Causal Relationships between Gut Microbiotas, Blood Metabolites, and Neuroendocrine Tumors: A Mediated Mendelian Randomization Study.

Introduction Neuroendocrine tumors (NETs) are a heterogeneous group of epithelial tumors originating from different anatomical sites, identifying the gut microbiota and metabolic mechanisms involved in the onset of NETs may help to develop appropriate disease prevention and monitoring strategies. Methods We employed a mediated two-sample Mendelian Randomization (MR) approach, analyzing gut microbiota from German studies and NET datasets from the 10th round of the FinnGen project. Mediation analyses were conducted using the metabolites dataset from the Canadian Longitudinal Study of Aging (CLSA) and the TwinsUK study. Instrumental variables (IVs) chosen according to established MR criteria and analyzed using the Wald ratio, inverse-variance weighted (IVW), MR-Egger, and weighted median methods. To ensure robustness, sensitivity analyses were performed using Cochrane's Q, Egger's intercept, MR-PRESSO, and leave-one-out (LOO) methods. Results Causal relationships were identified between the genetic determinants of 6, 5, 2, 1, 2, 3 gut microbiotas and the risk of colorectal, lung, pancreatic, rectum, small intestine and stomach NETs. Similarly, the genetic determinants of 4, 6, 1, 5, 10 and 7 metabolites were found to be causally related to the risk of colorectal, lung, pancreatic, rectum, small intestine and stomach NETs, respectively. Through Wald ratio and IVW methods, we preliminarily identified 957 microbiota-metabolite pairs with significant causal associations, and formed 13 mediated relationships between the impact of gut microbiotas on NETs. Conclusion Our study suggests that gut microbiotas and its derived metabolites may contribute to the onset of NET, offering a novel insight into the disease's pathogenesis.

Associations between serum metabolites and female cancers: A bidirectional two-sample mendelian randomization study.

Female cancers, especially breast, ovarian, cervical, and endometrial cancers, constitute a major threat to women's health worldwide. In view of the complex genetic background of cancers cannot be fully explained with current genetic information, we used a bidirectional two-sample mendelian randomization approach to explore the causal associations between serum metabolites and four major female cancers-breast, ovarian, cervical, and endometrial cancers. We analyzed the metabolites dataset from the Canadian Longitudinal Study of Aging and cancer datasets from the 10th round of the Finngen project. Replication analyses was performed with Cancer Association Consortium and Leo's studies. Instrumental variables were analyzed using methods including the Wald ratio, inverse-variance weighted, MR-Egger, and weighted median. To ensure robustness, sensitivity analyses were performed using Cochrane's Q, Egger's intercept, MR-PRESSO, and leave-one-out methods. After meticulous analysis, we obtained levels of 3-hydroxyoleoylcarnitine, hexadecanedioate, tetradecanedioate, and carnitine C14 with robust causal associations with breast cancer, levels of 5alpha-androstan-3alpha,17beta-diol monosulfate (1), androstenediol (3beta,17beta) monosulfate (1), androsterone sulfate, and 5alpha-androstan-3beta,17beta-diol disulfate causal associations with endometrial cancer. The reverse analysis showed that breast, ovarian, and endometrial cancer and survival of breast and ovarian cancer were found to have causal relationships with 8, 5, 2, 6, and 3 metabolites, respectively. These insights underscore the potential roles of specific metabolites in the etiology of female cancers, providing new biomarkers for early detection, risk stratification, and disease progression monitoring. Further research could elucidate how these metabolites influence specific pathways in cancer development, offering theoretical foundations for prevention and treatment strategies.

Associations between immune cell traits and autoimmune thyroid diseases: a bidirectional two-sample mendelian randomization study.

Autoimmune thyroid diseases (AITDs), mainly including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are common autoimmune disorders characterized by abnormal immune responses targeting the thyroid gland. We conducted a bidirectional two-sample MR analysis using the largest dataset of peripheral immune cell phenotypes from Sardinia, and the AITD dataset from the 10th round of the FinnGen and the UK Biobank project. Instrumental variables (IVs) were rigorously selected based on the three assumptions of MR and analyzed using the Wald ratio, inverse-variance weighted (IVW), MR-Egger, and weighted median methods. Additionally, sensitivity analyses were performed using Cochrane's Q, the Egger intercept, the MR-PRESSO, and the leave-one-out (LOO) method to ensure the robustness of the results. The Steiger test was utilized to identify and exclude potential reverse causation. The results showed that 3, 3, and 11 immune cell phenotypes were significantly associated with the risk of AITD. In GD, the proportion of naive CD4-CD8- (DN) T cells in T cells and the proportion of terminally differentiated CD4+T cells in T cells showed the strongest inducing and protective effects, respectively. In HT, lymphocyte count and CD45 on CD4+T cells showed the strongest inducing and protective effects, respectively. In autoimmune hypothyroidism, CD127 CD8+T cell count and terminally differentiated DN T cell count exhibited the strongest inducing and protective effects, respectively. Through MR analysis, our study provides direct genetic evidence of the impact of immune cell traits on AITD risk and lays the groundwork for potential therapeutic and diagnostic target discovery.

Primary synovial sarcoma of the thyroid gland: a CARE compliant case report and literature review.

Rationale: Synovial sarcoma is a subtype of soft tissue sarcoma. Synovial sarcoma in the head and neck region is relatively unusual. Primary synovial sarcoma of the thyroid gland (PSST) is first reported in 2003 by Inako Kikuchi. PSST is extremely rare with only 15 cases documented globally. PSST shows rapid disease progression and a relatively poor prognosis. However, diagnosis and therapy are challenging for clinical surgeons. In this article, we reported the 16th PSST case and reviewed the PSST cases globally for further clinical application. Patient concerns: The patient was referred to us because of gradually worsened dyspnea and dysphagia for 20 days. Physical examination showed a 5 × 4 cm mass with a clear boundary and good mobility. Contrast-enhanced ultrasonography (CEUS) and computed tomography (CT) showed a mass in the isthmus of the thyroid gland. The imageology diagnosis tends to be a benign thyroid nodule. Diagnosis: After surgery, histopathology, immunohistochemistry, and fluorescence, in situ hybridization indicated the mass to be primary synovial sarcoma of the thyroid gland with no local and distant metastasis. Interventions: The patient underwent total thyroidectomy and dissected the lymph nodes in the central compartment. This patient received postoperative chemotherapy (a combination of ifosfamide and epirubicin for five cycles). Patients tolerated chemotherapy well. No recurrence was found during the 9-month follow-up. Lessons: Although PSST is an extremely rare disease, we should raise our awareness when we encounter a rapidly growing, cystic-solid mixed thyroid mass with neck compression symptoms to avoid misdiagnosis. Intraoperatively, surgeons should refine surgical procedures to avoid capsular rupture and tumor local implantation metastasis. Intraoperative frozen section pathology is necessary sometimes, especially when the diagnosis could not be established before surgery.

Novel Long Non-coding RNA lncAMPC Promotes Metastasis and Immunosuppression in Prostate Cancer by Stimulating LIF/LIFR Expression.

Long non-coding RNAs (lncRNAs) participate in the development and progression of prostate cancer (PCa). We aimd to identify a novel lncRNA, named lncRNA activated in metastatic PCa (lncAMPC), and investigate its mechanisms and clinical significance in PCa. First, the biological capacity of lncAMPC in PCa was demonstrated both in vitro and in vivo. The lncAMPC was overexpressed in tumor tissue and urine of metastatic PCa patients and promoted PCa tumorigenesis and metastasis. Then, a mechanism study was conducted to determine how the lncAMPC-activated pathway contributed to PCa metastasis and immunosuppression. In the cytoplasm, lncAMPC upregulated LIF expression by sponging miR-637 and inhibiting its activity. In the nucleus, lncAMPC enhanced LIFR transcription by decoying histone H1.2 away from the upstream sequence of the LIFR gene. The lncAMPC-activated LIF/LIFR expressions stimulated the Jak1-STAT3 pathway to simultaneously maintain programmed death-ligand 1 (PD-L1) protein stability and promote metastasis-associated gene expression. Finally, the prognostic value of the expression of lncAMPC and its downstream genes in PCa patients was evaluated. High LIF/LIFR levels indicated shorter biochemical recurrence-free survival among patients who underwent radical prostatectomy. Therefore, the lncAMPC/LIF/LIFR axis plays a critical role in PCa metastasis and immunosuppression and may serve as a prognostic biomarker and potential therapeutic target.

Morbid obesity is adversely associated with perioperative outcomes in patients undergoing robot-assisted laparoscopic radical prostatectomy.

INTRODUCTION: Robot-assisted laparoscopic radical prostatectomy (RALRP) may be more challenging in obese individuals. This study aimed to evaluate whether obesity had an adverse effect on perioperative outcomes following RALRP. METHODS: Hospitalized patients who underwent RALRP from 2008-2014 were identified using the National Inpatient Sample database. We grouped RALRP patients into non-obese, obesity class I-II, and obesity class III (morbid obesity). Rates of blood transfusion, intraoperative and postoperative complications, in-hospital mortality, prolonged length of stay, and total costs were compared among the three groups by univariate regression, multivariate regression, and propensity score weighting analysis. RESULTS: Of 53 301 patients identified, 48 725 were non-obese, 3572 were diagnosed with obesity class I-II, and 1004 were diagnosed with morbid obesity. Compared to non-obesity (7.62%), overall postoperative complications were commonly observed in obesity class I-II (10.55%) and morbid obesity (17.11%). Multivariable analyses suggested that morbid obesity was associated with increased overall postoperative (odds ratio [OR] 2.00, 95% confidence interval [CI] 1.65-2.42), cardiac (OR 1.63, 95% CI 1.03-2.58), respiratory (OR 4.03, 95% CI 3.04-5.36), genitourinary (OR 1.77, 95% CI 1.08-2.90), miscellaneous medical (OR 1.94, 95% CI 1.58-2.39) complications, prolonged hospitalization (OR 1.86, 95% CI 1.57-2.21), and 12% higher total cost. Propensity score weighting analysis yielded similar results. Adequate covariate balance was achieved for all variables after weighting. CONCLUSIONS: Morbid obesity is adversely associated with perioperative outcomes in RALRP. Close management is required in patients undergoing RALRP with morbid obesity for potential worse prognosis.

Comprehensive investigation of alternative splicing and development of a prognostic risk score for prostate cancer based on six-gene signatures.

Purpose: To systematically document alternative splicing profiles of prostate cancer in relatively large populations in order to construct a prognostic predictors model for prostate cancer. Methods: Splicing data and clinical information of 495 prostate cancer patients were obtained from The Cancer Genome Atlas (TCGA). The SpliceSeq database was used to extract information regarding splicing events. Multiple bioinformatic tools were used for functional and pathway enrichment analysis as well as for construction of gene interaction networks. Candidate gene expression profiles were verified with clinical samples using QRT-PCR. Results: We detected a total of 44070 alternative splicing events of 10381 genes in prostate cancer. 7 and 14 KEGG pathways were enriched and were associated with overall and recurrence-free survival, respectively. The expression of 396 genes among the 1526 overall survival genes associated alternative splicing events were associated with overall survival. The expression of 483 genes among the 1916 recurrence-free survival genes associated alternative splicing events were associated with recurrence-free survival. Lastly, we constructed the prognosis risk score system based on the expression profiles of six-gene signatures which in combination had an AUC of 0.941 for overall survival associated alternative splicing events, followed by overall survival associated gene expressions with an AUC of 0.794, a recurrence-free survival associated gene expression with an AUC of 0.752 and recurrence-free survival associated alternative splicing events with an AUC of 0.735, indicating its strong ability to predict patient outcome. The expression profile of the six genes was also confirmed in different prostate cell lines and clinic samples. Conclusion: Our comprehensive investigation of alternative splicing not only provided insight into the biological pathways of alternative splicing involved in the development of prostate cancer but also revealed new potential biomarkers for prognosticating as well as novel therapeutic targets for development of prostate cancer treatment.