Using T2-weighted magnetic resonance imaging-derived radiomics to classify cervical lymphadenopathy in children.

BACKGROUND: Cervical lymphadenopathy is common in children and has diverse causes varying from benign to malignant, their similar manifestations making differential diagnosis difficult. OBJECTIVE: This study aimed to investigate whether radiomic models using conventional magnetic resonance imaging (MRI) could classify pediatric cervical lymphadenopathy. METHODS: A total of 419 cervical lymph nodes from 146 patients, and encompassing four common etiologies (Kikuchi disease, reactive hyperplasia, suppurative lymphadenitis and malignancy), were randomly divided into training and testing sets in a ratio of 7:3. For each lymph node, 1,218 features were extracted from T2-weighted images. Then, the least absolute shrinkage and selection operator (LASSO) models were used to select the most relevant ones. Two models were built using a support vector machine classifier, one was to classify benign and malignant lymph nodes and the other further distinguished four different diseases. The performance was assessed by receiver operating characteristic curves and decision curve analysis. RESULTS: By LASSO, 20 features were selected to construct a model to distinguish benign and malignant lymph nodes, which achieved an area under the curve (AUC) of 0.89 and 0.80 in the training and testing sets, respectively. Sixteen features were selected to construct a model to distinguish four different cervical lymphadenopathies. For each etiology, Kikuchi disease, reactive hyperplasia, suppurative lymphadenitis, and malignancy, an AUC of 0.97, 0.91, 0.88, and 0.87 was achieved in the training set, and an AUC of 0.96, 0.80, 0.82, and 0.82 was achieved in the testing set, respectively. CONCLUSION: MRI-derived radiomic analysis provides a promising non-invasive approach for distinguishing causes of cervical lymphadenopathy in children.

GDF9His209GlnfsTer6/S428T and GDF9Q321X/S428T bi-allelic variants caused female subfertility with defective follicle enlargement.

BACKGROUND: Antral follicles consist of an oocyte cumulus complex surrounding by somatic cells, including mural granulosa cells as the inner layer and theca cells as the outsider layer. The communications between oocytes and granulosa cells have been extensively explored in in vitro studies, however, the role of oocyte-derived factor GDF9 on in vivo antral follicle development remains elusive due to lack of an appropriate animal model. Clinically, the phenotype of GDF9 variants needs to be determined. METHODS: Whole-exome sequencing (WES) was performed on two unrelated infertile women characterized by an early rise of estradiol level and defect in follicle enlargement. Besides, WES data on 1,039 women undergoing ART treatment were collected. A Gdf9Q308X/S415T mouse model was generated based on the variant found in one of the patients. RESULTS: Two probands with bi-allelic GDF9 variants (GDF9His209GlnfsTer6/S428T, GDF9Q321X/S428T) and eight GDF9S428T heterozygotes with normal ovarian response were identified. In vitro experiments confirmed that these variants caused reduction of GDF9 secretion, and/or alleviation in BMP15 binding. Gdf9Q308X/S415T mouse model was constructed, which recapitulated the phenotypes in probands with abnormal estrogen secretion and defected follicle enlargement. Further experiments in mouse model showed an earlier expression of STAR in small antral follicles and decreased proliferative capacity in large antral follicles. In addition, RNA sequencing of granulosa cells revealed the transcriptomic profiles related to defective follicle enlargement in the Gdf9Q308X/S415T group. One of the downregulated genes, P4HA2 (a collagen related gene), was found to be stimulated by GDF9 protein, which partly explained the phenotype of defective follicle enlargement. CONCLUSIONS: GDF9 bi-allelic variants contributed to the defect in antral follicle development. Oocyte itself participated in the regulation of follicle development through GDF9 paracrine effect, highlighting the essential role of oocyte-derived factors on ovarian response.

Theranostic Bottle-Brush Polymers Tailored for Universal Solid-Tumor Targeting.

Designing an efficient nanocarrier to target multiple types of cancer remains a major challenge in the development of cancer nanomedicines. The majority of systemically administered nanoparticles (NPs) are rapidly cleared by the liver, resulting in poor tumor-targeting efficiency and severe side effects. Here, we present a delicately tailored design and synthesis of fluorescent bottle-brush polymers and screen nine derived NPs, each varying in size and surface coatings, for tumor imaging and targeted delivery. Our optimized polymer bearing (oligo(ethylene glycol) methyl ether methacrylate) in the side chains shows reduced macrophage uptake, prolonged blood-circulation time (up to 27 h), and exceptionally high accumulation in the tumor compared to the liver, elucidating an immune-evasion-induced tumor-targeting mechanism. High tumor accumulation significantly improved the antitumor efficacy. The outstanding tumor-targeting ability has been further validated across five distinct tumor models, including orthotopic glioblastoma and pancreatic cancer, which demonstrate the universality of our polymeric nanocarrier for tumor-targeting delivery.

Nuclear transport of phosphorylated LanCL2 promotes invadopodia formation and tumor progression of glioblastoma by activating STAT3/Cortactin signaling.

INTRODUCTION: Our previous study showed that the abscisic acid receptor lanthionine synthetase C-like 2 (LanCL2) is a significant prognostic factor for overall survival in young glioblastoma patients. However, the role of LanCL2 in glioblastoma remains unclear yet. OBJECTIVES: This study aims to investigate the role of LanCL2 in regulating in-vitro cell invasion and in-vivo tumor progression of glioblastoma and its underlying mechanism. METHODS: Tyrosine 198 or 295 residue of LanCL2 was mutated using site-directed mutagenesis to block its phosphorylation. The role of LanCL2 in glioblastoma was investigated using transwell or 3D invasion assay, matrix degradation assay and intracranial xenograft model. RESULTS: This study showed that nuclear transport of LanCL2 was enhanced by overexpression of LanCL2 or its ligand abscisic acid in glioblastoma cells. Knockdown of LanCL2 suppressed migration, invasion and invadopodia formation of glioblastoma cells, whereas overexpression of wild-type LanCL2 enhanced them. Blocking of Tyr295 residue phosphorylation of LanCL2 impeded its nuclear transport, retarded glioblastoma cell motility and invadopodia formation, and deceased the phosphorylation of Cortactin and STAT3. c-Met was identified as the upstream tyrosine kinase of Tyr295 residue of LanCL2, and inhibition of c-Met markedly suppressed the nuclear transport of LanCL2. Moreover, overexpression of wild-type LanCL2 significantly promoted orthotopic tumor growth of glioblastoma in vivo and led to poor survival of mice with median survival time of 33.5 days, whereas Tyr295 mutation rescued it with median survival time of 49 days. CONCLUSION: Our findings suggested that Tyr295 phosphorylation is crucial to the activation and nuclear transport of LanCL2, as well as invadopodia formation and tumor progression of glioblastoma, providing the evidence of a novel signaling axis c-Met/LanCL2/STAT3/Cortactin and the first observation of the importance of Tyr295 phosphorylation to LanCL2.

Analysis of the Relationship Between the Changes of Serum SAA, LP-PLA2, sCD40L and Carotid Atherosclerosis Plaque in Patients with Acute Cerebral Infarction.

Objective: To explore the relationship between Serum amyloid protein A(SAA), lipoprotein-associated Phospholipase A2 (Lp-PLA2) and soluble CD40 ligand (sCD40L) in detecting the stability of carotid Atherosclerosis plaque. Methods: We examined 90 patients admitted to our hospital with acute cerebral infarction from July 2020 to December 2022. Carotid artery ultrasounds were performed for all of them. These patients were then divided into two groups: the stable plaque group (45 cases) and the unstable plaque group (45 cases), based on the ultrasound results. Additionally, we included a control group of 30 healthy individuals from our hospital. We collected fasting blood samples from the patients upon admission and used enzyme-linked immunosorbent assays to measure the mass concentrations of sCD40L, Lp-PLA2, and SAA in their serum. The results of these biomarkers were compared and analyzed to assess potential associations with plaque stability in patients with cerebral infarction. Results: Comparison of general clinical data and laboratory data: except for High-density lipoprotein, there was a statistical difference between the control group and the cerebral infarction group (P < .05), there was no statistical difference in gender, smoking history, drinking history and age (P > .05). Compared with the control group, the mass concentrations of sCD40L, Lp-PLA2, and SAA in patients with stable and unstable plaques increased significantly (P < .05); Compared with the stable plaque group, the mass concentrations of sCD40L, Lp-PLA2, and SAA in unstable plaque patients increased with statistical significance (P < .05). Correlation analysis shows that the mass concentrations of sCD40L, Lp-PLA2, and SAA are positively correlated with the stability of carotid artery plaques. SCD40L, Lp-PLA2 and SAA have certain diagnostic significance in the subject's working characteristic curve (Receiver operating characteristic) as a marker molecule for the diagnosis of unstable plaque. sCD40L (AUC=0.883) has more diagnostic value than SAA (AUC=0.756) and Lp-PLA2 (AUC=0.826). A binary logistic regression analysis was conducted using the stability of carotid artery plaques as the dependent variable and sCD40L, Lp-PLA2, and SAA as independent variables. The results showed that elevated serum sCD40L, Lp-PLA2, and SAA were independent risk factors for unstable carotid artery plaques (P < .05). Conclusion: The concentrations of sCD40L, Lp-PLA2 and SAA are closely related to the formation and type of carotid Atherosclerosis plaque in patients with acute cerebral infarction. This has potentially important clinical implications for the management and prevention of cardiovascular disease.

A comprehensive preimplantation genetic testing approach for SEA-type α-thalassemia by fluorescent gap-polymerase chain reaction combined with haplotype analysis.

Introduction: This study aimed to evaluate the feasibility and necessity of using fluorescence Gap-polymerase chain reaction combined with haplotype analysis in preimplantation genetic testing for SEA-type α-thalassemia. Methods: A total of 26 preimplantation genetic testing biopsy cycles were performed in 25 families from June 2021 to February 2022. All couples were carriers of SEA-type α-thalassemia. Fluorescent Gap-polymerase chain reaction was used for detecting fragment deletion. Subsequently, according to the results of polymerase chain reaction, reference embryos were identified to establish haplotype using single nucleotide polymorphism array, and aneuploidy was screened simultaneously. In cases wherein the polymerase chain reaction results were inconsistent with the haplotype results, the reasons were investigated, either by retest of the biopsied samples or rebiopsy of the embryo. Results: Among the 172 embryos, 162 had consistent results when tested using both methods, resulting in a consistency rate of 94.2%. Conversely, 10 embryos had inconsistent results, mainly due to chromosome 16 aneuploidy (n = 7), allele dropout in Gap-polymerase chain reaction (n = 2), or incorrect haplotype due to poor sample amplification quality (n = 1). The clinical pregnancy rate of each frozen-thawed embryo transfer was 57.7% (15/26). Six families underwent prenatal diagnosis, which confirmed the results of preimplantation genetic testing. Conclusion: Fluorescent Gap-polymerase chain reaction combined with haplotype analysis is feasible and necessary for SEA-type α-thalassemia preimplantation genetic testing.

Comparison of effects of HucMSCs, exosomes, and conditioned medium on NASH.

To investigate the effects and potential mechanisms of human umbilical cord mesenchymal stem cells, exosomes, and their conditioned media on lipid storage in oleic acid (OA) and palmitic acid (PA) treated hepatocytes and high-fat methionine- choline deficient diet (HFMRCD) induced non-alcoholic steatohepatitis (NASH) mice. AML12 cells were stimulated with OA and PA to establish the lipid storage cell model. HucMSCs, exosomes, and culture medium were then co-cultured. At the same time, C57BL/6 mice were fed an HFMRCD for 6 or 8 weeks to establish a NASH mouse model. The effect of HucMSCs, exosomes, and culture medium on lipid droplet repair of hepatocytes or NASH mice was then assessed. The weight of hepatocytes or liver tissue, Oil Red O, hematoxylin-eosin staining, Masson staining, Western blot, and qPCR were used to detect the related IL-6, TNF-α, TGF-ß1 andEI24/AMPK/mTOR pathway expression in hepatocytes and liver tissue. Compared with the model group, the effect of HucMSCs-Ex on inhibiting the accumulation of lipid droplets was more obvious at the cell level. In vivo study showed that HucMSCs-Ex reduces activity scores in NASH mice and improves liver tissue morphology by reducing vacuolar degeneration, fat deposition, and collagen deposition of liver tissue. Western blot and qPCR results showed that inflammatory factors and AMPK/mTOR or EI24-related autophagy pathways were altered before and after treatment. HucMSCs, HucMSC-Ex, and CM can promote autophagy in hepatocytes or NASH mice through the AMPK/mTOR or EI24-related autophagy pathway and alleviate injury associated with lipid deposition, collagen deposition or inflammation, reversing the progression of NASH.

miR­137 is a diagnostic tumor­suppressive miRNA that targets SPHK2 to promote M1­type tumor­associated macrophage polarization.

The present study investigated the expression level of microRNA (miR)-137 in glioma tissues and cell lines and explored its potential diagnostic significance as well as its function effects on glioma cells. miR-137 expression level was detected in glioma tissues using in situ hybridization, and in glioma cell lines using reverse transcription-quantitative PCR (RT-qPCR). The diagnostic significance of miR-137 in glioma was assessed using receiver operating characteristic curve analyses. Quantibody® Human Inflammation Array 1 was used to evaluate the impact of ectopic miR-137 expression on release of cytokines in glioma cell lines. IL-13, TNF-α and IFN-γ levels were detected using ELISA. To confirm that sphingosine kinase 2 (SPHK2) is a target of miR-137, RT-qPCR, western blot analysis and dual-luciferase assay were adopted. The results demonstrated that miR-137 expression was downregulated in both glioma tissues and cell lines. Downregulation of miR-137 was significantly associated with high grade gliomas. Additionally, it was found that overexpression of miR-137 reduced IL-13, but promoted TNFα and IFN-γ production. SPHK2 knockdown inhibited IL-13 release, promoted TNF-α and IFN-γ production. SPHK2 was a direct target of miR-137. Collectively, the results of the present study indicated that miR-137 expression plays a tumor-suppressive role in glioma. It is downregulated in glioma and may promote M1-type TAMs polarization, and may be a diagnostic biomarker and potential therapeutic strategy for glioma treatment in the future.

HMGB1 induces macrophage pyroptosis in chronic endometritis.

BACKGROUND: Chronic endometritis (CE) reflects the local imbalance in the endometrial immune microenvironment after inflammation. High mobility group box 1 (HMGB1) is highly involved in both immunity and inflammation. In this study, we aimed to explore the roles of HMGB1 in the endometrium of patients with CE. METHODS: Endometrium and uterine fluid HMGB1 were tested in a cohort of infertile patients with or without CE. Expression levels of the pyroptosis marker, gasdermin D (GSDMD)-N-terminal (NT), in the human endometrium of patients with CE and controls were determined. Next, the role of HMGB1 as a driver of macrophage pyroptosis was investigated using human THP-1 cells in vitro and a CE mouse model in vivo. RESULTS: High expression levels of HMGB1 in biopsied endometrial tissue and uterine fluid were confirmed in a cohort of patients with CE. Positive correlation between the number of CD138+ cells and HMGB1 mRNA expression level were detected (rs = 0.592, P < 0.001). Meanwhile, we found that GSDMD-NT expression was significantly increased in the CE endometrium at both the transcriptional and translational levels. Moreover, co-localization of GSDMD-NT and macrophages was confirmed via the double immunostaining of GSDMD-NT and CD68. In vitro experiments revealed that macrophage pyroptosis was induced by HMGB1 in human THP-1-derived macrophages. Treatment with glycyrrhizic acid, an inhibitor of HMGB1, significantly suppressed endometrial pyroptosis and inflammation in the CE mouse model. CONCLUSIONS: HMGB1 effectively induced macrophage pyroptosis in the human endometrium, suggesting that its inhibition may serve as a novel treatment option for CE.

Impact of antibiotic cured chronic endometritis on perinatal outcomes: Re-evaluation of a cohort study with a detailed follow-up.

PROBLEM: The impact of antibiotic-cured chronic endometritis (CE) on perinatal outcomes of patients conceived with frozen embryo transfer (FET) was unclear. METHOD: This study was to re-evaluate the perinatal outcomes of a cohort of infertile patients who had undergone endometrial biopsy for CE detection from February 2018 to December 2019 and successfully delivered babies after FET. The study population was divided into two groups: the non-CE (NCE) group (0-4/HPF CD138) and the cured-CE (CCE) group (CD138+/HPF≥5 and has been cured after one or two rounds of antibiotic treatment). For subgroup analysis, the NCE group was further divided into subgroup 1 (CD138+/HPF = 0), subgroup 2 (CD138+/HPF = 1-4 with antibiotic treatment), and subgroup 3 (CD138+/HPF = 1-4 without antibiotic treatment) RESULTS: A total of 321 live births, including 210 in the NCE group and 111 in the CCE group were analyzed. The prevalence rates of premature rupture of the membrane and preterm birth were comparable between NCE and CCE (6.2% vs. 7.1% and 10.8% vs. 10.1%, respectively) groups. In addition, no differences were detected in the rates of placenta-mediated complications, such as preeclampsia, placenta abruption, or low birthweight. Multiple logistic analyses confirmed that CCE was not associated with an increased risk of any adverse perinatal outcomes. Subgroup analysis in NCE failed to find any significant differences in the incidences of obstetrical and neonatal complications. CONCLUSIONS: CCE might not increase the risks of adverse perinatal outcomes after antibiotic treatment.

Age at menarche and polycystic ovary syndrome: A Mendelian randomization study.

OBJECTIVE: The authors aimed to use a large two-sample Mendelian randomization (MR) study to reveal the causality between age at menarche (AAM) and polycystic ovary syndrome (PCOS) incidence. METHODS: The authors collected summary statistics from the hitherto largest genome-wide association studies conducted in AAM and PCOS in the same ancestry. MR with inverse variance weighting was conducted as the main analysis method, while weighted median and MR-Egger regression were used for comprehensive analysis. As for pleiotropy detection, inverse variance weighting, MR-Egger regression, Mendelian Randomization Pleiotropy Residual Sum and Outlier, as well as leave-one-out analysis were used to detect pleiotropy. Risk factor analysis was conducted to investigate the underlying mechanisms linking AAM to PCOS. RESULTS: Each standard deviation increment in AAM was associated with a significantly lower incidence of PCOS (odds ratio, 0.86 [95% confidence interval, 0.75-0.98]). After adjustment in horizontal pleiotropy by eliminating four outliers, this pathogenic association was still statistically detected. All pleiotropy indexes were without statistical differences, which suggested the conclusions were robust. It showed the causal association between later AAM and lower body mass index, lower fasting insulin level and insulin resistance. CONCLUSION: Our MR analysis verified that a slightly later onset age (15 to 18 years) at menarche could reduce the risk of PCOS. A more comprehensive investigation in a prospective setting is strongly advised.

METTL3 is essential for normal progesterone signaling during embryo implantation via m6A-mediated translation control of progesterone receptor.

Embryo implantation, a crucial step in human reproduction, is tightly controlled by estrogen and progesterone (P4) via estrogen receptor alpha and progesterone receptor (PGR), respectively. Here, we report that N6-methyladenosine (m6A), the most abundant mRNA modification in eukaryotes, plays an essential role in embryo implantation through the maintenance of P4 signaling. Conditional deletion of methyltransferase-like 3 (Mettl3), encoding the m6A writer METTL3, in the female reproductive tract using a Cre mouse line with Pgr promoter (Pgr-Cre) resulted in complete implantation failure due to pre-implantation embryo loss and defective uterine receptivity. Moreover, the uterus of Mettl3 null mice failed to respond to artificial decidualization. We further found that Mettl3 deletion was accompanied by a marked decrease in PGR protein expression. Mechanistically, we found that Pgr mRNA is a direct target for METTL3-mediated m6A modification. A luciferase assay revealed that the m6A modification in the 5' untranslated region (5'-UTR) of Pgr mRNA enhances PGR protein translation efficiency in a YTHDF1-dependent manner. Finally, we demonstrated that METTL3 is required for human endometrial stromal cell decidualization in vitro and that the METTL3-PGR axis is conserved between mice and humans. In summary, this study provides evidence that METTL3 is essential for normal P4 signaling during embryo implantation via m6A-mediated translation control of Pgr mRNA.

Temporal recording of mammalian development and precancer.

Key to understanding many biological phenomena is knowing the temporal ordering of cellular events, which often require continuous direct observations [1, 2]. An alternative solution involves the utilization of irreversible genetic changes, such as naturally occurring mutations, to create indelible markers that enables retrospective temporal ordering [3-8]. Using NSC-seq, a newly designed and validated multi-purpose single-cell CRISPR platform, we developed a molecular clock approach to record the timing of cellular events and clonality in vivo , while incorporating assigned cell state and lineage information. Using this approach, we uncovered precise timing of tissue-specific cell expansion during murine embryonic development and identified new intestinal epithelial progenitor states by their unique genetic histories. NSC-seq analysis of murine adenomas and single-cell multi-omic profiling of human precancers as part of the Human Tumor Atlas Network (HTAN), including 116 scRNA-seq datasets and clonal analysis of 418 human polyps, demonstrated the occurrence of polyancestral initiation in 15-30% of colonic precancers, revealing their origins from multiple normal founders. Thus, our multimodal framework augments existing single-cell analyses and lays the foundation for in vivo multimodal recording, enabling the tracking of lineage and temporal events during development and tumorigenesis.

Embryo selection through non-invasive preimplantation genetic testing with cell-free DNA in spent culture media: a protocol for a multicentre, double-blind, randomised controlled trial.

INTRODUCTION: Morphological evaluation is used to select embryos for in vitro fertilisation. However, it does not fully reflect the implantation potential. Preimplantation genetic testing for aneuploidies (PGT-A) can detect embryonic aneuploidy, but biopsy procedure is invasive. Currently, a non-invasive PGT (ni-PGT) approach using spent medium is being evaluated. However, the clinical benefit of ni-PGT has not been clearly demonstrated. A multicentre randomised trial is needed to verify whether ni-PGT can be an new effective tool for evaluating embryos. METHODS AND ANALYSIS: Overall, 1148 couples aged 35~42 (women) receiving in vitro fertilization-intracytoplasmic sperm injection are planned to be enrolled. Couples will be digitally randomised to (1) ni-PGT and (2) conventional morphology groups at a 1:1 treatment ratio. The primary outcome will be the ongoing pregnancy rate related to the first transfer cycle within 6 months after oocyte retrieval. ETHICS AND DISSEMINATION: The study protocol is approved by the Ethics Committee of Peking University Third Hospital and the participating hospitals. The results will be disseminated through international conferences and scientific journals. TRIAL REGISTRATION NUMBER: NCT04339166.

Risk factors related to chromosomal mosaicism in human blastocysts.

RESEARCH QUESTION: Do factors relating to patients, ART, or both, affect the incidence of chromosomal mosaicism in human blastocysts? DESIGN: Blastocysts (n = 5718) from 1198 PGT-A cycles were biopsied between 2015 and 2021. All samples were amplified with multiple displacement amplification, and MiSeq system was used for next-generation sequencing. Mosaicism prevalence, and ART and patient factors potentially affecting mosaicism, were analysed. RESULTS: Among 5718 blastocysts detected, 1245 were mosaic (21.8%). Day-6 biopsied blastocysts yielded a statistically significantly higher mosaicism rate than day-5 blastocysts (24.5% versus 19.1%; OR 1.174; 95% CI 1.017 to 1.355, P = 0.028). Mosaicism rate increased as morphological score declined (excellent quality [13.2%], good quality [19.0%], average quality [22.0%] and poor quality [26.4%], P < 0.001). Compared with excellent-quality embryos, the OR of mosaicism was 1.490 (95% CI 1.069 to 2.078, P = 0.019) for good-quality, 1.751 (95% CI 1.274 to 2.407, P = 0.001) for average-quality, and 2.113 (95% CI 1.512 to 2.952, P < 0.001) for poor-quality embryos. Biopsy technicians were related to the incidence of mosaicism. One of the four technicians had a significantly higher mosaicism rate than the others (27.9%; 20.9%; 20.5%; 20.5%, respectively; P < 0.001). Parental ages, female BMI, history of infertility, sperm quality, antral follicular counts, ovarian stimulation protocols, stimulation length, total gonadotrophin dosage and number of retrieved oocytes, were not related to the incidence of mosaicism. CONCLUSION: Slow developing, poor-quality blastocysts are at higher risk of mosaicism. Biopsy technician may contribute to artificial mosaicism as an extrinsic factor.

Impact of Radiation Therapy on Outcomes of Artificial Urinary Sphincter: A Systematic Review and Meta-Analysis.

BACKGROUND: To compare incontinence rates and complications in patients receiving artificial urinary sphincter (AUS) with or without radiotherapy (RT). METHODS: PubMed, Embase, ScienceDirect, CENTRAL, and Google Scholar databases were searched for studies comparing outcomes of AUS between patients with and without RT. Search limits were from 1st January 2002 to 15th September 2021. RESULTS: Eighteen studies were included. Meta-analysis revealed statistically significant reduced odds of the absence of incontinence in the RT group (OR: 0.35 95% CI: 0.21, 0.59 I 2 = 51% p < 0.0001) as compared to the no-RT group. We also noted statistically significant increased risk of revision surgery in the RT group (OR: 1.74 95% CI: 1.16, 2.60 I 2 = 73% p = 0.07). There was increased risk of infections (OR: 2.51 95% CI: 1.00, 6.29 I 2 = 46% p = 0.05) and erosions (OR: 2.00 95% CI: 1.15, 3.45 I 2 = 21% p = 0.01) in the RT group, but the difference was significant only for erosions. Meta-analysis revealed a statistically significant increased risk of explantation in patients with RT (OR: 3.00 95% CI: 1.16, 7.75 I 2 = 68% p = 0.02) but there was no difference in the risk of urethral atrophy (OR: 1.18 95% CI: 0.47, 2.94 I 2 = 46% p = 0.72) and mechanical failure (OR: 0.90 95% CI: 0.25, 3.27 I 2 = 54% p = 0.87) between the two groups. CONCLUSIONS: Our meta-analysis of recent studies indicates that RT significantly reduces the odds of achieving complete continence after AUS placement. History of RT does not increase the risk urethral atrophy or mechanical failure in patients with AUS. However, the risk of revision surgery, erosions and explantations is significantly increased in patients with RT with a non-significant but increased tendency of infections. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier: NCT02612389.

SARS-CoV-2 NSP5 and N protein counteract the RIG-I signaling pathway by suppressing the formation of stress granules.

As a highly pathogenic human coronavirus, SARS-CoV-2 has to counteract an intricate network of antiviral host responses to establish infection and spread. The nucleic acid-induced stress response is an essential component of antiviral defense and is closely related to antiviral innate immunity. However, whether SARS-CoV-2 regulates the stress response pathway to achieve immune evasion remains elusive. In this study, SARS-CoV-2 NSP5 and N protein were found to attenuate antiviral stress granule (avSG) formation. Moreover, NSP5 and N suppressed IFN expression induced by infection of Sendai virus or transfection of a synthetic mimic of dsRNA, poly (I:C), inhibiting TBK1 and IRF3 phosphorylation, and restraining the nuclear translocalization of IRF3. Furthermore, HEK293T cells with ectopic expression of NSP5 or N protein were less resistant to vesicular stomatitis virus infection. Mechanistically, NSP5 suppressed avSG formation and disrupted RIG-I-MAVS complex to attenuate the RIG-I-mediated antiviral immunity. In contrast to the multiple targets of NSP5, the N protein specifically targeted cofactors upstream of RIG-I. The N protein interacted with G3BP1 to prevent avSG formation and to keep the cofactors G3BP1 and PACT from activating RIG-I. Additionally, the N protein also affected the recognition of dsRNA by RIG-I. This study revealed the intimate correlation between SARS-CoV-2, the stress response, and innate antiviral immunity, shedding light on the pathogenic mechanism of COVID-19.

Retrospective analysis of the endometrial preparation protocols for frozen-thawed embryo transfers in women with endometrial polyps.

We aimed to explore the clinical effects of the endometrial preparation protocol for frozen-thawed embryo transfer (FET) in women with endometrial polyps. This retrospective study was performed at the Reproductive Medicine Centre of the First Affiliated Hospital of Sun Yat-sen University between January 2015 and May 2018 involving women diagnosed with endometrial polyps by hysteroscopy. The freeze-all strategy was performed in controlled ovarian stimulation cycles followed by FET cycles. Endometrial preparation protocols included: (i) gonadotropin-releasing hormone agonist-hormone replacement therapy (GnRHa-HRT); (ii) hormone replacement therapy (HRT); (iii) natural cycle (NC); and (iv) ovulation induction (OI). Recurrence rate of polyps and clinical results were compared among the four groups. If polyp recurrence was found in ultrasound scans during the FET cycles, the embryo transfers were cancelled. The recurrence rate of polyps was lower in the GnRHa-HRT protocol [2.13% (2/94)] than in the other three protocols [6.15% (26/423), 6.7% (28/418), and 4% (1/25) in the HRT, NC, and OI, respectively; p = 0.038], showing statistically significant difference. Pregnancy, early pregnancy loss, and live birth rates among the four protocols were similar (p = 0.922, p = 0.171, and p = 0.072, respectively). The GnRHa-HRT protocol used for FET in women with endometrial polyps could reduce the recurrence rate of the polyps. In addition, we found that it did not decrease pregnancy or live birth rates.

Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps.

Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC.

A Novel Nomogram for Individualized Gonadotropin Starting Dose in GnRH Antagonist Protocol.

Controlled ovarian stimulation (COS) is one of the most vital parts of in vitro fertilization-embryo transfer (IVF-ET). At present, no matter what kinds of COS protocols are used, clinicians have to face the challenge of selection of gonadotropin starting dose. Although several nomograms have been developed to calculate the appropriate gonadotropin starting dose in gonadotropin releasing hormone (GnRH) agonist protocol, no nomogram was suitable for GnRH antagonist protocol. This study aimed to develop a predictive nomogram for individualized gonadotropin starting dose in GnRH antagonist protocol. Single-center prospective cohort study was conducted, with 198 women aged 20-45 years underwent IVF/intracytoplasmic sperm injection (ICSI)-ET cycles. Blood samples were collected on the second day of the menstrual cycle. All women received ovarian stimulation using GnRH antagonist protocol. Univariate and multivariate analysis were performed to identify predictive factors of ovarian sensitivity (OS). A nomogram for gonadotropin starting dose was developed based on the multivariate regression model. Validation was performed using concordance statistics and bootstrap resampling. A multivariate regression model based on serum anti-Müllerian hormone (AMH) level, antral follicle count (AFC), and body mass index (BMI) was developed and accounted for 59% of the variability of OS. An easy-to-use predictive nomogram for gonadotropin starting dose was established with excellent accuracy. The concordance index (C-index) of the nomogram was 0.833 (95% CI, 0.829-0.837). Internal validation using bootstrap resampling further showed the good performance of the nomogram. In conclusion, gonadotropin starting dose in antagonist protocol can be predicted precisely by a novel nomogram.