YTHDF1's grip on CRC vasculature: insights into LINC01106 and miR-449b-5p-VEGFA axis.

BACKGROUND: Investigating the unexplored territory of lncRNA m6A modification in colorectal cancer (CRC) vasculature, this study focuses on LINC01106 and YTHDF1. METHODS: Clinical assessments reveal upregulated LINC01106 promoting vascular generation via the miR-449b-5p-VEGFA pathway. RESULTS: YTHDF1, elevated in CRC tissues, emerges as an adverse prognostic factor. Functional experiments showcase YTHDF1's inhibitory effects on CRC cell dynamics. Mechanistically, Me-CLIP identifies m6A-modified LINC01106, validated as a YTHDF1 target through Me-RIP. CONCLUSIONS: This study sheds light on the YTHDF1-mediated m6A modification of LINC01106, presenting it as a key player in suppressing CRC vascular generation.

Stiffness sensing via Piezo1 enhances macrophage efferocytosis and promotes the resolution of liver fibrosis.

Tissue stiffening is a predominant feature of fibrotic disorders, but the response of macrophages to changes in tissue stiffness and cellular context in fibrotic diseases remains unclear. Here, we found that the mechanosensitive ion channel Piezo1 was up-regulated in hepatic fibrosis. Macrophages lacking Piezo1 showed sustained inflammation and impaired spontaneous resolution of early liver fibrosis. Further analysis revealed an impairment of clearance of apoptotic cells by macrophages in the fibrotic liver. Macrophages showed enhanced efferocytosis when cultured on rigid substrates but not soft ones, suggesting stiffness-dependent efferocytosis of macrophages required Piezo1 activation. Besides, Piezo1 was involved in the efficient acidification of the engulfed cargo in the phagolysosomes and affected the subsequent expression of anti-inflammation genes after efferocytosis. Pharmacological activation of Piezo1 increased the efferocytosis capacity of macrophages and accelerated the resolution of inflammation and fibrosis. Our study supports the antifibrotic role of Piezo1-mediated mechanical sensation in liver fibrosis, suggesting that targeting PIEZO1 to enhance macrophage efferocytosis could induce fibrosis regression.

Causal relationship between circulating cytokines and follicular lymphoma: a two-sample Mendelian randomization study.

Follicular lymphoma (FL), derived from germinal centre (GC) B cells, is a kind of systemic neoplasm. Even though FL is indolent, it remains an incurable haematology Neoplasm. Accumulating evidence has suggested that the circulating cytokine is associated with the development of FL, yet the causal relationship between FL and circulating cytokines remains undetermined. Therefore, we conducted a two-sample Mendelian randomization (MR) to confirm the causal link between FL and levels of circulating cytokines with the use of summary data on circulating cytokines and FL. All these data from genome-wide association study were derived from the Genome-wide pQTL mapping which contains 14,824 individuals. FL data were acquired exclusively from FinnGen, where 218,792 individuals (522 cases vs. 218,270 controls) were involved. Various statistical methods, including the inverse variance weighted method (IVW), weighted median (WME), simple model, weighted model (WM) and MR-Egger, were used to evaluate the potential causal connection between circulating cytokines and FL. Sensitivity analysis, which involves the examination of the heterogeneity, pleiotropy, and leave-one-out method, was also performed to ensure more trustworthy results. A bidirectional MR test was performed to evaluate the direction of causal association between circulating cytokines and FL. Combining all the steps of MR analysis, we revealed four causal cytokines: C-X-C motif chemokine ligand 5 (CXCL5), interleukin-15 receptor A (IL15RA), interleukin-20 (IL20), and neurotrophin-3 (NT-3). The risk of FL may be inversely linked to CXCL5 (OR=0.73, CI: 0.545-0.979, P=0.036), IL-15RA (OR=0.669, CI: 0.451-0.993, P=0.046), and IL-20 (OR=0.565, CI: 0.325-0.981, P=0.043) but positively linked to NT-3 (OR=1.872, CI: 1.063-3.297, P=0.03). In addition, in our study, no causal effect of FL on cytokines was demonstrated and no significant heterogeneity and pleiotropy were found. Our research revealed the causal relationship between cytokines and FL, along with both the anti-protective effect of CXCL5, IL-15RA, and IL-20 and the protective effect of neurotrophin-3 on FL. These findings aim to provide new clues regarding the pathogenesis of FL and to extend the potential of circulating cytokines to therapeutic interventions.

Serratia plymuthica HK9-3 enhances tomato resistance against Phytophthora capsici by modulating antioxidant defense systems and rhizosphere micro-ecological condition.

Tomatoes are frequently challenged by various pathogens, among which Phytophthora capsici (P. capsici) is a destructive soil-borne pathogen that seriously threatens the safe production of tomatoes. Plant growth-promoting rhizobacteria (PGPR) positively induced plant resistance against multiple pathogens. However, little is known about the role and regulatory mechanism of PGPR in tomato resistance to P. capsici. Here, we identified a new strain Serratia plymuthica (S. plymuthica), HK9-3, which has a significant antibacterial effect on P. capsici infection. Meanwhile, stable colonization in roots by HK9-3, even under P. capsici infection, improved tomato growth parameters, root system architecture, photosynthetic capacity, and boosted biomass. Importantly, HK9-3 colonization significantly alleviated the damage caused by P. capsici infection through enhancing ROS scavenger ability and inducing antioxidant defense system and pathogenesis-related (PR) proteins in leaves, as evidenced by elevating the activities of peroxidase (POD), superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), phenylalanine ammonia lyase (PAL), polyphenol oxidase (PPO), and chitinase, ß-1,3-glucanase, and increasing the transcripts of POD, SOD, CAT, APX1, PAL1, PAL2, PAL5, PPO2, CHI17 and ß-1,3-glucanase genes. Notably, HK9-3 colonization not only effectively improved soil microecology and soil fertility, but also significantly enhanced fruit yield by 44.6% and improved quality. Our study presents HK9-3 as a promising and effective solution for controlling P. capsici infection in tomato cultivation while simultaneously promoting plant growth and increasing yield, which may have implications for P. capsici control in vegetable production.

Typicality- and instance-dependent label noise-combating: a novel framework for simulating and combating real-world noisy labels for endoscopic polyp classification.

Learning with noisy labels aims to train neural networks with noisy labels. Current models handle instance-independent label noise (IIN) well; however, they fall short with real-world noise. In medical image classification, atypical samples frequently receive incorrect labels, rendering instance-dependent label noise (IDN) an accurate representation of real-world scenarios. However, the current IDN approaches fail to consider the typicality of samples, which hampers their ability to address real-world label noise effectively. To alleviate the issues, we introduce typicality- and instance-dependent label noise (TIDN) to simulate real-world noise and establish a TIDN-combating framework to combat label noise. Specifically, we use the sample's distance to decision boundaries in the feature space to represent typicality. The TIDN is then generated according to typicality. We establish a TIDN-attention module to combat label noise and learn the transition matrix from latent ground truth to the observed noisy labels. A recursive algorithm that enables the network to make correct predictions with corrections from the learned transition matrix is proposed. Our experiments demonstrate that the TIDN simulates real-world noise more closely than the existing IIN and IDN. Furthermore, the TIDN-combating framework demonstrates superior classification performance when training with simulated TIDN and actual real-world noise.

Fn-OMV potentiates ZBP1-mediated PANoptosis triggered by oncolytic HSV-1 to fuel antitumor immunity.

Oncolytic viruses (OVs) show promise as a cancer treatment by selectively replicating in tumor cells and promoting antitumor immunity. However, the current immunogenicity induced by OVs for tumor treatment is relatively weak, necessitating a thorough investigation of the mechanisms underlying its induction of antitumor immunity. Here, we show that HSV-1-based OVs (oHSVs) trigger ZBP1-mediated PANoptosis (a unique innate immune inflammatory cell death modality), resulting in augmented antitumor immune effects. Mechanistically, oHSV enhances the expression of interferon-stimulated genes, leading to the accumulation of endogenous Z-RNA and subsequent activation of ZBP1. To further enhance the antitumor potential of oHSV, we conduct a screening and identify Fusobacterium nucleatum outer membrane vesicle (Fn-OMV) that can increase the expression of PANoptosis execution proteins. The combination of Fn-OMV and oHSV demonstrates potent antitumor immunogenicity. Taken together, our study provides a deeper understanding of oHSV-induced antitumor immunity, and demonstrates a promising strategy that combines oHSV with Fn-OMV.

A novel colorectal cancer screening framework with feature interpretability to identify high-risk populations for colonoscopy.

BACKGROUND AND AIM: Risk assessment is of paramount importance for the detection and treatment of colorectal cancer. We developed and validated a feature interpretability screening framework to identify high-risk populations and recommend colonoscopy for them. METHODS: We utilized a training cohort consisting of 1 252 605 participants who underwent colonoscopies in Shanghai from 2013 to 2015 to develop the screening framework. We incorporated Shapley additive explanation values into feature selection to provide interpretability for the framework. Two sampling methods were separately employed to mitigate potential model bias caused by class imbalance. Furthermore, we employed various machine learning algorithms to construct risk assessment models and compared their performance. We tested the screening models on an external validation cohort of 359 462 samples and conducted comprehensive evaluation and statistical analysis of the validation results. RESULTS: The external validation results demonstrated that the models in the proposed framework achieved sensitivity over 0.734, specificity over 0.790, and area under the receiver operating characteristic curve ranging from 0.808 to 0.859. In the predictions of the best-performing model, the prevalence rates of colorectal cancer were 0.059% and 1.056% in the low- and high-risk groups, respectively. If colonoscopies were performed only on the high-risk group predicted by the model, only 14.36% of total colonoscopies would be needed to detect 74.86% of colorectal cancer cases. CONCLUSIONS: We developed and validated a novel framework to identify populations at high risk for colorectal cancer. Those classified as high risk should undergo colonoscopy for further diagnosis.

Exploring the neuroprotective role of artesunate in mouse models of anti-NMDAR encephalitis: insights from molecular mechanisms and transmission electron microscopy.

BACKGROUND: The pathway involving PTEN-induced putative kinase 1 (PINK1) and PARKIN plays a crucial role in mitophagy, a process activated by artesunate (ART). We propose that patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis exhibit insufficient mitophagy, and ART enhances mitophagy via the PINK1/PARKIN pathway, thereby providing neuroprotection. METHODS: Adult female mice aged 8-10 weeks were selected to create a passive transfer model of anti-NMDAR encephalitis. We conducted behavioral tests on these mice within a set timeframe. Techniques such as immunohistochemistry, immunofluorescence, and western blotting were employed to assess markers including PINK1, PARKIN, LC3B, p62, caspase3, and cleaved caspase3. The TUNEL assay was utilized to detect neuronal apoptosis, while transmission electron microscopy (TEM) was used to examine mitochondrial autophagosomes. Primary hippocampal neurons were cultured, treated, and then analyzed through immunofluorescence for mtDNA, mtROS, TMRM. RESULTS: In comparison to the control group, mitophagy levels in the experimental group were not significantly altered, yet there was a notable increase in apoptotic neurons. Furthermore, markers indicative of mitochondrial leakage and damage were found to be elevated in the experimental group compared to the control group, but these markers showed improvement following ART treatment. ART was effective in activating the PINK1/PARKIN pathway, enhancing mitophagy, and diminishing neuronal apoptosis. Behavioral assessments revealed that ART ameliorated symptoms in mice with anti-NMDAR encephalitis in the passive transfer model (PTM). The knockdown of PINK1 led to a reduction in mitophagy levels, and subsequent ART intervention did not alleviate symptoms in the anti-NMDAR encephalitis PTM mice, indicating that ART's therapeutic efficacy is mediated through the activation of the PINK1/PARKIN pathway. CONCLUSIONS: At the onset of anti-NMDAR encephalitis, mitochondrial damage is observed; however, this damage is mitigated by the activation of mitophagy via the PINK1/PARKIN pathway. This regulatory feedback mechanism facilitates the removal of damaged mitochondria, prevents neuronal apoptosis, and consequently safeguards neural tissue. ART activates the PINK1/PARKIN pathway to enhance mitophagy, thereby exerting neuroprotective effects and may achieve therapeutic goals in treating anti-NMDAR encephalitis.

Cardiovascular adverse events associated with immune checkpoint inhibitors: A retrospective multicenter cohort study.

BACKGROUND: Over the past decade, immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment. However, ICIs inevitably may cause a spectrum of immune-related adverse events, among which cardiovascular toxicity, particularly myocarditis, while infrequent, has garnered increasing attention due to its high fatality rate. METHODS: We conducted a multicenter retrospective study to characterize ICI-associated cardiovascular adverse events. Logistic regression was performed to explore the risk factors for the development of myocarditis and severe myocarditis. Receiver operating characteristic curves were conducted to assess the diagnostic abilities of cardiac biomarkers to distinguish different cardiovascular toxicities, and the performance and calibration were evaluated using Hosmer-Lemeshow test. RESULTS: Forty-four patients were identified, including thirty-five myocarditis, five heart failure, three arrhythmias, and one myocardial infarction. Compared with other patients, myocarditis patients had higher cardiac troponin-I (cTnI) levels (p < 0.001), higher creatine kinase levels (p = 0.003), higher creatine kinase isoenzyme-MB (CK-MB) levels (p = 0.013), and shorter time to the incidence of adverse cardiovascular events (p = 0.022) after ICI treatment. Twenty-one patients (60%) were classified as severe myocarditis, and they presented higher cardiac troponin I (cTnI) levels (p = 0.013), higher N-terminal pro-B-type natriuretic peptide levels (p = 0.031), higher creatine kinase levels (p = 0.018), higher CK-MB levels (p = 0.026), and higher neutrophil to lymphocyte ratio (NLR) levels (p = 0.016) compared to non-severe myocarditis patients after ICI treatment. Multivariate logistic regression showed that CK-MB (adjusted odds ratio [OR]: 1.775, 95% confidence interval [CI]: 1.055-2.984, p = 0.031) was the independent risk factor of the development of ICI-associated myocarditis, and cTnI (adjusted OR: 1.021, 95% CI: 1.002-1.039, p = 0.03) and NLR (adjusted OR: 1.890, 95% CI: 1.026-3.483, p = 0.041) were the independent risk factors of ICI-associated severe myocarditis. The receiver operating characteristic curve showed an area under curve of 0.785 (95% CI: 0.642 to 0.928, p = 0.013) for CK-MB, 0.765 (95% CI: 0.601 to 0.929, p = 0.013) for cTnI, and 0.773 for NLR (95% CI: 0.597 to 0.948, p = 0.016). CONCLUSIONS: Elevated CK-MB after ICI treatment is the independent risk factor for the incidence of ICI-associated myocarditis, and elevated cTnI and NLR after ICI treatment are the independent risk factors for the development of ICI-associated severe myocarditis. CK-MB, cTnI, and NLR demonstrated a promising predictive utility for the identification of ICI-associated myocarditis and severe myocarditis.

Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity.

The multibasic furin cleavage site at the S1/S2 boundary of the spike protein is a hallmark of SARS-CoV-2 and plays a crucial role in viral infection. However, the mechanism underlying furin activation and its regulation remain poorly understood. Here, we show that GalNAc-T3 and T7 jointly initiate clustered O-glycosylations in the furin cleavage site of the SARS-CoV-2 spike protein, which inhibit furin processing, suppress the incorporation of the spike protein into virus-like-particles and affect viral infection. Mechanistic analysis reveals that the assembly of the spike protein into virus-like particles relies on interactions between the furin-cleaved spike protein and the membrane protein of SARS-CoV-2, suggesting a possible mechanism for furin activation. Interestingly, mutations in the spike protein of the alpha and delta variants of the virus confer resistance against glycosylation by GalNAc-T3 and T7. In the omicron variant, additional mutations reverse this resistance, making the spike protein susceptible to glycosylation in vitro and sensitive to GalNAc-T3 and T7 expression in human lung cells. Our findings highlight the role of glycosylation as a defense mechanism employed by host cells against SARS-CoV-2 and shed light on the evolutionary interplay between the host and the virus.

Selenium May Be Involved in Esophageal Squamous Cancer Prevention by Affecting GPx3 and FABP1 Expression: A Case-Control Study Based on Bioinformatic Analysis.

The role of selenium in the developmental process of esophageal cancer (EC) requires further investigation. To explore the relationship between selenium-related factors and EC through bioinformatic analysis, a case-control study was conducted to verify the results. Utilizing the GEPIA and TCGA databases, we delineated the differential expression of glutathione peroxidase 3 (GPx3) in EC and normal tissues, identified differentially expressed genes (DEGs), and a performed visualization analysis. Additionally, 100 pairs of dietary and plasma samples from esophageal precancerous lesions (EPLs) of esophageal squamous cancer (ESCC) cases and healthy controls from Huai'an district, Jiangsu, were screened. The levels of dietary selenium, plasma selenium, and related enzymes were analyzed using inductively coupled plasma mass spectrometry (ICP-MS) or ELISA kits. The results showed lower GPx3 expression in tumor tissues compared to normal tissues. Further analysis revealed that DEGs were mainly involved in the fat digestion and absorption pathway, and the core protein fatty acid binding protein 1 (FABP1) was significantly upregulated and negatively correlated with GPx3 expression. Our case-control study found that selenium itself was not associated with EPLs risk. However, both the decreased concentration of GPx3 and the increase in FABP1 were positively correlated with the EPLs risk (p for trend = 0.035 and 0.046, respectively). The different expressions of GPx3 and FABP1 reflect the potential of selenium for preventing ESCC at the EPLs stage. GPx3 may affect myocardial infarction through FABP1, which remains to be further studied.

Sono-activatable engineered bacteria for antitumor therapy.

Bacteria show promising potential in tumor treatment, but safety concerns limit their application. In this issue, Gao et al.1 develop ultrasound-controlled engineered bacteria through integrating sono-activatable gene circuits, achieving local production and release of therapeutic cargos in tumor.

Association between fine particulate matter and fecundability in Henan, China: A prospective cohort study.

OBJECTIVE: To investigate the relationship between ambient fine particulate matter (PM2.5) exposure and fecundability. METHODS: This study included 751,270 female residents from Henan Province who participated in the National Free Pre-conception Check-up Projects during 2015-2017. Ambient cycle-specific PM2.5 exposure was assessed at the county level for each participant using satellite-based PM2.5 concentration data at 1-km resolution. Cox proportional hazards models with time-varying exposure were used to estimate the association between fecundability and PM2.5 exposure, adjusted for potential individual risk factors. RESULTS: During the study period, 568,713 participants were pregnant, monthly mean PM2.5 concentrations varied from 25.5 to 114.0 µg/m3 across study areas. For each 10 µg/m3 increase in cycle-specific PM2.5, the hazard ratio for fecundability was 0.951 (95 % confidence interval: 0.950-0.953). The association was more pronounced in women who were older, with urban household registration, history of pregnancy, higher body mass index (BMI), hypertension, without exposure to tobacco, or whose male partners were older, with higher BMI, or hypertension. CONCLUSION: In this population-based prospective cohort, ambient cycle-specific PM2.5 exposure was associated with reduced fecundability. These findings may support the adverse implications of severe air pollution on reproductive health.

Combined ROS Sensitive Folate Receptor Targeted Micellar Formulations of Curcumin Effective Against Rheumatoid Arthritis in Rat Model.

Introduction: Rheumatoid arthritis (RA) is an inflammatory immune-mediated disease that involves synovitis, cartilage destruction, and even joint damage. Traditional agents used for RA therapy remain unsatisfactory because of their low efficiency and obvious adverse effects. Therefore, we here established RA microenvironment-responsive targeted micelles that can respond to the increase in reactive oxygen species (ROS) levels in the joint and improve macrophage-specific targeting of loaded drugs. Methods: We here prepared ROS-responsive folate-modified curcumin micelles (TK-FA-Cur-Ms) in which thioketal (TK) was used as a ROS-responsive linker for modifying polyethylene glycol 5000 (PEG5000) on the micellar surface. When micelles were in the ROS-overexpressing inflammatory microenvironment, the PEG5000 hydration layer was shed, and the targeting ligand FA was exposed, thereby enhancing cellular uptake by macrophages through active targeting. The targeting, ROS sensitivity and anti-inflammatory properties of the micelles were assessed in vitro. Collagen-induced arthritis (CIA) rats model was utilized to investigate the targeting, expression of serum inflammatory factors and histology change of the articular cartilage by micelles in vivo. Results: TK-FA-Cur-Ms had a particle size of 90.07 ± 3.44 nm, which decreased to 78.87 ± 2.41 nm after incubation with H2O2. The micelles exhibited in vitro targeting of RAW264.7 cells and significantly inhibited inflammatory cytokine levels. Pharmacodynamic studies have revealed that TK-FA-Cur-Ms prolonged the drug circulation and exhibited augmented cartilage-protective and anti-inflammatory effects in vivo. Conclusion: The unique ROS-responsive targeted micelles with targeting, ROS sensitivity and anti-inflammatory properties were successfully prepared and may offer an effective therapeutic strategy against RA.

Triggering Receptor Expressed on Myeloid Cells 2 Mediates the Involvement of M2-Type Macrophages in Pulmonary Tuberculosis Infection.

Background: Macrophage play a significant work in the development of tuberculosis. This study aims to investigate the relationship between TREM2 and macrophage polarization, as well as the related cytokines. Methods: This study involved 43 pulmonary tuberculosis patients and 37 healthy controls. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of M1/M2 macrophage-related cytokines IL-10 and IL-12 in the peripheral blood of pulmonary tuberculosis patients. The relative mRNA expression levels of TREM2, IL-10 and IL-12 were detected using quantitative real-time PCR (qRT-PCR). Additionally, Spearman rank correlation analysis was used to preliminarily assess the correlation between TREM2 and M1 / M2 macrophages. Hematoxylin-eosin (HE) staining was performed to observe the pathological manifestations of pulmonary tuberculosis lesions. Immunohistochemical (IHC) staining was used to observe the localization of the macrophage-specific molecule CD68, the M1 specific molecule iNOS, the M2 specific molecule CD163, and TREM2. Results: The lesions of pulmonary tuberculosis patients showed Langhans multinucleated macrophages and tuberculous granulomas. The ELISA results indicated that the expression levels of IL-10 and IL-12 were significantly increased in peripheral blood of pulmonary tuberculosis patients. Additionally, the relative mRNA expression levels of TREM2, IL-10 and IL-12 were also significantly higher in the pulmonary tuberculosis group. Furthermore, a positive correlation was observed between TREM2 and IL-10, which are secreted by M2 macrophages. IHC revealed significant positivity of TREM2 and macrophage-related markers in tuberculous granuloma. Specifically, TREM2 and M2 macrophage marker CD163 were significantly expressed in the cytoplasm and membrane of Langhans multinucleated macrophages. Conclusion: The role of macrophage polarization in pulmonary tuberculosis is significant, and further investigation is needed to understand relationship between TREM2 and M2 macrophages.

Molecular subtype construction and prognosis model for stomach adenocarcinoma characterized by metabolism-related genes.

Background: Metabolic reprogramming is implicated in cancer progression. However, the impact of metabolism-associated genes in stomach adenocarcinomas (STAD) has not been thoroughly reviewed. Herein, we characterized metabolic transcription-correlated STAD subtypes and evaluated a metabolic RiskScore for evaluation survival. Method: Genes related to metabolism were gathered from previous study and metabolic subtypes were screened using ConsensusClusterPlus in TCGA-STAD and GSE66229 dataset. The ssGSEA, MCP-Count, ESTIMATE and CIBERSORT determined the immune infiltration. A RiskScore model was established using the WGCNA and LASSO Cox regression in the TCGA-STAD queue and verified in the GSE66229 datasets. RT-qPCR was employed to measure the mRNA expressions of genes in the model. Result: Two metabolism-related subtypes (C1 and C2) of STAD were constructed on account of the expression profiles of 113 prognostic metabolism genes with different immune outcomes and apparently distinct metabolic characteristic. The overall survival (OS) of C2 subtype was shorter than that of C1 subtype. Four metabolism-associated genes in turquoise model, which closely associated with C2 subtype, were employed to build the RiskScore (MATN3, OSBPL1A, SERPINE1, CPNE8) in TCGA-train dataset. Patients developed a poorer prognosis if they had a high RiskScore than having a low RiskScore. The promising effect of RiskScore was verified in the TCGA-test, TCGA-STAD and GSE66229 datasets. The prediction reliability of the RiskScore was validated by time-dependent receiver operating characteristic curve (ROC) and nomogram. Moreover, samples with high RiskScore had an enhanced immune status and TIDE score. Moreover, MATN3, OSBPL1A, SERPINE1 and CPNE8 mRNA levels were all elevated in SGC7901 cells. Inhibition of OSBPL1A decreased SGC7901 cells invasion numbers. Conclusion: This work provided a new perspective into heterogeneity in metabolism and its association with immune escape in STAD. RiskScore was considered to be a strong prognostic label that could help individualize the treatment of STAD patients.

MiR26a reverses enzalutamide resistance in a bone-tumor targeted system with an enhanced effect on bone metastatic CRPC.

Resistance to androgen receptor (AR) inhibitors, including enzalutamide (Enz), as well as bone metastasis, are major challenges for castration-resistant prostate cancer (CRPC) treatment. In this study, we identified that miR26a can restore Enz sensitivity and inhibit bone metastatic CRPC. To achieve the highest combination effect of miR26a and Enz, we developed a cancer-targeted nano-system (Bm@PT/Enz-miR26a) using bone marrow mesenchymal stem cell (BMSC) membrane and T140 peptide to co-deliver Enz and miR26a. The in vitro/in vivo results demonstrated that miR26a can reverse Enz resistance and synergistically shrink tumor growth, invasion, and metastasis (especially secondary metastasis) in both subcutaneous and bone metastatic CRPC mouse models. We also found that the EZH2/SFRP1/WNT5A axis may be involved in this role. These findings open new avenues for treating bone metastatic and Enz-resistant CRPC.

Deep causal learning for pancreatic cancer segmentation in CT sequences.

Segmenting the irregular pancreas and inconspicuous tumor simultaneously is an essential but challenging step in diagnosing pancreatic cancer. Current deep-learning (DL) methods usually segment the pancreas or tumor independently using mixed image features, which are disrupted by surrounding complex and low-contrast background tissues. Here, we proposed a deep causal learning framework named CausegNet for pancreas and tumor co-segmentation in 3D CT sequences. Specifically, a causality-aware module and a counterfactual loss are employed to enhance the DL network's comprehension of the anatomical causal relationship between the foreground elements (pancreas and tumor) and the background. By integrating causality into CausegNet, the network focuses solely on extracting intrinsic foreground causal features while effectively learning the potential causality between the pancreas and the tumor. Then based on the extracted causal features, CausegNet applies a counterfactual inference to significantly reduce the background interference and sequentially search for pancreas and tumor from the foreground. Consequently, our approach can handle deformable pancreas and obscure tumors, resulting in superior co-segmentation performance in both public and real clinical datasets, achieving the highest pancreas/tumor Dice coefficients of 86.67%/84.28%. The visualized features and anti-noise experiments further demonstrate the causal interpretability and stability of our method. Furthermore, our approach improves the accuracy and sensitivity of downstream pancreatic cancer risk assessment task by 12.50% and 50.00%, respectively, compared to experienced clinicians, indicating promising clinical applications.

Splenectomy versus splenic preservation in total gastrectomy for gastric cancer: a systematic review and meta-analysis comparing survival benefits and short-term complications.

BACKGROUND: There is an ongoing debate regarding the comparative merits of splenectomy (SP) and splenic preservation in the surgical management of gastric cancer. This systematic review and meta-analysis aims to shed light on potential differences in survival outcomes and postoperative complications associated with these two procedures. METHOD: An exhaustive literature search was conducted across multiple databases, namely PubMed, Embase, Cochrane Library, and Web of Science. We utilized a random-effects model via RevMan 5.4 software to conduct a meta-analysis of the hazard ratios (HRs) and risk ratios (RRs) associated with SP and spleen preservation. Subgroup analyses were based on various attributes of the included studies. We employed funnel plots to assess publication bias, and sensitivity analysis was conducted to gauge the stability of the combined results. Both funnel plots and sensitivity analysis were performed using Stata 12. RESULT: Our research incorporated 23 observational studies and three randomized controlled trials, involving a total of 6,255 patients. SP did not yield superior survival outcomes in comparison to splenic preservation, a conclusion that aligns with the combined results of the randomized controlled trials. No statistically significant difference in survival prognosis was observed between SP and splenic preservation, irrespective of whether the patients had proximal gastric cancer or proximal gastric cancer invading the stomach's greater curvature. SP exhibited a higher incidence of all postoperative complications, notably pancreatic fistula and intraabdominal abscesses. However, it did not significantly differ from splenic preservation in terms of anastomotic leakage, incision infection, intestinal obstruction, intra-abdominal bleeding, and pulmonary infection. No significant difference in postoperative mortality between SP and splenic preservation was found. Funnel plots suggested no notable publication bias, and sensitivity analysis affirmed the stability of the combined outcomes. CONCLUSION: Despite the lack of significant differences in certain individual complications and postoperative mortality, the broader pattern of our data suggests that SP is associated with a greater overall frequency of postoperative complications, without providing additional survival benefits compared to splenic preservation. Thus, the routine implementation of SP is not advocated.

When doctors perform surgery for gastric (stomach) cancer, they sometimes remove the spleen, a procedure known as splenectomy (SP). However, there's a debate on whether removing the spleen is better than preserving it. Our study aimed to compare these two methods in terms of patient survival and the risk of complications after surgery. To do this, we looked at data from 26 studies involving 6,255 patients. Our analysis was thorough, using advanced statistical methods to ensure accuracy. Here's what we found: patients who had their spleen removed did not live longer than those who kept their spleen. Whether the cancer was just in the upper part of the stomach or had spread to the nearby large curve of the stomach, the survival rates were similar for both groups. Patients who underwent SP faced more postoperative complications, especially issues like pancreatic fistula and intra-abdominal abscesses. However, for some complications like leakage from the surgical joint, infection of the wound, bowel obstruction, internal bleeding, and lung infections, there was no significant difference between the two groups. The chances of dying post-surgery were similar whether patients had their spleen removed or not. Our findings suggest that routinely removing the spleen during gastric cancer surgery does not improve survival rates and is linked to more postoperative complications. Therefore, it may be better to avoid removing the spleen unless absolutely necessary.