBXW7 mutation, and to revert an endogenous FBXW7 mutation in HEC-1-B grade 2 endometrioid endometrial cancer (G2EEC) cells to the wild-type genotype. Proteomic profiling based on liquid chromatography-tandem mass spectrometry was used to determine protein differences between the HEC-50B derivative lines and parental cells. Western blot analysis was performed to assess differential protein levels of CRISPR-edited derivative lines originating from HEC-50B, ARK1 (SEC), ARK4 (SEC), HEC-1-B, and JHUEM-1 (G2EEC) cell lines in comparison with parental cells. RESULTS: Results of this study demonstrated the effects of FBXW7 mutations on the proteome and phosphoproteome of HEC-50B G3EEC cells and highlighted proteins that also exhibited altered levels in FBXW7-mutated ARK1 and ARK4 SEC cells, including 2 potentially druggable proteins: L1 cell adhesion molecule (L1CAM) and transglutaminase 2 (TGM2). Furthermore, they demonstrated that reversion of an endogenous FBXW7 mutation to the wild-type genotype in JHUEM-1 and HEC-1-B G2EEC cells resulted in decreased L1CAM and TGM2 protein levels. CONCLUSIONS: L1CAM and TGM2 protein levels are affected by FBXW7 mutations in ECs.

The Ratio of Mitochondrial DNA to Genomic DNA Copy Number in Cumulus Cell May Serve as a Biomarker of Embryo Quality in IVF Cycles.

Previous studies have reported that the mitochondrial DNA (mtDNA) contents of cumulus cells (CCs) in ovarian follicular fluid are correlated with embryo quality. Quantification of mtDNA CCs has been suggested as a biomarker of embryo viability. The aim of this study was to determine the relationship between mitochondrial DNA (mtDNA)/genomic DNA (gDNA) ratio in CCs and IVF outcomes such as fertilization rates and embryo quality in infertile women. This is an observational study on 144 cumulus-oocyte complexes obtained from 144 patients undergoing IVF-intracytoplasmic sperm injection (ICSI) at a single fertility center. The CCs in ovarian follicular fluid from patients undergoing IVF-ICSI were collected by ovum pick-up. A relative copy number quantification was used to determine mtDNA/gDNA ratio. Quantitative real-time PCR for various markers (ß2M and mtMinArc gene) was used to determine average mtDNA/gDNA ratio of CCs. Investigation of the correlation between mtDNA/gDNA ratio in CCs and IVF outcomes showed no statistically significant correlation between the mtDNA/gDNA ratio in CCs and fertilization rates. However, mtDNA/gDNA ratio and embryo quality showed a statistically significant positive correlation. A significantly higher mtDNA/gDNA ratio was observed in the good quality embryo group compared with the poor quality embryo group (P < 0.05). In addition, the mtDNA/gDNA ratio showed negative correlation with the patient's age (correlation coefficient= -0.228, P < 0.05). Results of this study demonstrate a negative correlation of mtDNA/gDNA ratio in CCs with patient's age, and a low copy number of mtDNA in CCs may have adverse effects on embryo quality in IVF cycles. These results suggest that the ratio of mtDNA/gDNA in CCs may serve as a biomarker in predicting IVF outcomes.

Peripheral blood natural killer cell proportion and ovarian function in women with recurrent implantation failure.

Current knowledge of the association between peripheral natural killer (NK) cell proportion and ovarian function in reproductive-age women is limited. We explored the association between NK cell proportion and ovarian function in women who underwent in-vitro fertilization (IVF) treatment. This was a retrospective cohort study using the data of 20-44-year-old women with recurrent implantation failure (RIF) who were tested for NK cell proportion and anti-Müllerian hormone (AMH). Indicators of ovarian function included AMH, observed-to-(age-appropriate) reference AMH ratio, high FSH, peak E2 and total number of oocytes during the first IVF cycle following the test. We used different model specification controlling for women's age, and body mass index. Among a total of 936 women, majority showed lower AMH compared to age-appropriate level. Average NK cell proportion was 13.5 ± 5.7%. Number of oocytes showed positive association with NK cell (ß = 0.040, p = .025). In the subgroup with NK ≥ 18%, NK cell proportion was negatively associated with AMH (-0.106, p = .012), AMH ratio (-0.049, p = .014) and number of oocytes (-0.021, p < .001) while the associations with others remain close to null. High NK cell proportion may be harmful to ovarian reserve or function.

Androgen receptor with short polyglutamine tract preferably enhances Wnt/ß-catenin-mediated prostatic tumorigenesis.

Polyglutamine (polyQ) tract polymorphism within the human androgen receptor (AR) shows population heterogeneity. African American men possess short polyQ tracts significantly more frequently than Caucasian American men. The length of polyQ tracts is inversely correlated with the risk of prostate cancer, age of onset, and aggressiveness at diagnosis. Aberrant activation of Wnt signaling also reveals frequently in advanced prostate cancer, and an enrichment of androgen and Wnt signaling activation has been observed in African American patients. Here, we assessed aberrant expression of AR bearing different polyQ tracts and stabilized ß-catenin in prostate tumorigenesis using newly generated mouse models. We observed an early onset oncogenic transformation, accelerated tumor cell growth, and aggressive tumor phenotypes in the compound mice bearing short polyQ tract AR and stabilized ß-catenin. RNA sequencing analysis showed a robust enrichment of Myc-regulated downstream genes in tumor samples bearing short polyQ AR versus those with longer polyQ tract AR. Upstream regulator analysis further identified Myc as the top candidate of transcriptional regulators in tumor cells from the above mouse samples with short polyQ tract AR and ß-catenin. Chromatin immunoprecipitation analyses revealed increased recruitment of ß-catenin and AR on the c-Myc gene regulatory locus in the tumor tissues expressing stabilized ß-catenin and shorter polyQ tract AR. These data demonstrate a promotional role of aberrant activation of Wnt/ß-catenin in combination with short polyQ AR expression in prostate tumorigenesis and suggest a potential mechanism underlying aggressive prostatic tumor development, which has been frequently observed in African American patients.

Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration.

Prostate embryonic development, pubertal and adult growth, maintenance, and regeneration are regulated through androgen signaling-mediated mesenchymal-epithelial interactions. Specifically, the essential role of mesenchymal androgen signaling in the development of prostate epithelium has been observed for over 30 years. However, the identity of the mesenchymal cells responsible for this paracrine regulation and related mechanisms are still unknown. Here, we provide the first demonstration of an indispensable role of the androgen receptor (AR) in sonic hedgehog (SHH) responsive Gli1-expressing cells, in regulating prostate development, growth, and regeneration. Selective deletion of AR expression in Gli1-expressing cells during embryogenesis disrupts prostatic budding and impairs prostate development and formation. Tissue recombination assays showed that urogenital mesenchyme (UGM) containing AR-deficient mesenchymal Gli1-expressing cells combined with wildtype urogenital epithelium (UGE) failed to develop normal prostate tissue in the presence of androgens, revealing the decisive role of AR in mesenchymal SHH responsive cells in prostate development. Prepubescent deletion of AR expression in Gli1-expressing cells resulted in severe impairment of androgen-induced prostate growth and regeneration. RNA-sequencing analysis showed significant alterations in signaling pathways related to prostate development, stem cells, and organ morphogenesis in AR-deficient Gli1-expressing cells. Among these altered pathways, the transforming growth factor ß1 (TGFß1) pathway was up-regulated in AR-deficient Gli1-expressing cells. We further demonstrated the activation of TGFß1 signaling in AR-deleted prostatic Gli1-expressing cells, which inhibits prostate epithelium growth through paracrine regulation. These data demonstrate a novel role of the AR in the Gli1-expressing cellular niche for regulating prostatic cell fate, morphogenesis, and renewal, and elucidate the mechanism by which mesenchymal androgen-signaling through SHH-responsive cells elicits the growth and regeneration of prostate epithelium.

Aberrant activation of hepatocyte growth factor/MET signaling promotes ß-catenin-mediated prostatic tumorigenesis.

Co-occurrence of aberrant hepatocyte growth factor (HGF)/MET proto-oncogene receptor tyrosine kinase (MET) and Wnt/ß-catenin signaling pathways has been observed in advanced and metastatic prostate cancers. This co-occurrence positively correlates with prostate cancer progression and castration-resistant prostate cancer development. However, the biological consequences of these abnormalities in these disease processes remain largely unknown. Here, we investigated the aberrant activation of HGF/MET and Wnt/ß-catenin cascades in prostate tumorigenesis by using a newly generated mouse model in which both murine Met transgene and stabilized ß-catenin are conditionally co-expressed in prostatic epithelial cells. These compound mice displayed accelerated prostate tumor formation and invasion compared with their littermates that expressed only stabilized ß-catenin. RNA-Seq and quantitative RT-PCR analyses revealed increased expression of genes associated with tumor cell proliferation, progression, and metastasis. Moreover, Wnt signaling pathways were robustly enriched in prostate tumor samples from the compound mice. ChIP-qPCR experiments revealed increased ß-catenin recruitment within the regulatory regions of the Myc gene in tumor cells of the compound mice. Interestingly, the occupancy of MET on the Myc promoter also appeared in the compound mouse tumor samples, implicating a novel role of MET in ß-catenin-mediated transcription. Results from implanting prostate graft tissues derived from the compound mice and controls into HGF-transgenic mice further uncovered that HGF induces prostatic oncogenic transformation and cell growth. These results indicate a role of HGF/MET in ß-catenin-mediated prostate cancer cell growth and progression and implicate a molecular mechanism whereby nuclear MET promotes aberrant Wnt/ß-catenin signaling-mediated prostate tumorigenesis.

Association of Early Menarche with Adolescent Health in the Setting of Rapidly Decreasing Age at Menarche.

STUDY OBJECTIVE: This study aimed to investigate the association between age at menarche (AAM) and adverse health indicators in adolescent girls. DESIGN: A retrospective cohort study. SETTING: Population-based survey data. PARTICIPANTS: A total of 319,437 female participants aged 12-18 years from the Korea Youth Risk Behaviour Web-based Survey. INTERVENTIONS AND MAIN OUTCOME MEASURES: We assessed associations between AAM (categorized as ≤10, 11, and ≥12) and health indicators (poor self-rated health, high psychological stress, unhappiness, sexual initiation, and pregnancy). Covariates were individual-level (bodyweight, living with family, parent's education, household wealth, and presence of parents and siblings) and community-level factors (year of birth, single-sex education and level of school, urbanization level of school area, year of survey, and regional deprivation). Odds ratios (ORs) for each adverse health indicator were examined by each AAM group using multivariable regression analyses. For pregnancy, we calculated relative risks (RRs) using a log-binomial regression model. RESULTS: Age at menarche was <12 in 42% of our study population. Nearly one-half of the girls born in the early 2000s went through menarche before the age of 12 years, whereas only one-third of girls born in the early 1990s went through menarche before the age of 12 years. Girls who experienced menarche at age ≤10 or age 11 years were more likely to show self-rated poor health (AAM ≤ 10: OR, 1.28; 95% confidence intervals [CI], 1.22-1.34; AAM = 11: OR, 1.16; 95% CI, 1.12-1.21), high stress (OR, 1.19; 95% CI, 1.14-1.23, and OR, 1.10; 95% CI, 1.06-1.14), and sexual initiation (OR, 2.21; 95% CI, 2.05-2.38, and OR, 1.32; 95% CI, 1.23-1.41) compared to those with AAM ≥12 years when data were adjusted for all covariates. AAM ≤10 years was associated with consistently higher odds for poor health than AAM ≥12 years. The ORs of sexual initiation increased with earlier AAM. Risk of pregnancy was similar across AAM groups when individual- and community-level covariates were controlled for. CONCLUSION: Early menarche, defined as <12 years, can be still a useful indicator in adolescent health interventions to identify high-risk groups in the setting of declining AAM.

A Novel Mutation in an NPXY Motif of ß Integrin Reveals Phenotypes Similar to him-4/hemicentin.

Integrin, an αß heterodimeric cell surface receptor for the extracellular matrix (ECM), carries two tyrosine phosphorylation motifs in the cytoplasmic tail of the ß subunit. NPXY (Asn-Pro-x-Tyr) is a conserved tyrosine phosphorylation motif that binds to the phospho-tyrosine binding (PTB) domain. We generated a tyrosine to glutamic acid (E) mutation to modify tyrosine (Y) into a negatively charged amino NPXY in the ßpat-3 integrin of Caenorhabditis elegans. The transgenic rescue animal displayed defects in gonad migration and tail morphology. Also, the mutant animals produced a high number of males, suggesting that the Y to E mutation in ßpat-3 integrin causes a phenotype similar to that of Him mutant. Further analyses revealed that males of pat-3(Y804E) and him-4/hemicentin share additional phenotypes such as abnormal gonad and unsuccessful mating. A pat-3 transgenic rescue mutant with a non-polar phenylalanine (F) in NPXY, pat-3(Y792/804F), suppressed the high male number, defective mating, inviable zygote, and the abnormal gonad of him-4 mutants, indicating that Y to F mutation in both NPXY motifs suppressed the him-4 phenotypes. This finding supports the idea that the ECM determines the activation state in integrin NPXY motifs; him-4/hemicentin may directly or indirectly interact with integrins and maintain the NPXY non-charged. Our findings provide new insight into a suppressive role of an ECM molecule in integrin NPXY phosphorylation.

The comprehensive role of E-cadherin in maintaining prostatic epithelial integrity during oncogenic transformation and tumor progression.

E-cadherin complexes with the actin cytoskeleton via cytoplasmic catenins and maintains the functional characteristics and integrity of the epithelia in normal epithelial tissues. Lost expression of E-cadherin disrupts this complex resulting in loss of cell polarity, epithelial denudation and increased epithelial permeability in a variety of tissues. Decreased expression of E-cadherin has also been observed in invasive and metastatic human tumors. In this study, we investigated the effect of E-cadherin loss in prostatic epithelium using newly developed genetically engineered mouse models. Deletion of E-cadherin in prostatic luminal epithelial cells with modified probasin promoter driven Cre (PB-Cre4) induced the development of mouse prostatic intraepithelial neoplasia (PIN). An increase in levels of cytoplasmic and nuclear ß-catenin appeared in E-cadherin deleted atypical cells within PIN lesions. Using various experimental approaches, we further demonstrated that the knockdown of E-cadherin expression elevated free cytoplasmic and nuclear ß-catenin and enhanced androgen-induced transcription and cell growth. Intriguingly, pathological changes representing prostatic epithelial cell denudation and increased apoptosis accompanied the above PIN lesions. The essential role of E-cadherin in maintaining prostatic epithelial integrity and organization was further demonstrated using organoid culture approaches. To directly assess the role of loss of E-cadherin in prostate tumor progression, we generated a new mouse model with bigenic Cdh1 and Pten deletion in prostate epithelium. Early onset, aggressive tumor phenotypes presented in the compound mice. Strikingly, goblet cell metaplasia was observed, intermixed within prostatic tumor lesions of the compound mice. This study provides multiple lines of novel evidence demonstrating a comprehensive role of E-cadherin in maintaining epithelial integrity during the course of prostate oncogenic transformation, tumor initiation and progression.

Obstetrical, neonatal, and long-term outcomes of children conceived from in vitro matured oocytes.

OBJECTIVE: To investigate the obstetrical, neonatal, and long-term outcomes of in vitro maturation (IVM) compared with conventional in vitro fertilization (IVF) in women with polycystic ovarian syndrome (PCOS). DESIGN: Matched retrospective case-control study. SETTING: University fertility clinic. PATIENT(S): One hundred eighty-four patients undergoing IVM were compared with 366 patients undergoing conventional IVF. All had PCOS and were matched for patient age, gestational age at birth, and the number of fetuses. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Obstetrics, neonatal outcomes, and childhood medical problems and development. RESULT(S): Women's mean age at oocytes retrieval was 32.6 ± 2.9 years. Children's mean age was 7.5 ± 2.3 years. There were no differences in the frequency of obstetrical and neonatal outcomes between the two groups. No difference was found in birth weights between the two groups. The incidence of congenital anomalies was similar between the groups (4.3% in IVM group vs. 4.1% in IVF group). No significant difference was observed between the two groups in the frequency and duration of hospitalization during childhood. Growth developmental status of both groups was within normal range. CONCLUSION(S): In a matched setting between IVM and IVF babies born from women with PCOS, no significant increased risk associated with IVM was been identified after a mean follow-up of 7.5 years.

Loss of the tumor suppressor, Tp53, enhances the androgen receptor-mediated oncogenic transformation and tumor development in the mouse prostate.

Recent genome analysis of human prostate cancers demonstrated that both AR gene amplification and TP53 mutation are among the most frequently observed alterations in advanced prostate cancer. However, the biological role of these dual genetic alterations in prostate tumorigenesis is largely unknown. In addition, there are no biologically relevant models that can be used to assess the molecular mechanisms for these genetic abnormalities. Here, we report a novel mouse model, in which elevated transgenic AR expression and Trp53 deletion occur simultaneously in mouse prostatic epithelium to mimic human prostate cancer cells. These compound mice developed an earlier onset of high-grade prostatic intraepithelial neoplasia and accelerated prostate tumors in comparison with mice harboring only the AR transgene. Histological analysis showed prostatic sarcomatoid and basaloid carcinomas with massive squamous differentiation in the above compound mice. RNA-sequencing analyses identified a robust enrichment of the signature genes for human prostatic basal cell carcinomas in the above prostate tumors. Master regulator analysis revealed SOX2 as a transcriptional regulator in prostatic basal cell tumors. Elevated expression of SOX2 and its downstream target genes were detected in prostatic tumors of the compound mice. Chromatin immunoprecipitation analyses implicate a coregulatory role of AR and SOX2 in the expression of prostatic basal cell signature genes. Our data demonstrate a critical role of SOX2 in prostate tumorigenesis and provide mechanistic insight into prostate tumor aggressiveness and progression mediated by aberrant AR and p53 signaling pathways.