Mitochondrial DNA copy number and cancer risks: A comprehensive Mendelian randomization analysis.

Mitochondrial DNA plays a critical role in the pathophysiology of cancer. However, the associations between mitochondrial DNA copy number (mtDNA-CN) and cancer risk are controversial. Mendelian randomization (MR) analyses were performed using three independent instrumental variables (IVs) to explore potential associations between mtDNA-CN and 20 types of cancer. The three sets of IVs were primarily obtained from participants in the UK Biobank and the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium using different methods. The outcome data of cancers were investigated using summary statistics from the FinnGen cohort. The potential causal associations were evaluated using the MR-Egger regression, weighted median, inverse-variance weighted (IVW), and weighted mode methods. The robustness of IVW estimates was validated using leave-one-out sensitivity analysis. Additionally, a meta-analysis was conducted to pool results from three sets of IVs. The results revealed that genetically predicted mtDNA-CN was not associated with cancer risk (odds ratio = 1.02; 95% confidence interval: 0.95-1.10). Subgroup analyses indicated no causal association between mtDNA-CN and breast, lung, prostate, skin, colorectal, gastric, liver, cervical uteri, esophageal, thyroid, bladder, pancreas, kidney, corpus uteri, ovary, brain, larynx, and anus cancers. It was observed that mtDNA-CN was associated with lip, oral cavity, and testis cancers. However, these results should be interpreted with caution because a small number of patients with lip and oral cavity or testis cancers were included. The comprehensive MR analysis demonstrated that mtDNA-CN is not a suitable biomarker for tumor risk assessment.

Mitochondrial DNA copy number is associated with Crohn's disease: a comprehensive Mendelian randomization analysis.

Mitochondrial DNA plays a critical role in the pathophysiological process of inflammation. However, the relationship between mitochondrial DNA copy number (mtDNA-CN) and inflammatory bowel diseases (IBD) remains poorly understood. We conducted a comprehensive Mendelian randomization (MR) using three instrumental variables (IVs) to explore the causal associations between mtDNA-CN and IBD, including Crohn's disease (CD), ulcerative colitis (UC). MR-Egger regression, weighted median, inverse-variance weighted (IVW), and weighted mode methods were used to evaluate the potential causal associations. The robustness of the IVW estimates was determined using the leave-one-out sensitivity test. A meta-analysis was conducted to pool the results from the three sets of IVs. Upon analysis, the findings of the current study revealed that genetically predicted mtDNA-CN was not associated with IBD (CD + UC) and UC. The results of MR analyses between mtDNA-CN and CD risk were inconsistent by using three sets of IVs. After a meta-analysis, we found that genetically predicted mtDNA-CN was associated with CD risk (odds ratio = 2.09; 95% confidence interval: 1.37-3.18). This finding was also confirmed by multivariable MR analyses and remained robust when tested with the leave-one-out sensitivity test. In conclusion, genetically predicted mtDNA-CN was found to be associated with CD risk. Therefore, mtDNA levels in the blood could potentially be used as a marker for CD risk assessment. Further studies are needed to elucidate the underlying mechanisms and validate the results of this study.

Development and validation of metabolic models for predicting survival and immune status of hepatocellular carcinoma patients.

BACKGROUND: Metabolic reprogramming is associated with the carcinogenesis of hepatocellular carcinoma (HCC). The effects of metabolism-related genes on predicting survival and immune status in HCC remain unclear. OBJECTIVES: To develop and validate metabolic models for predicting the survival and immune status of HCC patients. MATERIAL AND METHODS: The metabolic core genes for overall survival (OS) and disease-free survival (DFS) were retrieved. Then, glycolysis and fatty acid metabolism prognostic models were constructed and validated using The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) data. Decision trees based on machine learning were developed for classifying the prognostic risks of HCC patients. The associations between the metabolic signatures, immunotherapy and immune cell infiltration were investigated. Experimental validations were performed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). RESULTS: We identified 30 prognostic core genes for glycolysis metabolism and 12 prognostic core genes for fatty acid metabolism. Subsequently, 2 glycolysis models and 2 fatty acid metabolism models were developed to predict the OS and DFS of HCC patients, respectively. Two decision trees were constructed to classify the low-, intermediateand high-risk groups of HCC patients for OS and DFS. Moreover, the patients in the high-risk groups of glycolysis and fatty acid metabolic models tended to have higher expression of programmed cell death ligand-1 (PD-L1 or CD274), programmed cell death 1 (PDCD1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and lymphocyte activating 3 (LAG3). Most of the metabolic core genes were significantly associated with immune cell infiltration. In addition, ATP-binding cassette subfamily B member 6 (ABCB6), peptidylprolyl isomerase A (PPIA), uroporphyrinogen decarboxylase (UROD), and non-SMC condensin II complex subunit H2 (NCAPH2) were positively correlated with both tumor mutational burden (TMB) and microsatellite instability (MSI) scores. The expression of ABCB6, PPIA, UROD, and NCAPH2 was validated using RT-qPCR and IHC. CONCLUSIONS: We established novel prognostic models based on metabolism-related genes to better predict the outcome and immune status of HCC patients.

N6-methyladenosine modification and metabolic reprogramming of digestive system malignancies.

N6-methyladenosine (m6A) is a eukaryotic post-transcriptional modification involved in cell growth and developmental processes, including RNA transcription, alternative splicing, degradation, and translation. It is also involved in the development of various cancers. Metabolic reprogramming enables cancer cells to obtain nutrition from the tumor microenvironment, which is a hallmark of cancer. Numerous studies have shown that m6A modification induces metabolic reprogramming in cancer by regulating the expression of metabolic core genes or activation of metabolic signaling pathways. Digestive system malignancies include esophageal, gastric, colorectal, liver, pancreatic, and other cancers, all of which are associated with poor outcomes. This review summarizes the role of m6A modification in the metabolic reprogramming of digestive system malignancies, with the aim of identifying therapeutic strategies.

MiRNA-124-3p.1 sensitizes hepatocellular carcinoma cells to sorafenib by regulating FOXO3a by targeting AKT2 and SIRT1.

As a multikinase inhibitor, sorafenib is commonly used to treat patients with advanced hepatocellular carcinoma (HCC), however, acquired resistance to sorafenib is a major obstacle to the effectiveness of this treatment. Thus, in this study, we investigated the mechanisms underlying sorafenib resistance as well as approaches devised to increase the sensitivity of HCC to sorafenib. We demonstrated that miR-124-3p.1 downregulation is associated with early recurrence in HCC patients who underwent curative surgery and sorafenib resistance in HCC cell lines. Regarding the mechanism of this phenomenon, we identified FOXO3a, an important cellular stress transcriptional factor, as the key factor in the function of miR-124-3p.1 in HCC. We showed that miR-124-3p.1 binds directly to AKT2 and SIRT1 to reduce the levels of these proteins. Furthermore, we showed that AKT2 and SIRT1 phosphorylate and deacetylate FOXO3a. We also found that miR-124-3p.1 maintains the dephosphorylation and acetylation of FOXO3a, leading to the nuclear location of FOXO3a and enhanced sorafenib-induced apoptosis. Moreover, the combination of miR-124-3p.1 mimics and sorafenib significantly enhanced the curative efficacy of sorafenib in a nude mouse HCC xenograft model. Collectively, our data reveal that miR-124-3p.1 represents a predictive indicator of early recurrence and sorafenib sensitivity in HCC. Furthermore, we demonstrate that miR-124-3p.1 enhances the curative efficacy of sorafenib through dual effects on FOXO3a. Thus, the miR-124-3p.1-FOXO3a axis is implicated as a potential target for the diagnosis and treatment of HCC.

Single-Incision Laparoscopic Intragastric Surgery for Gastric Submucosal Tumors Located Near the Esophagogastric Junction.

Background: Laparoscopic local resection of the stomach for gastric submucosal tumors (SMTs) is widely accepted by surgeons. For SMTs located near the esophagogastric junction (EGJ), simple laparoscopic wedge resection is rarely performed owing to concerns of causing cardia deformities or stenosis. Single-incision laparoscopic intragastric surgery (sLIGS) has been used to treat SMTs located near the EGJ in carefully selected cases. Methods: We modified sLIGS using a subxiphoid incision. Thirteen consecutive patients with intraluminal or intramural growth type gastric SMTs located near the EGJ underwent sLIGS at our institution from July 2018 to April 2020. Results: Thirteen operations were successfully performed using sLIGS, including eight full-thickness resections and five submucosal resections. There were no conversions to an open procedure and all tumors were confirmed to have negative margins on pathology. The mean operation time was 100 ± 10 minutes (range, 85-160 minutes). The mean blood loss was 50 ± 10 mL (range, 50-100 mL). The mean length of postoperative hospital stay was 7 ± 1.5 days (6-10 days). One patient was found to have oozing of blood confirmed by gastroscopy postoperatively and recovered after stopping antiplatelet therapy. Ten cases were gastrointestinal stromal tumor (GIST), two cases were leiomyoma, and one case was neuroendocrine neoplasm. Of the 10 GISTs, 9 were classified as low risk; 1 showed medium risk and the patient received adjuvant imatinib therapy. There were no tumor recurrences during a mean follow-up of 14 ± 4 months (range, 5-25 months). Conclusions: This modified sLIGS for the treatment of the gastric SMTs located near the EGJ is simple and safe. This can be used as an alternative treatment for gastric SMTs near the EGJ.

Quantitative Nanomechanical Mapping of Polyolefin Elastomer at Nanoscale with Atomic Force Microscopy.

Elastomeric nanostructures are normally expected to fulfill an explicit mechanical role and therefore their mechanical properties are pivotal to affect material performance. Their versatile applications demand a thorough understanding of the mechanical properties. In particular, the time dependent mechanical response of low-density polyolefin (LDPE) has not been fully elucidated. Here, utilizing state-of-the-art PeakForce quantitative nanomechanical mapping jointly with force volume and fast force volume, the elastic moduli of LDPE samples were assessed in a time-dependent fashion. Specifically, the acquisition frequency was discretely changed four orders of magnitude from 0.1 up to 2 k Hz. Force data were fitted with a linearized DMT contact mechanics model considering surface adhesion force. Increased Young's modulus was discovered with increasing acquisition frequency. It was measured 11.7 ± 5.2 MPa at 0.1 Hz and increased to 89.6 ± 17.3 MPa at 2 kHz. Moreover, creep compliance experiment showed that instantaneous elastic modulus E1, delayed elastic modulus E2, viscosity η, retardation time τ were 22.3 ± 3.5 MPa, 43.3 ± 4.8 MPa, 38.7 ± 5.6 MPa s and 0.89 ± 0.22 s, respectively. The multiparametric, multifunctional local probing of mechanical measurement along with exceptional high spatial resolution imaging open new opportunities for quantitative nanomechanical mapping of soft polymers, and can potentially be extended to biological systems.

Vitamins and Helicobacter pylori: An Updated Comprehensive Meta-Analysis and Systematic Review.

BACKGROUND: Over recent decades, epidemiological studies have shown relationships between vitamins and Helicobacter pylori (H. pylori) infection and eradication, but the results are controversial. METHODS: A comprehensive meta-analysis and systematic review were conducted to clarify the relationships between common types of vitamins and H. pylori. We applied meta-regression, subgroup analysis and sensitivity analysis to obtain available evidence. Articles published from January 1991 to June 2021 in PubMed, EMBASE, and the Cochrane Library were searched. RESULTS: In total, we identified 48 studies. The results indicate that H. pylori -positive patients had lower serum vitamin B12 [standardized mean difference (SMD) = -0.30; 95% confidence interval (CI): -0.53 - -0.08], folate (SMD = -0.69; 95% CI: -1.34 - -0.04), vitamin C (SMD = -0.37; 95%CI: -0.57 - -0.18) and vitamin D (SMD = -0.34; 95% CI: -0.49 - -0.18) levels than H. pylori-negative patients. Patients in which H. pylori had been successfully eradicated had higher serum vitamin D levels (SMD = 1.37; 95% CI: 0.37-2.38) than in patients in which eradication had been unsuccessful. The serum vitamin B12 levels of H. pylori-positive patients improved after successful H. pylori eradication therapy (SMD = 1.85; 95% CI: 0.81-2.90), and antioxidant vitamin supplementation to an H. pylori eradication regimen improved the eradication rate (risk ratio = 1.22; 95% CI: 1.02-1.44 for per-protocol analysis; risk ratio = 1.25; 95% CI: 1.06-1.47 for intention-to-treat analysis). CONCLUSIONS: H. pylori infections decrease the serum levels of several types of vitamins, eradication of H. pylori could rescue its adverse effects, and antioxidant vitamin supplementation may improve the H. pylori eradication rate. SYSTEMATIC REVIEW REGISTRATION: identifier: CRD42021268127.