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Cell Death Discovery Jun 2024As the mean age of first-time mothers increases in the industrialized world, inquiries into causes of human reproductive senescence have followed. Rates of ovulatory...
As the mean age of first-time mothers increases in the industrialized world, inquiries into causes of human reproductive senescence have followed. Rates of ovulatory dysfunction and oocyte aneuploidy parallel chronological age, but poor reproductive outcomes in women older than 35 years are also attributed to endometrial senescence. The current studies, using primary human endometrial stromal cell (ESC) cultures as an in vitro model for endometrial aging, characterize the proinflammatory cytokine, IL-1β-mediated and passage number-dependent effects on ESC phenotype. ESC senescence was accelerated by incubation with IL-1β, which was monitored by RNA sequencing, ELISA, immunocytochemistry and Western blotting. Senescence associated secreted phenotype (SASP) proteins, IL-1β, IL-6, IL-8, TNF-α, MMP3, CCL2, CCL5, and other senescence-associated biomarkers of DNA damage (p16, p21, HMGB1, phospho-γ-histone 2 A.X) were noted to increase directly in response to 0.1 nM IL-1β stimulation. Production of the corresponding SASP proteins increased further following extended cell passage. Using enzyme inhibitors and siRNA interference, these effects of IL-1β were found to be mediated via the c-Jun N-terminal kinase (JNK) signaling pathway. Hormone-induced ESC decidualization, classical morphological and biochemical endocrine responses to estradiol, progesterone and cAMP stimulation (prolactin, IGFBP-1, IL-11 and VEGF), were attenuated pari passu with prolonged ESC passaging. The kinetics of differentiation responses varied in a biomarker-specific manner, with IGFBP-1 and VEGF secretion showing the largest and smallest reductions, with respect to cell passage number. ESC hormone responsiveness was most robust when limited to the first six cell passages. Hence, investigation of ESC cultures as a decidualization model should respect this limitation of cell aging. The results support the hypotheses that "inflammaging" contributes to endometrial senescence, disruption of decidualization and impairment of fecundity. IL-1β and the JNK signaling pathway are pathogenetic targets amenable to pharmacological correction or mitigation with the potential to reduce endometrial stromal senescence and enhance uterine receptivity.
PubMed: 38879630
DOI: 10.1038/s41420-024-02048-6 -
Reproductive Biology and Endocrinology... Jun 2024
PubMed: 38879543
DOI: 10.1186/s12958-024-01244-4 -
Cell Communication and Signaling : CCS Jun 2024Sex-specific gonadal differentiation is directed by complex signalling promoting development in either male or female direction, while simultaneously inhibiting the...
Sex-specific gonadal differentiation is directed by complex signalling promoting development in either male or female direction, while simultaneously inhibiting the opposite pathway. In mice, the WNT/β-catenin pathway promotes ovarian development and the importance of actively inhibiting this pathway to ensure normal testis development has been recognised. However, the implications of alterations in the tightly regulated WNT/β-catenin signalling during human fetal gonad development has not yet been examined in detail. Thus, the aim of this study was to examine the consequences of dysregulating the WNT/β-catenin signalling pathway in the supporting cell lineage during sex-specific human fetal gonad development using an established and extensively validated ex vivo culture model. Inhibition of WNT/β-catenin signalling in human fetal ovary cultures resulted in only minor effects, including reduced secretion of RSPO1 and reduced cell proliferation although this was not consistently found in all treatment groups. In contrast, promotion of WNT/β-catenin signalling in testes severely affected development and function. This included disrupted seminiferous cord structures, reduced cell proliferation, reduced expression of SOX9/AMH, reduced secretion of Inhibin B and AMH as well as loss of the germ cell population. Additionally, Leydig cell function was markedly impaired with reduced secretion of testosterone, androstenedione and INSL3. Together, this study suggests that dysregulated WNT/β-catenin signalling during human fetal gonad development severely impairs testicular development and function. Importantly, our study highlights the notion that sufficient inhibition of the opposite pathway during sex-specific gonadal differentiation is essential to ensure normal development and function also applies to human fetal gonads.
Topics: Humans; Male; Wnt Signaling Pathway; Testis; Female; Sex Differentiation; Fetus; Cell Differentiation; Cell Proliferation; beta Catenin; Leydig Cells; Ovary
PubMed: 38879537
DOI: 10.1186/s12964-024-01704-9 -
BMC Pregnancy and Childbirth Jun 2024To evaluate the potential connections between marginal cord insertion during the first trimester and furcate cord insertion later in pregnancy.
OBJECTIVES
To evaluate the potential connections between marginal cord insertion during the first trimester and furcate cord insertion later in pregnancy.
METHODS
This is a prospective study of screening data on the cord insertion site in 3178 singleton pregnancies. The cord insertion site was examined in two stages. The first stage was screening for the cord insertion site between 10-13 weeks of gestation, the purpose is to determine the category of umbilical cord insertion. The second stage, performed at 22-28 weeks of gestation, was to follow up on the relationship between the cord insertion site and the placenta and to identify any changes in the category of umbilical cord insertion. This was performed to diagnose or exclude furcate cord insertion by identifying whether the umbilical cord trunk separated or branched before it reached the placenta. Factors influencing progression to furcate cord insertion and perinatal complications were assessed.
RESULTS
Fourteen cases (0.44%) with progression to furcate cord insertion, all of which showed marginal cord insertion on ultrasound in the first trimester (p < 0.001). without progression to furcate cord insertion, there were no changes in the category of umbilical cord insertion in 3050 cases (96.40%) compared to the early pregnancy. 114 cases (3.60%) with changes in the category of umbilical cord insertion that was not consistent with furcate cord insertion. A total of 14 cases progressed to furcate cord insertion, all showed the cord insertion site were in close proximity, and 11 (78.57%) cases showed a low insertion site (p < 0.001). Regarding the choice of mode of delivery, elective caesarean delivery was done in 8/14 (57.14%). The incidences of spontaneous vaginal delivery were 5/14 (35.71%) (p < 0.001). One (7.14%) case of progression to furcate cord insertion due to haematoma at the root of the umbilical cord ended with an emergency caesarean section. In terms of perinatal complications, marginal cord insertion that progressed to furcate cord insertion had higher incidences of SGA infants, abnormal placental morphology, retention of the placenta, and cord-related adverse pregnancy outcomes than not progressed to furcate cord insertion (p < 0.05).
CONCLUSIONS
Marginal cord insertion in the first trimester has the potential to progress to furcate cord insertion. We suggest that ultrasound-diagnosed marginal cord insertion in the first trimester should be watched carefully in the second trimester, which is clinically useful to accurately determine the category of cord insertion and to improve the rate of prenatal diagnosis of furcate cord insertion.
Topics: Humans; Pregnancy; Female; Pregnancy Trimester, First; Umbilical Cord; Prospective Studies; Adult; Ultrasonography, Prenatal; Placenta; Gestational Age; Infant, Newborn
PubMed: 38879535
DOI: 10.1186/s12884-024-06562-4 -
Diagnostic Pathology Jun 2024Ovarian clear cell carcinoma (OCCC), well known for its chemoresistance to platinum-based chemotherapy, exhibited a good response in clinical trials of anti-PD-1/PD-L1...
BACKGROUND
Ovarian clear cell carcinoma (OCCC), well known for its chemoresistance to platinum-based chemotherapy, exhibited a good response in clinical trials of anti-PD-1/PD-L1 inhibitors. By assessing PD-L1 expression, we sought to determine the potential therapeutic benefit of PD-1/PD-L1 inhibitors in OCCC.
METHODS AND RESULTS
The retrospective study included 152 individuals with OCCC between 2019 and 2022 at Peking Union Medical College Hospital. Paired tumors of primary versus recurrent lesions (17 pairs from 15 patients) or primary versus metastatic lesions (11 pairs from 9 patients) were also included. The 22C3 pharmDx assay and whole sections were used for PD-L1 immunohistochemical staining. Pathologists with experience in premarket clinical trials evaluated PD-L1 expression based on various diagnostic criteria (TPS 1%, CPS 1, or CPS 10). The number and percentage of positive PD-L1 cases were 34 (22.4%, TPS ≥ 1%) and 59 (38.8%, CPS ≥ 1), respectively. Thirty-three (21.7%) of the cases had high PD-L1 expression (CPS ≥ 10). Half of the platinum-resistant patients (11/22) were PD-L1 positive (CPS ≥ 1). In addition, positive PD-L1 expression (CPS ≥ 1) was related to clinicopathological characteristics that represented a worse prognosis, such as advanced stages, lymph node metastasis, and distant metastasis (p = 0.032, p < 0.001 and p = 0.003, separately). PD-L1 was expressed equally or more in the recurrent lesion compared with its matched primary lesion.
CONCLUSIONS
In conclusion, anti-PD-1/PD-L1 inhibitors are a promising therapeutic choice for OCCC. For evaluation of PD-L1 expression, CPS is more recommended than TPS. Evaluation of recurrent lesion was still suitable and predictive when the primary tumor tissue was not available. Distant metastatic lesions can serve as alternative samples for PD-L1 evaluation, while usage of lymphatic metastatic lesions is not recommended.
Topics: Humans; Female; B7-H1 Antigen; Retrospective Studies; Middle Aged; Ovarian Neoplasms; Adult; Aged; Biomarkers, Tumor; Adenocarcinoma, Clear Cell; Immunohistochemistry; Drug Resistance, Neoplasm; Neoplasm Recurrence, Local; Aged, 80 and over
PubMed: 38879528
DOI: 10.1186/s13000-024-01510-4 -
Pilot and Feasibility Studies Jun 2024Women with gestational diabetes mellitus (GDM) are at a greater risk of developing type 2 diabetes mellitus (T2DM) than women without GDM. Despite this elevated risk,...
BACKGROUND
Women with gestational diabetes mellitus (GDM) are at a greater risk of developing type 2 diabetes mellitus (T2DM) than women without GDM. Despite this elevated risk, few trials on the prevention of T2DM among South Asian women with GDM have been reported. Therefore, this study aimed to assess the feasibility of conducting a diabetes prevention program on women with a history of GDM to inform the development of a contextually relevant definitive trial.
METHODS
Using a randomized controlled trial, women with GDM (n = 180) who delivered at the study hospitals (one public and one private teaching hospital, Karachi) with fasting blood glucose levels < 120 mg/dl at 6 weeks postpartum were randomized to the intervention (n = 88) or control arms (n = 92). Women in the intervention group received individualized home-based educational sessions from trained community health workers at 0, 1, 3, 6, and 9 months. In addition, they received short text messages, prerecorded messages, and printed educational material (calendars and pamphlets) for reinforcement. The intervention was centered on equipping women with knowledge, skills, and confidence to eat a healthy diet rich in fruits, vegetables, and low-fat dairy products and perform regular physical activity based on walking and household chores to reduce weight (up to 5% of their initial body weight). Women in the control arm received standard care. The feasibility outcomes of the study included screening, recruitment, and retention rates and in-depth interviews at 6 months post-intervention to explore women's experiences with the intervention. Descriptive analysis and thematic analysis were performed.
RESULTS
Of the 324 women screened during the antenatal care visits and after delivery, 255 (78.7%) were contactable 6 weeks postpartum, and 180 (70.6%) were eligible and randomized to intervention (n = 88) and control (n = 92) groups. Loss to follow-up in the intervention and control arms was 22.7% (n = 20/88) and 18.5% (n = 17/92), respectively. Women expressed satisfaction with home-based counseling and follow-up visits, text message reminders, and printed material in the form of a calendar through our qualitative interviews.
CONCLUSIONS
Home-based lifestyle modification intervention augmented with text messages and printed material is feasible. However, to evaluate the intervention's effectiveness, a larger trial is warranted to assess its long-term impact on diabetes prevention.
TRIAL REGISTRATION
ISRCTN, ISRCTN11387113 . Registered 5 December 2017-retrospectively registered.
PubMed: 38879496
DOI: 10.1186/s40814-024-01514-3 -
BMC Neurology Jun 2024The application of cerebellar transcranial magnetic stimulation (TMS) in stroke patients has received increasing attention due to its neuromodulation mechanisms.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The application of cerebellar transcranial magnetic stimulation (TMS) in stroke patients has received increasing attention due to its neuromodulation mechanisms. However, studies on the effect and safety of cerebellar TMS to improve balance capacity and activity of daily living (ADL) for stroke patients are limited. This systematic review and meta-analysis aimed to investigate the effect and safety of cerebellar TMS on balance capacity and ADL in stroke patients.
METHOD
A systematic search of seven electronic databases (PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Wanfang and Chinese Scientific Journal) were conducted from their inception to October 20, 2023. The randomized controlled trials (RCTs) of cerebellar TMS on balance capacity and/or ADL in stroke patients were enrolled. The quality of included studies were assessed by Physiotherapy Evidence Database (PEDro) scale.
RESULTS
A total of 13 studies involving 542 participants were eligible. The pooled results from 8 studies with 357 participants showed that cerebellar TMS could significantly improve the post-intervention Berg balance scale (BBS) score (MD = 4.24, 95%CI = 2.19 to 6.29, P < 0.00001; heterogeneity, I = 74%, P = 0.0003). The pooled results from 4 studies with 173 participants showed that cerebellar TMS could significantly improve the post-intervention Time Up and Go (TUG) (MD=-1.51, 95%CI=-2.8 to -0.22, P = 0.02; heterogeneity, I = 0%, P = 0.41). The pooled results from 6 studies with 280 participants showed that cerebellar TMS could significantly improve the post-intervention ADL (MD = 7.75, 95%CI = 4.33 to 11.17, P < 0.00001; heterogeneity, I = 56%, P = 0.04). The subgroup analysis showed that cerebellar TMS could improve BBS post-intervention and ADL post-intervention for both subacute and chronic stage stroke patients. Cerebellar high frequency TMS could improve BBS post-intervention and ADL post-intervention. Cerebellar TMS could still improve BBS post-intervention and ADL post-intervention despite of different cerebellar TMS sessions (less and more than 10 TMS sessions), different total cerebellar TMS pulse per week (less and more than 4500 pulse/week), and different cerebellar TMS modes (repetitive TMS and Theta Burst Stimulation). None of the studies reported severe adverse events except mild side effects in three studies.
CONCLUSIONS
Cerebellar TMS is an effective and safe technique for improving balance capacity and ADL in stroke patients. Further larger-sample, higher-quality, and longer follow-up RCTs are needed to explore the more reliable evidence of cerebellar TMS in the balance capacity and ADL, and clarify potential mechanisms.
Topics: Humans; Transcranial Magnetic Stimulation; Activities of Daily Living; Postural Balance; Stroke Rehabilitation; Cerebellum; Stroke; Randomized Controlled Trials as Topic
PubMed: 38879485
DOI: 10.1186/s12883-024-03720-1 -
Asian Journal of Surgery Jun 2024
PubMed: 38879359
DOI: 10.1016/j.asjsur.2024.05.277 -
The American Journal of Pathology Jun 2024Chorioamnionitis generates prostaglandin E and F, promoting fetal membrane rupture, cervical ripening, and uterine contractions. 15-hydroxyprostaglandin dehydrogenase...
Chorioamnionitis generates prostaglandin E and F, promoting fetal membrane rupture, cervical ripening, and uterine contractions. 15-hydroxyprostaglandin dehydrogenase (HPGD) contributes to pregnancy maintenance by inactivating prostaglandins. The role of decidual cells in regulating HPGD expression at the maternal-fetal interface was investigated. HPGD immunostaining was primarily detected in anchoring villi and choriodecidual extravillous trophoblasts (EVTs) of first, second and third trimester. Chorionic EVTs adjacent to decidua parietalis exhibited significantly higher HPDG levels than those adjacent to amnion. HPGD HSCORE levels were significantly lower in choriodecidua from chorioamnionitis vs. gestational age-matched controls (Mean±SEM; 132.6±3.8 vs. 31.2±7.9; P<0.05). Conditioned media supernatant (CMS) from in vitro decidualized term decidual cells (TDCs) upregulated HPGD levels in EVTs differentiated from human trophoblastic stem cells, primary trophoblasts and HTR8/SV cells. However, CMS from 5 μg/mL LPS or 10 ng/mL IL-1β pretreated TDC cultures downregulated HPGD levels in HTR8/SV cultures. Similarly, direct treatment of HTR8/SV cultures with LPS or IL-1β significantly reduced HPGD levels vs. control (0.57±0.1 or 0.47±0.1, vs. 1.03±0.03; P<0.05) but not in TDC-CMS pretreated HTR8/SV cultures. Collectively, the results uncover a novel decidual cell-mediated paracrine mechanism which stimulates levels of trophoblastic HPGD, whose function is to inactivate labor-inducing prostaglandins, thereby promoting uterine quiescence during pregnancy. However, infectious/inflammatory stimuli in decidual cells cause a paracrine inhibition of trophoblastic HPGD expression, increasing PGE/F levels, thereby contributing to preterm birth.
PubMed: 38879084
DOI: 10.1016/j.ajpath.2024.05.005 -
Journal of Obstetrics and Gynaecology... Jun 2024Postoperative cognitive decline (POCD) is characterized by deficits in attention, memory, executive function, and information processing that persist beyond the early...
BACKGROUND
Postoperative cognitive decline (POCD) is characterized by deficits in attention, memory, executive function, and information processing that persist beyond the early postoperative period. Its incidence ranges from 10%-25% after noncardiac surgery. Limited literature exists on POCD after gynaecologic oncology surgery.
OBJECTIVE
Our primary objective was to identify the incidence of POCD among patients 55 years or older undergoing major gynaecologic oncology surgery.
METHODS
This mixed-methods, prospective, observational cohort study followed patients 55 years or older who underwent surgery for gynaecologic malignancies between February and July 2022. Semi-structured interviews and the Mini-Mental State Exam (MMSE) were administered before surgery as well as 1 and 3 months after. Assessments were delivered virtually and in-person in the context of the COVID-19 pandemic. POCD was defined as ≥ two-point decline from baseline MMSE score.
RESULTS
Twenty-four patients participated; 19 completed the 1-month follow-up, and 15 completed the 3-month follow-up. The average age was 64 (range: 56-90). The mean preoperative MMSE score was 16.6 out of 17 (virtual) and 12.9 out of 13 (in-person). Two patients had a 1-point decline in their 1-month MMSE score; both recovered by 3 months. One patient had a 1-point decline in their 3-month MMSE score. Semi-structured interviews revealed common themes of "brain fog" at the 1-month follow-up and mild, persistent attention and word-finding deficits at 3 months postoperatively.
CONCLUSION
This study's qualitative component captured subtle subjective findings suggestive of potential POCD. Larger studies are required, and a more extensive neuropsychological test battery may be required to elicit subtle findings not clearly reflected by MMSE scores.
PubMed: 38878823
DOI: 10.1016/j.jogc.2024.102584