Does neoadjuvant therapy contribute to increased risk in anastomotic leakage of esophageal cancer? A network meta-analysis.

AIM: Conflicting results have been reported about the impact of neoadjuvant therapy on anastomotic leakage (AL) after esophagectomy. We aimed to unravel the potential effect of neoadjuvant therapy on AL after esophagectomy through a network meta-analysis. METHODS: A Bayesian network meta-analysis was performed by retrieving relevant literature from PubMed, EMbase, The Cochrane Library and Web of Science Core Collection. Randomized clinical trials (RCTs) and retrospective studies (RS) comparing the following treatment modalities were included: neoadjuvant chemoradiation (nCRT), neoadjuvant chemotherapy (nCT), neoadjuvant radiotherapy (nR), neoadjuvant immunochemotherapy (nICT), and surgery alone (SA). Subgroup analyses by radiation dose, examined lymph nodes (ELN), route of reconstruction, site of anastomosis, and surgical approach were also conducted. RESULTS: A total of 62 studies with 12,746 patients were included for the present study, among which 17 were RCTs. There were no significantly statistical differences observed among the five treatment modalities in AL for both RCTs (nCRT-nICT: risk ratio 1.51, 95% confidence interval 0.52-4.4; nCT-nICT: 1.71, 0.56-5.08; nICT-nR: 0.79, 0.12-8.02; nICT-SA: 0.59, 0.2-1.84) and RS (nCRT-nICT: odds ratio 1.53, 95% confidence interval 0.84-2.84; nCT-nICT: 1.56, 0.87-2.88; nICT-SA: 0.6, 0.31-1.12; nICT-nR: 1.08, 0.09-36.02). Subgroup analysis revealed that no significant difference in AL was observed among the five treatment modalities except for the impact of nCRT versus nCT (0.21, 0.05-0.73) on AL with a radiation dose ≥41.4 Gy. CONCLUSIONS: Neoadjuvant therapy do not significantly increase the incidence of AL after esophagectomy. Administration of irradiation with a moderate dose is not associated with elevated risk in AL. Clinicians can be less apprehensive about prescribing nCRT.

Dissecting the shared genetic architecture between anti-Müllerian hormone and age at menopause based on genome-wide association study.

BACKGROUND: While the phenotypic association between anti-Müllerian hormoneand age at menopause has been widely studied, the role of anti-Müllerian hormone in predicting the age at menopause is currently controversial, and the genetic architecture or causal relationships underlying these 2 traits is not well understood. AIM: We aimed to explore the shared genetic architecture between anti-Müllerian hormone and age at menopause, to identify shared pleiotropic loci and genes, and to investigate causal association and potential causal mediators. STUDY DESIGN: Using summary statistics from publicly available genome-wide association studies on anti-Müllerian hormone (N=7049) and age at menopause (N=201,323) in Europeans, we investigated the global genetic architecture between anti-Müllerian hormone and age at menopause through linkage disequilibrium score regression. We employed pleiotropic analysis under composite null hypothesis, Functional Mapping and Annotation of Genetic Associations, multimarker analysis of GenoMic annotation, and colocalization analysis to identify loci and genes with pleiotropic effects. Tissue enrichment analysis based on Genotype-Tissue Expression data was conducted using the Linkage Disequilibrium Score for the specific expression of genes analysis. Functional genes that were shared were additionally identified through summary data-based Mendelian randomization. The relationship between anti-Müllerian hormone and age at menopause was examined through 2-sample Mendelian randomization, and potential mediators were further explored using colocalization and metabolite-mediated analysis. RESULTS: A positive genetic association (correlation coefficient=0.88, P=1.33×10-5) was observed between anti-Müllerian hormone and age at menopause. By using pleiotropic analysis under composite null hypothesis and Functional Mapping and Annotation of Genetic Associations, 42 significant pleiotropic loci were identified that were associated with anti-Müllerian hormone and age at menopause, and 10 of these (rs10734411, rs61913600, rs2277339, rs75770066, rs28416520, rs9796, rs11668344, rs403727, rs6011452, and rs62237617) had colocalized loci. Additionally, 245 significant pleiotropic genes were identified by multimarker analysis of GenoMic annotation. Genetic associations between anti-Müllerian hormone and age at menopause were markedly concentrated in various tissues including whole blood, brain, heart, liver, muscle, pancreas, and kidneys. Further, summary data-based Mendelian randomization analysis revealed 9 genes that may have a causative effect on both anti-Müllerian hormone and age at menopause. A potential causal effect of age at menopause on anti-Müllerian hormone was suggested by 2-sample Mendelian randomization analysis, with very-low-density lipoprotein identified as a potential mediator. CONCLUSION: Our study revealed a shared genetic architecture between anti-Müllerian hormone and age at menopause, providing a basis for experimental investigations and individual therapies to enhance reproductive outcomes. Furthermore, our findings emphasized that relying solely on anti-Müllerian hormone is not sufficient for accurately predicting the age at menopause, and a combination of other factors needs to be considered. Exploring new therapeutics aimed at delaying at the onset of menopause holds promise, particularly when targeting shared genes based on their shared genetic architecture.

Maternal smoking, consumption of alcohol, and caffeinated beverages during pregnancy and the risk of childhood brain tumors: a meta-analysis of observational studies.

BACKGROUND: We conducted this meta-analysis to investigate the potential association between maternal smoking, alcohol and caffeinated beverages consumption during pregnancy and the risk of childhood brain tumors (CBTs). METHODS: A thorough search was carried out on PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Internet to identify pertinent articles. Fixed or random effects model was applied to meta-analyze the data. RESULTS: The results suggested a borderline statistically significant increased risk of CBTs associated with maternal smoking during pregnancy (OR 1.04, 95% CI 0.99-1.09). We found that passive smoking (OR 1.12, 95% CI 1.03-1.20), rather than active smoking (OR 1.00, 95% CI 0.93-1.07), led to an increased risk of CBTs. The results suggested a higher risk in 0-1 year old children (OR 1.21, 95% CI 0.94-1.56), followed by 0-4 years old children (OR 1.12, 95% CI 0.97-1.28) and 5-9 years old children (OR 1.11, 95% CI 0.95-1.29). This meta-analysis found no significant association between maternal alcohol consumption during pregnancy and CBTs risk (OR 1.00, 95% CI 0.80-1.24). An increased risk of CBTs was found to be associated with maternal consumption of caffeinated beverages (OR 1.16, 95% CI 1.07-1.26) during pregnancy, especially coffee (OR 1.18, 95% CI 1.00-1.38). CONCLUSIONS: Maternal passive smoking, consumption of caffeinated beverages during pregnancy should be considered as risk factors for CBTs, especially glioma. More prospective cohort studies are warranted to provide a higher level of evidence.

A pathological joint-liver axis mediated by matrikine-activated CD4+ T cells.

The knee joint has long been considered a closed system. The pathological effects of joint diseases on distant organs have not been investigated. Herein, our clinical data showed that post-traumatic joint damage, combined with joint bleeding (hemarthrosis), exhibits a worse liver function compared with healthy control. With mouse model, hemarthrosis induces both cartilage degeneration and remote liver damage. Next, we found that hemarthrosis induces the upregulation in ratio and differentiation towards Th17 cells of CD4+ T cells in peripheral blood and spleen. Deletion of CD4+ T cells reverses hemarthrosis-induced liver damage. Degeneration of cartilage matrix induced by hemarthrosis upregulates serological type II collagen (COL II), which activates CD4+ T cells. Systemic application of a COL II antibody blocks the activation. Furthermore, bulk RNAseq and single-cell qPCR analysis revealed that the cartilage Akt pathway is inhibited by blood treatment. Intra-articular application of Akt activator blocks the cartilage degeneration and thus protects against the liver impairment in mouse and pig models. Taken together, our study revealed a pathological joint-liver axis mediated by matrikine-activated CD4+ T cells, which refreshes the organ-crosstalk axis and provides a new treatment target for hemarthrosis-related disease. Intra-articular bleeding induces cartilage degradation through down-reulation of cartilage Akt pathway. During this process, the soluble COL II released from the damaged cartilage can activate peripheral CD4+ T cells, differention into Th17 cells and secretion of IL-17, which consequently induces liver impairment. Intra-articular application of sc79 (inhibitor of Akt pathway) can prevent the cartilage damage as well as its peripheral influences.

Halogen-Atom Transfer Enabled Catalytic Enantioselective Coupling to Chiral Trifluoromethylated Alkynes via Dual Nickel and Photocatalysis.

With halogen-atom transfer as an effective tool, a novel catalytic enantioselective protocol to generate chiral trifluoromethylated alkynes has been established by a cooperative photoredox and nickel catalysis system, providing a straightforward and modular route to access this type of product in good yields and enantioselectivities. The halogen-atom transfer process is essential for the reaction and this novel strategy offers another promising way to utilize alkyl halides with highly negative reduction potentials. It firstly expands nickel-catalyzed asymmetric reductive cross-couplings of organohalides from the traditional single-electron transfer to halogen-atom transfer.

Oligogenic basis of premature ovarian insufficiency: an observational study.

BACKGROUND: The etiology of premature ovarian insufficiency, that is, the loss of ovarian activity before 40 years of age, is complex. Studies suggest that genetic factors are involved in 20-25% of cases. The aim of this study was to explore the oligogenic basis of premature ovarian insufficiency. RESULTS: Whole-exome sequencing of 93 patients with POI and whole-genome sequencing of 465 controls were performed. In the gene-burden analysis, multiple genetic variants, including those associated with DNA damage repair and meiosis, were more common in participants with premature ovarian insufficiency than in controls. The ORVAL-platform analysis confirmed the pathogenicity of the RAD52 and MSH6 combination. CONCLUSIONS: The results of this study indicate that oligogenic inheritance is an important cause of premature ovarian insufficiency and provide insights into the biological mechanisms underlying premature ovarian insufficiency.