Pregnancy necessitates dynamic maternal metabolic adaptations where fatty acids (FAs) serve dual roles as energy substrates and immunomodulators. However, the effects of specific FAs on gestational immunity and pregnancy outcomes remain elusive. In the present study, we administered saturated palmitic acid (PA), monounsaturated oleic acid (OA), polyunsaturated arachidonic acid (AA), or vehicle solutions daily to pregnant mice (gestational day 0.5 [GD0.5]–7.5) and performed comprehensive immune profiling at GD13.5. Mendelian randomization (MR) analysis was employed to evaluate translational relevance in human pregnancies. AA increased embryo resorption rates and decreased both embryonic and placental weights, aligning with MR evidence linking elevated maternal circulating AA to miscarriage risk. Decidual AA exposure amplified pro-inflammatory macrophages (CD11c+), cytotoxic natural killer (NK) cells (NKp46+, IFN-γ+), and cytotoxic T lymphocytes (CTLs, TNF-α+), contrasting OA-driven expansion of M2-like macrophages (CD206+) and pregnancy-protective NK cells (B220+CD11c+). Systemically, AA polarized Th1/CTL dominance (IFN-γ+CD8+) and Ly-6Chigh monocyte retention, whereas OA enhanced Th2 responses and Ly-6Clow monocyte maturation. Paradoxically, AA up-regulated ULN tolerogenic dendritic cells (DCs) and IL-10 expressing regulatory B cells, suggesting tissue-specific lipid sensing. PA activated splenic IFN-γ+ NKs but spared decidual/ULN tolerance. In summary, distinct FAs differentially program gestational immunity in a tissue-specific manner: OA enforces systemic tolerance, while AA drives localized inflammation despite compensatory ULN immunosuppression. These findings advocate personalized FA interventions to optimize pregnancy outcomes.

Recurrent implantation failure (RIF) remains a major challenge in assisted reproductive technology, and the molecular mechanisms underlying endometrial receptivity are incompletely understood. This study aimed to comprehensively characterize transcriptomic alterations, including alternative splicing events (ASEs), differential gene expression (DEGs), and immune cell dynamics across different phases of endometrial receptivity in women with RIF. Endometrial biopsies were collected from 90 healthy fertile controls and 73 RIF patients during pre-receptive, receptive, and post-receptive phases. High-throughput RNA sequencing was performed, and bioinformatic analyses were conducted to identify ASEs, DEGs, immune cell composition, and RNA-binding protein (RBP) networks. Skipped exons and mutually exclusive exons were the predominant splicing events observed. Both ASEs and DEGs were significantly enriched in pathways regulating cell adhesion, cytoskeletal organization, and immune modulation. KHDRBS3 emerged as a potential key RBP involved in splicing regulation during the window of implantation. Immune profiling revealed dynamic alterations in CD8 + T cells, NK cells, and monocytes between non-receptive and receptive phases, suggesting immune dysregulation associated with implantation failure. Drug repurposing analysis identified several small molecules targeting ASE-related genes, offering promising therapeutic options for RIF. These findings highlight the coordinated changes in alternative splicing, gene expression, and immune cell composition that characterize endometrial receptivity and provide insights that may guide the development of novel diagnostic biomarkers and targeted interventions to improve reproductive outcomes.

The establishment of placentation and maternal-fetal tolerance are important determinants of a successful pregnancy. Tacrolimus, also known as FK506, is a calcineurin inhibitor that has often been used for pregnant women after solid organ transplantation. Previous therapeutic interventions have shown the benefits of using the immuno-suppressive agent FK506 in improving clinical pregnancy and live birth rates and reducing the risk of spontaneous miscarriage. However, the mechanism(s) by which FK506 is involved in these processes have not been fully elucidated. To further characterize its function in early pregnancy, we explored the effect of FK506 on the human-derived first trimester extravillous trophoblast cells (HTR8/SVneo cells) and found that FK506 promoted invasion, tube formation and proliferation, but inhibited apoptosis of HTR8/SVneo cells. Based on the integrated metabolomics and transcriptomics analyses, the present study provided the cellular and molecular cues evidently showing that FK506 had positive effects on the placentation and maternal-fetal tolerance through modulating FASN-CEACAM1 pathway. The spontaneous-abortion-prone model gave further evidence that FK506 exerted a protective effect on pregnancy by regulating the FASN-CEACAM1 axis. These findings might provide a new fundamental mechanism and promising potential of low-dose FK506 in preventing pregnancy loss.

Despite impressive progress being made in investigating the mechanisms underlying endometriosis, the pathophysiology of this disease remains unclear. Although typical methods used for diagnosing endometriosis such as ultrasound, magnetic resonance imaging, and blood tests are available, these are also inefficient, and effective noninvasive diagnostic methods are lacking. The advances in high-throughput omics techniques have enabled metabolomics to become an effective approach for discovering promising biomarkers. The aberrant metabolism associated with serious symptoms of endometriosis in women has been revealed in recent years. Analyzing the global metabolic patterns in patients with endometriosis may help deepen the understanding of the disease mechanism and have a significant impact on future diagnostic and treatment methods for endometriosis. Herein, we reviewed relevant studies on metabolic changes in patients with endometriosis and discussed the changes in metabolites both in biological fluids and endometriosis tissues. The findings discussed in this review have potential diagnostic implications and will enhance the understanding of the pathophysiological processes underlying the disease.

Objective:The objective of this study was to evaluate the developmental and hormonal safety profile of different doses of allylestrenol administered during gestation in SD rats, focusing on selected physiological and reproductive indices in the Parental (F0) and First-generation offspring (F1) generations. Methods:In this study, 138 successfully mated Sprague-Dawley (SD) female rats were randomly divided into solvent control (Sol-C), progesterone injection control (PgI-C), progesterone soft-gel capsule control (PgSC-C), low-dose allylestrenol (Alt-LD, 5 mg kg-1), medium-dose allylestrenol (Alt-MD, 10 mg kg-1), and high-dose allylestrenol (Alt-HD, 20 mg kg-1) groups, with 16 successfully mated female rats in each group. Satellite groups were also established, each consisting of 7 successfully mated female rats. Results:Estradiol levels on gestation day 19 (GD19) were reduced in the Alt-HD compared to the Sol-C (P < 0.05). Compared with the Sol-C, there was no significant change in the anogenital distance (AGD) on postnatal day 21 (PND21) and PND54 in both male and female littermates in each allylestrenol dose group (P > 0.05). Testosterone levels were significantly elevated in the Alt-MD and Alt-LD groups compared to the Sol-C (P < 0.05). On GD19, the estradiol level was significantly reduced only in the Alt-HD group (9.981 ± 0.514 ng/mL) compared with the Sol-C group (18.725 ± 4.770 ng/mL; P < 0.05). The low-dose (Alt-LD: 17.575 ± 3.017 ng/mL) and medium-dose (Alt-MD: 11.927 ± 3.663 ng/mL) groups showed numerically lower values than Sol-C, but the difference was not statistically significant after adjustment. 95% CIs for Sol-C, Alt-MD, and Alt-HD were [17.1, 20.3], [10.2, 13.7], and [9.4, 10.5] ng/mL, respectively. Conclusion:Allylestrenol at doses of 5, 10, and 20 mg kg-1 did not result in overt developmental abnormalities in maternal or offspring rats across selected early endpoints. However, further long-term and functional evaluations across generations are needed to fully establish its safety profile.

Interleukin (IL)-18 is one of the members of IL-1 family cytokines, it was originally named as interferon gamma (IFN-γ) inducing factor. IL-18 is a pleiotropic immune regulator and has a bidirectional regulatory effect on immunity. It exerts a potent pro-inflammatory effect by inducing the expression of IFN-γ, also has an important anti-inflammatory role. In recent years, IL-18 has received widespread attention and become a research hotspot. Previous studies have described the roles of IL-18 in the pathogenesis of many diseases. However, the biologic activities of IL-18 and its role in the reproductive endocrine and reproductive immune related diseases are still not well understood, such as endometriosis (EMS), recurrent spontaneous abortion (RSA), polycystic ovary syndrome (PCOS), and infertility, which are closely related to inflammation and immunity. Here, we reviewed the research progress of IL-18 in these diseases in the past few years. This article provides an overview of the latest knowledge about the roles of IL-18 in these diseases, with a view to providing new possibilities for the diagnosis and treatment of reproductive endocrine and reproductive immune related disorders.

Endometriosis (EMS) is an estrogen-dependent disorder that affects about 10% of reproductive-age women. EMS affects female neuroendocrine and reproductive functions, greatly compromising female reproductive health and quality of life. However, the pathogenesis of EMS has not been fully elucidated, and effective treatment options are still lacking. The neuroendocrine–immune axis can achieve cross-regulation through the interaction of neurotransmitters, hormone-like substances, cytokines, and their receptors to maintain body homeostasis, and this imbalance of regulation is involved in the occurrence and development of EMS. In this narrative review, we summarize recent progress on the role of the neuroendocrine–immune axis in the pathogenesis of endometriosis, as well as the emergence of novel therapies targeting this axis. This review aims to offer a novel perspective for the in-depth exploration of EMS pathogenesis and the identification of potential effective treatments.

Endometriosis (EMS) is a prevalent estrogen-dependent gynecological disorder characterized by ectopic growth of endometrial tissue. Central to its pathophysiology, peritoneal CD14hi macrophages exhibit a pro-EMS phenotype and drive disease progression. These macrophages originate from CD16-CD14+ monocytes and co-express functional surface markers critical for EMS development. We demonstrate that endometrial stromal cells (ESCs) exert significantly stronger regulatory effects on CD14hi macrophage polarization than estrogen alone. Crucially, CD16 maintains peritoneal CD14hi macrophage homeostasis in ovarian EMS. To investigate CD16's role in vivo, we established a novel EMS mouse model (WH-EMS) by intraperitoneal grafting of wild-type uterine tissues into FcγRIII-/- (CD16-deficient) female mice. Within this model, peritoneal FcγRIII- macrophages exhibited impaired immunocompetence (diminished CD80 and IL4 expression), whereas macrophages infiltrating ectopic lesions displayed pronounced immune tolerance (elevated IL-4 expression). Pharmacologically targeting CD16 downstream signaling, PI3Kγ inhibition via IPI-549 attenuated ESC-induced differentiation of both CD14hi and CD14low macrophages in vitro, ultimately ameliorating pathological conditions in WH-EMS mice. This cumulative evidence indicates that CD14hi macrophages promote EMS progression through CD16-dependent mechanisms. Consequently, therapeutic targeting of CD16 or its downstream effectors (e.g., PI3Kγ) represents a promising strategy for clinical EMS management.

BACKGROUND:Preeclampsia is a serious disease of pregnancy that lacks early diagnosis methods or effective treatment, except delivery. Dysregulated uterine immune cells and spiral arteries are implicated in preeclampsia, but the mechanistic link remains unclear.METHODS:Single-cell RNA sequencing and spatial transcriptomics were used to identify immune cell subsets associated with preeclampsia. Cell-based studies and animal models including conditional knockout mice and a new preeclampsia mouse model induced by recombinant mouse galectin-9 were applied to validate the pathogenic role of a CD11chigh subpopulation of decidual macrophages (dMφ) and to determine its underlying regulatory mechanisms in preeclampsia. A retrospective preeclampsia cohort study was performed to determine the value of circulating galectin-9 in predicting preeclampsia.RESULTS:We discovered a distinct CD11chigh dMφ subset that inhibits spiral artery remodeling in preeclampsia. The proinflammatory CD11chigh dMφ exhibits perivascular enrichment in the decidua from patients with preeclampsia. We also showed that trophoblast-derived galectin-9 activates CD11chigh dMφ by means of CD44 binding to suppress spiral artery remodeling. In 3 independent preeclampsia mouse models, placental and plasma galectin-9 levels were elevated. Galectin-9 administration in mice induces preeclampsia-like phenotypes with increased CD11chigh dMφ and defective spiral arteries, whereas galectin-9 blockade or macrophage-specific CD44 deletion prevents such phenotypes. In pregnant women, increased circulating galectin-9 levels in the first trimester and at 16 to 20 gestational weeks can predict subsequent preeclampsia onset.CONCLUSIONS:These findings highlight a key role of a distinct perivascular inflammatory CD11chigh dMφ subpopulation in the pathogenesis of preeclampsia. CD11chigh dMφ activated by increased galectin-9 from trophoblasts suppresses uterine spiral artery remodeling, contributing to preeclampsia. Increased circulating galectin-9 may be a biomarker for preeclampsia prediction and intervention.

Spontaneous abortion is associated with aberrant lipid metabolism, but the underlying mechanisms remain unclear. Here, we show that lipids are accumulated in decidual stromal cells (DSCs) and macrophages (dMφs) in women with miscarriage and mouse abortion-prone models. Moreover, we show that excessive lipids from DSCs are transferred to dMφs via a CD36-dependent mechanism that induces inflammation in dMφs. In particular, DSC-derived arachidonic acid (AA) is internalized by dMφs via CD36, which activates cyclooxygenase 2-dependent prostaglandin E2 production and interleukin (IL)-1β expression. In mice, AA injection induces miscarriage, whereas conditional knockout of Cd36 in dMφs ameliorates AA-induced embryo loss. Additionally, DSC-derived prolactin (PRL) inhibits CD36-mediated lipid intake in dMφs, and PRL administration reduces embryo loss in pregnant mice treated with CD36+ Mφs. Our findings reveal a critical interplay between DSCs and dMφs in dysregulated lipid metabolism that may contribute to miscarriage, in which PRL may be harnessed as a therapeutic agent.

Endometriosis is a common estrogen-dependent condition that impacts 8–10% of women in their reproductive age, resulting in notable pain, morbidity, and infertility. Despite extensive research endeavors, the precise cause of endometriosis remains elusive, and the mechanisms contributing to its associated infertility are still not well comprehended. Natural killer (NK) cells, vital innate immune cells crucial for successful pregnancy, have been investigated for their potential involvement in the pathogenesis of endometriosis. Prior research has mainly concentrated on the diminished cytotoxicity of NK cells in endometrial fragments that evade the uterus. Interestingly, accumulating evidence suggests that NK cells play multifaceted roles in regulating the biology of endometrial stromal cells (ESCs), promoting local immune tolerance, influencing endometrial receptivity, oocyte development, and embryo implantation, thereby contributing to infertility and miscarriage in patients with endometriosis. In this comprehensive review, our goal is to summarize the current literature and provide an overview of the implications of NK cells in endometriosis, especially concerning infertility and pregnancy loss, under the influence of estrogen.

PROBLEM:Endometriosis (EMS) is an estrogen-dependent disease which is characterized with estrogen-dependent growth of ectopic endometrium and increased local estrogen production. EMS performs tumor-like biological functions such as invasiveness and angiogenesis. Rab27b is a member of the Rab family of GTPases, which is strongly associated with the growth, invasion and metastasis of a variety of tumors. However, little is known about the function of Rab27b in EMS. In this study, we intended to investigate the impact of Rab27b and its downstream molecule in the development of EMS.METHOD OF STUDY:Normal endometrium and endometriotic lesions were collected to investigate the expression levels of Rab27b. Then, ESCs were transfected with Rab27b siRNA. We analyzed the influence of Rab27b on the proliferation and invasive activity of ESCs. Conditioned media harvested from Rab27b siRNA-treated ESCs were used to treat HUVECs. HUVEC Tube formation and ELISA were performed to explored the interactions between ESCs and HUVEC. In addition, ESCs were treated with different concentrations of estrogen. Based on biological database predictions, we explored possible mechanisms through which estrogen regulates the expression of Rab27b.RESULTS:The expressions of Rab27b were significantly higher in endometriotic lesions than that in normal endometrium. Rab27b can promote the cell proliferation, migration and invasion of ESCs. The elevated expression of Rab27b, on the one hand, promotes the secretion of MMP9 and increases the invasiveness of ESCs. On the other hand, Rab27b may play a key role in the communication between ESC and endothelial cells, by simulating VEGF secretion and neovascularization. Besides, estrogen upregulated phosphorylated FOXO1 levels in ectopic ESCs, resulting in the promotion of Rab27b expression levels.CONCLUSION:Rab27b plays a key role in the development of EMS, which may provide new insights into the pathogenesis of EMS. Our findings may also contribute to the development of therapeutic interventions for EMS.

To investigate the balancing mechanisms between decidualization-associated inflammation and pregnancy-related immunotolerance. Decidual samples from women with normal pregnancy (n = 58) or unexplained spontaneous miscarriage (n = 13), peripheral blood from normal pregnancy and endometria from non-pregnancy (n = 10) were collected. Primary endometrial stromal cells (ESCs), decidual stromal cells (DSCs), decidual immune cells (DICs) and peripheral blood mononuclear cells (PBMCs) were isolated. The plasmid carrying neuropilin-1 (NRP1) gene was transfected into ESC for overexpression. To induce decidualization in vitro, ESCs were treated with a combination of 10 nM estradiol, 100 nM progesterone and 0.5 mM cAMP. Anti-Sema3a and anti-NRP1 neutralizing antibodies were applied to block the ligand–receptor interactions. RNA-seq analysis was performed to identify differentially expressed genes in DSCs and DICs, and NRP1 expression was verified by Western blotting and flow cytometry. The secretion of inflammatory mediators was measured using a multifactor cytometric bead array. The effects of Sema3a-NRP1 pathway on DICs were determined by flow cytometry. Statistical differences between groups were compared using the T test and one way or two-way ANOVA. Combined with five RNA-seq datasets, NRP1 was the only immune checkpoint changing oppositely between DSCs and DICs. The decreased expression of NRP1 in DSCs allowed intrinsic inflammatory responses required for decidualization, while its increased expression in DICs enhanced tolerant phenotypes beneficial to pregnancy maintenance. DSC-secreted Sema3a promoted immunosuppression in DICs via NRP1 binding. In women with miscarriage, NRP1 was abnormally elevated in DSCs but diminished in decidual macrophages and NK cells. NRP1 is a multifunctional controller that balances the inflammatory states of DSCs and DICs in gravid uterus. Abnormal expression of NRP1 is implicated in miscarriage.

Preeclampsia is a gestational disease characterized by two major pathological changes-shallow trophoblast invasion and impaired spiral artery remodeling. Atrial natriuretic peptide (ANP) is a kind of peptide hormone that regulates blood pressure, while the lack of active ANP participates in preeclampsia pathogenesis. However, the underlying mechanism of how ANP modulates trophoblasts function remains unclarified. Here, we performed isobaric tags for relative and absolute quantification (iTRAQ) in ANP-treated HTR-8/SVneo cells and identified Protein Kinase 3 (PKN3) as the downstream factor of ANP, which was downregulated in preeclamptic placenta. Chromatin immunoprecipitation analysis and luciferase assays showed that NFYA was one of the transcription factors for the PKN3 promoter, which was also regulated by ANP treatment in HTR-8/SVneo cells. Transmission electron microscopy and Western Blotting in HTR-8/SVneo cells indicated that ANP inhibited autophagy via AMPK-mTORC1 signaling, while excess autophagy was observed in preeclamptic placenta. The increased expression of PKN3 and enhanced cell invasion ability in HTR-8/SVneo cells induced by ANP could be abolished by autophagy activation or transfection with PKN3 shRNA or NFYA shRNA or NPR-A shRNA via regulating the invasion-related genes and the epithelial mesenchymal transition molecules. Our results demonstrated that ANP could enhance trophoblast invasion by upregulating PKN3 via NFYA promotion through autophagy inhibition in an AMPK/mTORC1 signaling-dependent manner.

T-cell immunoglobulin mucin-3 (Tim-3) is an important checkpoint that induces maternal–fetal tolerance in pregnancy. Macrophages (Mφs) play essential roles in maintaining maternal–fetal tolerance, remodeling spiral arteries, and regulating trophoblast biological behaviors. In the present study, the formation of the labyrinth zone showed striking defects in pregnant mice treated with Tim-3 neutralizing antibodies. The adoptive transfer of Tim-3+Mφs, rather than Tim-3−Mφs, reversed the murine placental dysplasia resulting from Mφ depletion. With the higher production of angiogenic growth factors (AGFs, including PDGF-AA, TGF-α, and VEGF), Tim-3+dMφs were more beneficial in promoting the invasion and tube formation ability of trophoblasts. The blockade of AGFs in Tim-3+Mφs led to the narrowing of the labyrinthine layer of the placenta, compromising maternal–fetal tolerance, and increasing the risk of fetal loss. Meanwhile, the AGFs-treated Tim-3−Mφs could resolve the placental dysplasia and fetal loss resulting from Mφ depletion. These findings emphasized the vital roles of Tim-3 in coordinating Mφs-extravillous trophoblasts interaction via AGFs to promote pregnancy maintenance and in extending the role of checkpoint signaling in placental development. The results obtained in our study also firmly demonstrated that careful consideration of reproductive safety should be taken when selecting immune checkpoint and AGF blockade therapies in real-world clinical care.

The development of reproductive immunology in China can be traced back to the implementation of Family Planning as a national policy in the 1970s, which led to a surge in demand for contraceptive methods.1 In 1985, the Chinese Society for Reproductive Immunology (CSRI) was established as a collaborative research group focused on contraceptive vaccination, with an initial focus on clinical applications such as the development of vaccines to induce immune responses against sperm and ova. Over the years, the CSRI has expanded its research scope to include basic research on the immune mechanisms underlying fertility and infertility, encompassing topics such as the role of cytokines and regulatory T cells in pregnancy maintenance and fetal tolerance. The CSRI has also broadened its international collaborations to enhance its research network and increase its impact on reproductive immunology.2,3 Despite significant breakthroughs in basic research, the clinical application of these discoveries has been limited, partly due to regulatory hurdles and challenges in translating basic research into clinical practice. This special issue aims to showcase recent clinical progress in reproductive immunology inChina, including the contribution of autoimmunity to recurrent pregnancy loss, the use of immunological indicators for predicting pregnancy failure and guiding clinical intervention, and the implications of immune dysregulation during pregnancy for clinical management.

To investigate the prognostic factors in and role of postoperative radiotherapy (PORT) for surgically resected thymomas.A total of 1540 patients with pathologically confirmed thymomas undergoing resection between 2000 and 2018 were identified retrospectively from the SEER (Surveillance, Epidemiology, and End Results) database. Tumors were restaged as local (limited to thymus), regional (invasion to mediastinal fat and other neighboring structures), or distant stage. Disease-specific survival (DSS) and overall survival (OS) were estimated by the Kaplan–Meier method and the log-rank test. Adjusted hazard ratios (HRs) with 95% CIs were calculated by Cox proportional hazards modeling.Tumor stage and histology were independent predictors of both DSS (regional: HR, 3.711; 95% CI, 2.006-6.864; distant: HR, 7.920; 95% CI, 4.061-15.446; type B2/B3: HR, 1.435; 95% CI, 1.008-2.044) and OS (regional: HR, 1.461; 95% CI, 1.139-1.875; distant: HR, 2.551; 95% CI, 1.855-3.509; type B2/B3: HR, 1.409; 95% CI, 1.153-1.723). For patients with regional stage and type B2/B3 thymomas, PORT was associated with better DSS after thymectomy/thymomectomy (HR, 0.268; 95% CI, 0.099-0.727), but the association was not significant after extended thymectomy (HR, 1.514; 95% CI, 0.516-4.44). Among patients with lymph node metastases, those who received PORT (HR, 0.372; 95% CI, 0.146-0.949), chemotherapy (HR, 0.843; 95% CI, 0.303-2.346), or both (HR, 0.296, 95% CI, 0.071-1.236) had a better OS.The extent of invasion and tumor histology were independent predictors of worse survival following surgical resection of thymoma. Patients with regional invasion and type B2/B3 thymoma who undergo thymectomy/thymomectomy may benefit from PORT, while patients with nodal metastases may benefit from multimodal therapy, including PORT and chemotherapy.

Iron is necessary for various critical biological processes, but iron overload is also dangerous since labile iron is redox-active and toxic. We found that low serum iron and decidual local iron deposition existed simultaneously in recurrent pregnancy loss (RPL) patients. Mice fed with a low-iron diet (LID) also showed iron deposition in the decidua and adverse pregnancy outcomes. Decreased ferroportin (cellular iron exporter) expression that inhibited the iron export from decidual stromal cells (DSCs) might be the reason for local iron deposition in DSCs from low-serum-iron RPL patients and LID-fed mice. Iron supplementation reduced iron deposition in the decidua of spontaneous abortion models and improved pregnancy outcomes. Local iron overload caused ferroptosis of DSCs by downregulating glutathione (GSH) and glutathione peroxidase 4 levels. Both GSH and cystine (for the synthesis of GSH) supplementation reduced iron-induced lipid reactive oxygen species (ROS) and cell death in DSCs. Ferroptosis inhibitor, cysteine, and GSH supplementation all effectively attenuated DSC ferroptosis and reversed embryo loss in the spontaneous abortion model and LPS-induced abortion model, making ferroptosis mitigation a potential therapeutic target for RPL patients. Further study that improves our understanding of low-serum-iron-induced DSC ferroptosis is needed to inform further clinical evaluations of the safety and efficacy of iron supplementation in women during pregnancy.

Estimation of the solid component in walled-off pancreatic necrosis (WOPN) during endoscopic ultrasound (EUS) is an important parameter to guide the selection of stent for drainage but is often not objectively quantified.We aimed to study the interobserver agreement (IOA) among endosonographers assessing debris in the pancreatic fluid collection and their choice of stent. EUS videos of 15 patients having pancreatic fluid collection with concurrent magnetic resonance imaging (MRI) assessment of debris were independently reviewed by 40 endosonographers for the percentage of debris (10% increments) and their choice of stent (plastic or metal). The Fleiss kappa (κ) coefficient was used to assess IOA. Post-hoc analysis was done using wider debris intervals (20% or greater increments).Poor agreement was observed for the percentage of debris (κ = 0.188), which did not improve (κ = 0.196) even after including only expert endosonographers with more than 10 years of experience (n = 33). There was fair agreement (κ = 0.266) with reference MRI on the percentage of debris. On post-hoc analysis, the IOA (κ = 0.56, substantial agreement) and agreement with MRI (κ = 0.59, substantial agreement) improved as the debris intervals widened (<10%, 10%-50%, >50%). The agreement for stent selection (plastic vs metal) was poor (κ = 0.174) and did not improve with case volume (κ = 0.153 among respondents with >25 EUS-guided drainage/year; n = 21) or years of experience (κ = 0.195 for >10-year experience; n = 33).IOA between endosonographers regarding estimation of debris in WOPN and subsequent stent choice for drainage is poor. The experience of endosonographers did not improve IOA. Studies to standardize the EUS criteria for debris assessment in WOPN and subsequent therapeutic approaches are warranted.

Endometriosis is widely perceived as an estrogen-dependent chronic disorder with infertility and pelvic pain. Although the etiology of endometriosis has remained elusive, many studies have proclaimed the relevance of immune system disorders with endometriosis. With the discovery that the dysregulation of multiple biological functions in endometriosis is caused by the aberrant differentiation of T helper cells, a shift towards Th2 immune response may account for the disease progression. This review attempts to present mechanisms of cytokines, chemokines, signal pathways, transcription factors and some other factors related with the derivation of Th1/Th2 immune response involved in the development of endometriosis. The current understanding of treatment approaches and potential therapeutic targets will also be outlined with brief discussion.