Elevated serum homocysteine levels associated with poor recurrence-free and overall survival in patients with colorectal cancer.

This study aimed to evaluate the significance of homocysteine (HCY) levels in predicting recurrence-free survival (RFS) and overall survival (OS) in colorectal cancer (CRC) patients. This retrospective study involved 1272 CRC patients. The risk of mortality increased with increasing HCY levels in CRC patients. The optimal HCY cutoff value in CRC patients was 15.2 µmol/L. The RFS (45.8% vs. 60.5%, p < 0.001) and OS (48.2% vs. 63.2%, p < 0.001) of patients with high HCY levels were significantly lower than those of patients with low HCY levels. Patients with high HCY levels were older, male, had large tumours, high carcinoembryonic antigen (CEA) levels, and long hospital stays, and incurred high hospitalisation costs. Multivariate analysis showed that when HCY levels exceeded 15.2 µmol/L, the risk of adverse RFS and OS increased by 55.7% and 61.4%, respectively. Subgroup analysis showed that HCY levels could supplement CEA levels and pathological staging. We constructed HCY-based prognostic nomograms, which demonstrated feasible discrimination and calibration values better than the traditional tumour, node, metastasis staging system for predicting RFS and OS. Elevated serum HCY levels were strongly associated with poor RFS and OS in CRC patients. HCY-based prognostic models are effective tools for a comprehensive evaluation of prognosis.

Ferroptosis Altered microRNAs Expression in HT-1080 Fibrosarcoma Cells Based on Small RNA Sequencing and Bioinformatics Analysis.

Iron is an essential trace element in the human body. However, excess iron is harmful and may cause ferroptosis. The expression and role of microRNAs (miRNAs) in ferroptosis remain largely unknown. A model of ferroptosis induced by ferric ammonium citrate in HT-1080 cells was established in this study. The miRNAs expression profiles of the control and iron groups were obtained using small RNA sequencing and verified using qRT-PCR. A total of 1346 known miRNAs and 80 novel miRNAs were identified, including 12 up-regulated differentially expressed miRNAs (DE-miRNAs) and 16 down-regulated DE-miRNAs. SP1 was the most important upstream transcription factor regulating DE-miRNAs. The downstream target genes of DE-miRNAs were predicted based on miRDB, TargetScan, and miRBase databases, and 403 common target genes were screened. GO annotation and KEGG analysis revealed that the target genes were mainly involved in various biological processes and regulatory pathways, especially the MAPK signaling pathway and PI3K-Akt signaling pathway. Afterwards, a target genes network was constructed using STRING and Cytoscape, and the hub genes were compared with the ferroptosis database (FerrDb V2) to discover the hub genes related to ferroptosis. EGFR, GSK3B, PARP1, VCP, and SNCA were screened out. Furthermore, a DE-miRNAs-target genes network was constructed to explore key DE-miRNAs. hsa-miR-200c-3p, hsa-miR-26b-5p, and hsa-miR-7-5p were filtered out. Comprehensive bioinformatics analysis of miRNAs and its upstream and downstream regulation in ferroptosis in HT-1080 cells using small RNA sequencing is helpful for understanding the role of miRNAs in iron overload-related diseases and ferroptosis-targeted therapy for cancer.

Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancer.

The immune checkpoint blockade (ICB) response in human cancers is closely linked to the gut microbiota. Here, we report that the abundance of commensal Lactobacillus johnsonii is positively correlated with the responsiveness of ICB. Supplementation with Lactobacillus johnsonii or tryptophan-derived metabolite indole-3-propionic acid (IPA) enhances the efficacy of CD8+ T cell-mediated αPD-1 immunotherapy. Mechanistically, Lactobacillus johnsonii collaborates with Clostridium sporogenes to produce IPA. IPA modulates the stemness program of CD8+ T cells and facilitates the generation of progenitor exhausted CD8+ T cells (Tpex) by increasing H3K27 acetylation at the super-enhancer region of Tcf7. IPA improves ICB responsiveness at the pan-cancer level, including melanoma, breast cancer, and colorectal cancer. Collectively, our findings identify a microbial metabolite-immune regulatory pathway and suggest a potential microbial-based adjuvant approach to improve the responsiveness of immunotherapy.

Pancreas-directed AAV8-hSPINK1 gene therapy safely and effectively protects against pancreatitis in mice.

OBJECTIVE: Currently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in SPINK1 (encoding trypsin inhibitor) are common in patients with CP and are associated with acute attacks and progression of the disease. This preclinical study was conducted to explore the potential of adeno-associated virus type 8 (AAV8)-mediated overexpression of human SPINK1 (hSPINK1) for pancreatitis therapy in mice. DESIGN: A capsid-optimised AAV8-mediated hSPINK1 expression vector (AAV8-hSPINK1) to target the pancreas was constructed. Mice were treated with AAV8-hSPINK1 by intraperitoneal injection. Pancreatic transduction efficiency and safety of AAV8-hSPINK1 were dynamically evaluated in infected mice. The effectiveness of AAV8-hSPINK1 on pancreatitis prevention and treatment was studied in three mouse models (caerulein-induced pancreatitis, pancreatic duct ligation and Spink1 c.194+2T>C mouse models). RESULTS: The constructed AAV8-hSPINK1 vector specifically and safely targeted the pancreas, had low organ tropism for the heart, lungs, spleen, liver and kidneys and had a high transduction efficiency (the optimal expression dose was 2×1011 vg/animal). The expression and efficacy of hSPINK1 peaked at 4 weeks after injection and remained at significant level for up to at least 8 weeks. In all three mouse models, a single dose of AAV8-hSPINK1 before disease onset significantly alleviated the severity of pancreatitis, reduced the progression of fibrosis, decreased the levels of apoptosis and autophagy in the pancreas and accelerated the pancreatitis recovery process. CONCLUSION: One-time injection of AAV8-hSPINK1 safely targets the pancreas with high transduction efficiency and effectively ameliorates pancreatitis phenotypes in mice. This approach is promising for the prevention and treatment of CP.

The prognostic value of preoperative D-dimer to albumin ratio for overall survival and progression-free survival in colorectal cancer.

Introduction: This study aimed to explore the predictive value of the D-dimer-to-albumin ratio (DAR) for progression-free survival (PFS) and overall survival (OS) in patients with colorectal cancer (CRC). Methods: The Kaplan-Meier method was used to plot survival curves for PFS and OS. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive efficacy of the DAR for PFS and OS in patients with CRC. Cox proportional hazards regression analysis was used to analyze prognostic factors influencing outcomes. A nomogram based on the DAR was constructed to predict 1-, 3-, and 5-year prognoses of patients with CRC; its predictive ability was evaluated using the concordance index (C-index) and calibration curves. Additionally, the clinical utility of the DAR-based nomogram was validated using an internal randomized validation cohort. Results: A total of 1,339 patients with CRC who underwent surgery were enrolled. The optimal cut-off value for DAR was determined to be 3.320, dividing patients into low (<3.320 [n = 470]) and high (≥3.320 [n = 869]) DAR groups. Compared with other composite immune inflammatory markers, DAR exhibited superior prognostic predictive efficacy. Patients with a high DAR had a significantly worse prognosis than those with a low DAR (PFS, 50.9% versus [vs.] 69.4%, p < 0.001; OS, 52.9% vs. 73.8%, p < 0.001). DAR also demonstrated significant prognostic stratification for most tumor subgroups, particularly in the stage III-IV subgroup and normal carcinoembryonic antigen subgroup. DAR has been identified as an independent predictive indicator of PFS/OS in patients with CRC. For every standard deviation increase in DAR, the risk for PFS/OS in patients with CRC was reduced by 9.5% (hazard ratio [HR] 1.095 [95% confidence interval (CI) 1.013-1.185]; p = 0.022) and 9.3% (HR 1.093 [95% CI 1.012-1.180]; p = 0.024), respectively. The DAR-based nomogram was confirmed to demonstrate good prognostic prediction accuracy and achieved high evaluation in the internal validation cohort. Conclusion: Preoperative DAR is a promising biomarker for predicting PFS and OS among patients with CRC. The DAR-based prognostic prediction nomogram may serve as an effective tool for the comprehensive assessment of prognosis in patients with CRC.

Tuftelin1 drives experimental pulmonary fibrosis progression by facilitating stress fiber assembly.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) with unknown etiology, characterized by sustained damage repair of epithelial cells and abnormal activation of fibroblasts, the underlying mechanism of the disease remains elusive. METHODS: To evaluate the role of Tuftelin1 (TUFT1) in IPF and elucidate its molecular mechanism. We investigated the level of TUFT1 in the IPF and bleomycin-induced mouse models and explored the influence of TUFT1 deficiency on pulmonary fibrosis. Additionally, we explored the effect of TUFT1 on the cytoskeleton and illustrated the relationship between stress fiber and pulmonary fibrosis. RESULTS: Our results demonstrated a significant upregulation of TUFT1 in IPF and the bleomycin (BLM)-induced fibrosis model. Disruption of TUFT1 exerted inhibitory effects on pulmonary fibrosis in both in vivo and in vitro. TUFT1 facilitated the assembly of microfilaments in A549 and MRC-5 cells, with a pronounced association between TUFT1 and Neuronal Wiskott-Aldrich syndrome protein (N-WASP) observed during microfilament formation. TUFT1 can promote the phosphorylation of tyrosine residue 256 (Y256) of the N-WASP (pY256N-WASP). Furthermore, TUFT1 promoted transforming growth factor-ß1 (TGF-ß1) induced fibroblast activation by increasing nuclear translocation of pY256N-WASP in fibroblasts, while wiskostatin (Wis), an N-WASP inhibitor, suppressed these processes. CONCLUSIONS: Our findings suggested that TUFT1 plays a critical role in pulmonary fibrosis via its influence on stress fiber, and blockade of TUFT1 effectively reduces pro-fibrotic phenotypes. Pharmacological targeting of the TUFT1-N-WASP axis may represent a promising therapeutic approach for pulmonary fibrosis.

Lactobacillus Intestinalis Primes Epithelial Cells to Suppress Colitis-Related Th17 Response by Host-Microbe Retinoic Acid Biosynthesis.

Gut microbiome is integral to the pathogenesis of ulcerative colitis. A novel probiotic Lactobacillus intestinalis (L. intestinalis) exerts a protective effect against dextran sodium sulfate-induced colitis in mice. Based on flow cytometry, colitis-associated Th17 cells are the target of L. intestinalis, which is supported by the lack of protective effects of L. intestinalis in T cell-null Rag1-/- mice or upon anti-IL-17-A antibody-treated mice. Although L. intestinalis exerts no direct effect on T cell differentiation, it decreases C/EBPA-driven gut epithelial SAA1 and SAA2 production, which in turn impairs Th17 cell differentiation. Cometabolism of L. intestinalis ALDH and host ALDH1A2 contributed to elevated biosynthesis of retinoic acid (RA), which accounts for the anti-colitis effect in RAR-α -mediated way. In a cohort of ulcerative colitis patients, it is observed that fecal abundance of L. intestinalis is negatively associated with the C/EBPA-SAA1/2-Th17 axis. Finally, L. intestinalis has a synergistic effect with mesalazine in alleviating murine colitis. In conclusion, L. intestinalis and associated metabolites, RA, have potential therapeutic effects for suppressing colonic inflammation by modulating the crosstalk between intestinal epithelia and immunity.

The value of carcinoembryonic antigen stage in staging, prognosis, and management of colorectal cancer: results from two cohort studies.

Background: Combining the carcinoembryonic antigen (CEA) level (C stage) with TNM staging can provide a more comprehensive prognostic assessment of colorectal cancer (CRC). However, the clinical value of incorporating CEA status into the TNM staging system needs to be evaluated. Methods: We used the SEER database (N = 49,350) and a retrospective cohort from China (N = 1,440). A normal CEA level was staged as C0 and an elevated CEA level was staged as C1. Restricted cubic spline analysis was used to examine the dose-response relationship between the CEA level and survival. The Kaplan-Meier method with the log-rank test was used to plot survival curves. Multivariable Cox proportional hazards regression models with forward stepwise variable selection were used to estimate the hazard ratios and 95% confidence intervals. Results: Patients with C1 were more likely to have advanced disease than those with C0. CEA on a continuous scale was positively associated with mortality risk. Compared with patients with C0 stage, those with C1 stage had significantly lower survival rates. In the SEER dataset, C1 was independently associated with poor prognosis in patients with CRC, with an approximately 70% increased risk of mortality. Patients with C1 stage had significantly lower survival than those with C0 stage at all clinical stages. Incorporating the C stage into the TNM staging refined the prediction of prognosis of patients with CRC, with a gradual decline in prognosis from stage I C0 to stage IV C1. A similar pattern was observed in the present retrospective cohort study. At each lymph node stage, patients with C1 had significantly lower 5-year survival rates than patients with C0. Compared with lymph node positivity, CEA positivity may have a stronger correlation with a worse prognosis. Conclusion: Our findings not only validated the independent prognostic significance of CEA in CRC but also demonstrated its enhanced prognostic value when combined with TNM staging. Our study provides evidence supporting the inclusion of C stage in the TNM staging system.

The cancer inflammation prognostic index is a valuable biomarker for predicting the survival of patients with stage I-III colorectal cancer.

This study aimed to assess the relationship between the Cancer-Inflammation Prognostic Index (CIPI) and disease-free survival (DFS) and overall survival (OS) in patients with stage I-III colorectal cancer (CRC). The relationship between the CIPI and survival was evaluated using restricted cubic splines. Survival curves were established using the Kaplan-Meier method and the log-rank test. Cox proportional hazards models were used to explore independent prognostic factors for CRC. Meaningful variables from the multivariate analysis were used to construct prognostic nomograms. The relationship between the CIPI values on a continuous scale and the risk of DFS/OS mortality was an inverted L-shape. Patients with a high CIPI had significantly lower DFS (53.0% vs. 68.5%, p < 0.001) and OS (55.5% vs. 71.7%, p < 0.001) than those with a low CIPI. The CIPI can also serve as an effective auxiliary tool to further distinguish the prognosis of patients with CRC at the same pathological stage, especially for stages II and III. After multivariate adjustment, a high CIPI was found to be an independent risk factor for DFS (HR 1.443, 95% CI 1.203-1.730, p < 0.001) and OS (HR 1.442, 95% CI 1.189-1.749, p < 0.001) in CRC patients. These nomograms have the advantage of integrating individual profiles, tumour characteristics, and serum inflammatory markers, providing favourable discrimination and calibration values. Compared with traditional TNM staging, nomograms have a better predictive performance. The CIPI is an effective and easy-to-use clinical tool for predicting the recurrence and overall mortality of patients with stage I-III CRC.

Bifidobacterium adolescentis orchestrates CD143+ cancer-associated fibroblasts to suppress colorectal tumorigenesis by Wnt signaling-regulated GAS1.

BACKGROUND: The interplay between gut microbiota and tumor microenvironment (TME) in the pathogenesis of colorectal cancer (CRC) is not well explored. Here, we elucidated the functional role of Bifidobacterium adolescentis (B.a) on CRC and investigated its possible mechanism on the manipulation of cancer-associated fibroblasts (CAFs) in CRC. METHODS: Different CRC animal models and various cell line models were established to explore the function of B.a on CRC. The single-cell RNA sequencing (scRNA-seq) or flow cytometry was used to detect the cell subsets in the TME of CRC. Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), or immunofluorescence staining were performed to examine the activation of Wnt signaling and growth arrest specific 1 (GAS1) on CD143+ CAFs. Chromatin immunoprecipitation quantitative real-time PCR (CHIP-qPCR) was performed to investigate the regulation of transcription factor 4 (TCF4) on GAS1. Multi-immunofluorescence assay examined the expression level of CD143 and GAS1 on tissue microarray. RESULTS: We found that B.a abundance was significantly reduced in CRC patients from two independent cohorts and the bacteria database of GMrepo. Supplementation with B.a suppressed ApcMin/+ spontaneous or AOM/DSS-induced tumorigenesis in mice. scRNA-seq revealed that B.a facilitated a subset of CD143+ CAFs by inhibiting the infiltration of Th2 cells, while promoting the TNF-alpha+ B cells in TME. CD143+ CAFs highly expressed GAS1 and exhibited tumor suppressive effect. Mechanistically, GAS1 was activated by the Wnt/ß-catenin signaling in CD143+ CAFs. B.a abundance was correlated with the expression level of CD143 and GAS1. The level of CD143+ CAFs predicted the better survival outcome in CRC patients. CONCLUSIONS: These results highlighted that B.a induced a new subset of CD143+ CAFs by Wnt signaling-regulated GAS1 to suppress tumorigenesis and provided a novel therapeutic target for probiotic-based modulation of TME in CRC.

Plasma non-transferrin-bound iron uptake by the small intestine leads to intestinal injury and intestinal flora dysbiosis in an iron overload mouse model and Caco-2 cells.

Iron overload often occurs during blood transfusion and iron supplementation, resulting in the presence of non-transferrin-bound iron (NTBI) in host plasma and damage to multiple organs, but effects on the intestine have rarely been reported. In this study, an iron overload mouse model with plasma NTBI was established by intraperitoneal injection of iron dextran. We found that plasma NTBI damaged intestinal morphology, caused intestinal oxidative stress injury and reactive oxygen species (ROS) accumulation, and induced intestinal epithelial cell apoptosis. In addition, plasma NTBI increased the relative abundance of Ileibacterium and Desulfovibrio in the cecum, while the relative abundance of Faecalibaculum and Romboutsia was reduced. Ileibacterium may be a potential microbial biomarker of plasma NTBI. Based on the function prediction analysis, plasma NTBI led to the weakening of intestinal microbiota function, significantly reducing the function of the extracellular structure. Further investigation into the mechanism of injury showed that iron absorption in the small intestine significantly increased in the iron group. Caco-2 cell monolayers were used as a model of the intestinal epithelium to study the mechanism of iron transport. By adding ferric ammonium citrate (FAC, plasma NTBI in physiological form) to the basolateral side, the apparent permeability coefficient (Papp) values from the basolateral to the apical side were greater than 3×10-6 cm s-1. Intracellular ferritin level and apical iron concentration significantly increased, and SLC39A8 (ZIP8) and SLC39A14 (ZIP14) were highly expressed in the FAC group. Short hairpin RNA (shRNA) was used to knock down ZIP8 and ZIP14 in Caco-2 cells. Transfection with ZIP14-specific shRNA decreased intracellular ferritin level and inhibited iron uptake. These results revealed that plasma NTBI may cause intestinal injury and intestinal flora dysbiosis due to the uptake of plasma NTBI from the basolateral side into the small intestine, which is probably mediated by ZIP14.

Role of PDLIM1 in hepatic stellate cell activation and liver fibrosis progression.

Liver fibrosis is caused by chronic hepatic injury and may lead to cirrhosis, and even hepatocellular carcinoma. When hepatic stellate cells (HSCs) are activated by liver injury, they transdifferentiate into myofibroblasts, which secrete extracellular matrix proteins that generate the fibrous scar. Therefore, it is extremely urgent to find safe and effective drugs for HSCs activation treatment to prevent liver against fibrosis. Here, we reported that PDZ and LIM domain protein 1 (PDLIM1), a highly conserved cytoskeleton organization regulator, was significantly up-regulated in fibrotic liver tissues and TGF-ß-treated HSC-T6 cells. Through transcriptome analysis, we found that knockdown of PDLIM1 resulted in a significant downregulation of genes related to inflammation and immune-related pathways in HSC-T6 cells. Moreover, PDLIM1 knockdown significantly inhibited the activation of HSC-T6 cells and the trans-differentiation of HSC-T6 cells into myofibroblasts. Mechanistically, PDLIM1 is involved in the regulation of TGF-ß-mediated signaling pathways in HSCs activation. Thus, targeting PDLIM1 may provide an alternative method to suppress HSCs activation during liver injury. CCCTC-binding factor (CTCF), a master regulator of genome architecture, is upregulated during HSCs activation. PDLIM1 knockdown also indirectly reduced CTCF protein expression, however, CTCF binding to chromatin was not significantly altered by CUT&Tag analysis. We speculate that CTCF may cooperate with PDLIM1 to activate HSCs in other ways. Our results suggest that PDLIM1 can accelerate the activation of HSCs and liver fibrosis progression and could be a potential biomarker for monitoring response to anti-fibrotic therapy.

Single-Cell RNA Sequencing Provides New Insights into Therapeutic Roles of Thyroid Hormone in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal interstitial lung disease without an effective cure. Herein, we explore the role of 3,5,3'-triiodothyronine (T3) administration on lung alveolar regeneration and fibrosis at the single-cell level. T3 supplementation significantly altered the gene expression in fibrotic lung tissues. Immune cells were rapidly recruited into the lung after the injury; there were much more M2 macrophages than M1 macrophages in the lungs of bleomycin-treated mice; and M1 macrophages increased slightly, whereas M2 macrophages were significantly reduced after T3 treatment. T3 enhanced the resolution of pulmonary fibrosis by promoting the differentiation of Krt8+ transitional alveolar type II epithelial cells into alveolar type I epithelial cells and inhibiting fibroblast activation and extracellular matrix production potentially by regulation of Nr2f2. In addition, T3 regulated the crosstalk of macrophages with fibroblasts, and the Pros1-Axl signaling axis significantly facilitated the attenuation of fibrosis. The findings demonstrate that administration of a thyroid hormone promotes alveolar regeneration and resolves fibrosis mainly by regulation of the cellular state and cell-cell communication of alveolar epithelial cells, macrophages, and fibroblasts in mouse lungs in comprehensive ways.

Serum creatinine/cystatin C ratio as a prognostic indicator for patients with colorectal cancer.

Background: This study aimed to explore the relationship between creatinine/cystatin C ratio and progression-free survival (PFS) and overall survival (OS) in colorectal cancer (CRC) patients undergoing surgical treatment. Methods: A retrospective analysis was conducted on 975 CRC patients who underwent surgical resection from January 2012 to 2015. Restricted three-sample curve to display the non-linear relationship between PFS/OS and creatinine-cystatin C ratio. Cox regression model and Kaplan-Meier method were used to evaluate the effect of the creatinine-cystatin C ratio on the survival of CRC patients. Prognostic variables with p-value ≤0.05 in multivariate analysis were used to construct prognostic nomograms. The receiver operator characteristic curve was used to compare the efficacy of prognostic nomograms and the traditional pathological stage. Results: There was a negative linear relationship between creatinine/cystatin C ratio and adverse PFS in CRC patients. Patients with low creatinine/cystatin C ratio had significantly lower PFS/OS than those with high creatinine/cystatin C ratio (PFS, 50.8% vs. 63.9%, p = 0.002; OS, 52.5% vs. 68.9%, p < 0.001). Multivariate analysis showed that low creatinine/cystatin C ratio was an independent risk factor for PFS (HR=1.286, 95%CI = 1.007-1.642, p=0.044) and OS (HR=1.410, 95%CI=1.087-1.829, p=0.010) of CRC patients. The creatinine/cystatin C ratio-based prognostic nomograms have good predictive performance, with a concordance index above 0.7, which can predict the 1-5-year prognosis. Conclusion: Creatinine/cystatin C ratio may be an effective prognostic marker for predicting PFS and OS in CRC patients, aid in pathological staging, and along with tumour markers help in-depth prognostic stratification in CRC patients.

Causal associations between modifiable risk factors and pancreatitis: A comprehensive Mendelian randomization study.

Background: The pathogenesis of pancreatitis involves diverse environmental risk factors, some of which have not yet been clearly elucidated. This study systematically investigated the causal effects of genetically predicted modifiable risk factors on pancreatitis using the Mendelian randomization (MR) approach. Methods: Genetic variants associated with 30 exposure factors were obtained from genome-wide association studies. Summary-level statistical data for acute pancreatitis (AP), chronic pancreatitis (CP), alcohol-induced AP (AAP) and alcohol-induced CP (ACP) were obtained from FinnGen consortia. Univariable and multivariable MR analyses were performed to identify causal risk factors for pancreatitis. Results: Genetic predisposition to smoking (OR = 1.314, P = 0.021), cholelithiasis (OR = 1.365, P = 1.307E-19) and inflammatory bowel disease (IBD) (OR = 1.063, P = 0.008) as well as higher triglycerides (OR = 1.189, P = 0.016), body mass index (BMI) (OR = 1.335, P = 3.077E-04), whole body fat mass (OR = 1.291, P = 0.004) and waist circumference (OR = 1.466, P = 0.011) were associated with increased risk of AP. The effect of obesity traits on AP was attenuated after correcting for cholelithiasis. Genetically-driven smoking (OR = 1.595, P = 0.005), alcohol consumption (OR = 3.142, P = 0.020), cholelithiasis (OR = 1.180, P = 0.001), autoimmune diseases (OR = 1.123, P = 0.008), IBD (OR = 1.066, P = 0.042), type 2 diabetes (OR = 1.121, P = 0.029), and higher serum calcium (OR = 1.933, P = 0.018), triglycerides (OR = 1.222, P = 0.021) and waist-to-hip ratio (OR = 1.632, P = 0.023) increased the risk of CP. Cholelithiasis, triglycerides and the waist-to-hip ratio remained significant predictors in the multivariable MR. Genetically predicted alcohol drinking was associated with increased risk of AAP (OR = 15.045, P = 0.001) and ACP (OR = 6.042, P = 0.014). After adjustment of alcohol drinking, genetic liability to IBD had a similar significant causal effect on AAP (OR = 1.137, P = 0.049), while testosterone (OR = 0.270, P = 0.002) a triglyceride (OR = 1.610, P = 0.001) and hip circumference (OR = 0.648, P = 0.040) were significantly associated with ACP. Genetically predicted higher education and household income levels could lower the risk of pancreatitis. Conclusions: This MR study provides evidence of complex causal associations between modifiable risk factors and pancreatitis. These findings provide new insights into potential therapeutic and prevention strategies.

Prognostic significance of sarcopenia diagnosed based on the anthropometric equation for progression-free survival and overall survival in patients with colorectal cancer.

Background: The purpose of this study was to investigate the prognostic significance of sarcopenia diagnosed based on anthropometric equations for progression-free survival (PFS) and overall survival (OS) in patients with colorectal cancer (CRC). Methods: A total of 1,441 CRC patients who underwent surgical treatment between January 2012 and December 2016 were enrolled in this study. Sarcopenia was diagnosed according to validated anthropometric equations. The Kaplan-Meier method with the log-rank test was used to estimate the survival curve. Cox proportional hazards regression models with forward selection were used to evaluate risk factors affecting the prognosis of CRC patients. R package "survival" was used to build the prognostic nomograms to predict 1-5 years of PFS and OS in CRC patients. The concordance index (C-index) and calibration curve were used to evaluate the prognostic accuracy of the prognostic nomogram. Results: Two hundred and seventy-one patients (18.8%) were diagnosed with sarcopenia. Sarcopenia was significantly associated with advanced age, large tumor size, and high mortality. Compared with the non-sarcopenia patients, the PFS of sarcopenia patients was worse (5-year PFS, 48.34 vs. 58.80%, p = 0.003). Multivariate survival analysis showed that patients with sarcopenia had a higher risk (23.9%) of adverse PFS (HR, 1.239; 95%CI: 1.019-1.505, p = 0.031) than patients without sarcopenia. The OS of patients with sarcopenia was significantly worse than that of patients without sarcopenia (5-year OS: 50.92 vs. 61.62%, p = 0.001). In CRC patients, sarcopenia was independently associated with poor OS (HR: 1.273, 95%CI: 1.042-1.556, p < 0.001). Moreover, sarcopenia effectively differentiated the OS of CRC patients in the normal carcinoembryonic antigen (CEA) subgroup but not in the high CEA subgroup. Notably, sarcopenia can provide effective prognostic stratification in CRC patients at different pathological stages. Nomograms that integrated prognostic features were built to predict the risk of adverse outcomes in CRC patients. The C-index and calibration curves showed that these nomograms had good prediction accuracy. Internal validation confirmed that our nomogram has wide application potential. Conclusion: Sarcopenia diagnosed based on anthropometric equations is an independent risk factor for PFS and OS in CRC patients.

Prognostic significance of preoperative prognostic immune and nutritional index in patients with stage I-III colorectal cancer.

BACKGROUND: To explore the value of preoperative prognostic immune and nutritional index (PINI) in predicting postoperative complications and long-term outcomes in patients with stage I-III colorectal cancer (CRC). METHODS: Restricted cubic splines were used to assess the relationship between PINI and survival in patients with CRC. The Kaplan-Meier method and log-rank test were used to plot the survival curves. The Cox proportional hazards model was used to evaluate independent prognostic predictors in patients with CRC. A logistic regression analysis was performed to identify independent predictors of postoperative complications. The least absolute shrinkage and selection operator (LASSO) logistic regression algorithm was used for feature screening. RESULTS: An evident positive dose-response relationship between PINI and survival in patients with CRC was identified. Compared with patients with a high PINI, those with a low PINI had worse disease-free survival (DFS) (47.9% vs. 66.9%, p < 0.001) and overall survival (OS) (49.7% vs. 70.2%, p < 0.001). The Cox proportional hazards model revealed that PINI was independently associated with DFS (hazard ratio [HR], 0.823; 95% confidence interval [CI], 0.754-0.898; p < 0.001) and OS (HR, 0.833; 95% CI, 0.761-0.912; p < 0.001) in patients with CRC. In the logistic regression analysis, PINI was an independent factor affecting postoperative complications in patients with CRC (odds ratio, 0.710; 95%CI: 0.610-0.810, p < 0.001). The LASSO logistic regression algorithm was used to screen for effective prognostic variables. Finally, we constructed PINI-based nomograms to predict postoperative 1-5-year PFS, and OS in patients with CRC. CONCLUSION: PINI is an effective biomarker for predicting postoperative complications, DFS, and OS in patients with stage I-III CRC.

Neutrophil-albumin ratio as a biomarker for postoperative complications and long-term prognosis in patients with colorectal cancer undergoing surgical treatment.

Background: To explore the prognostic value of the preoperative neutrophil-albumin ratio (NAR) in patients with colorectal cancer (CRC) undergoing surgical treatment. Materials and methods: The standardized log-rank statistic was used to determine the optimal cut-off value for NAR. A logistic regression model was used to evaluate the value of NAR in predicting postoperative complications. Cox proportional hazards models were used to assess the independent association of NAR with progression-free survival (PFS) and overall survival (OS) in CRC patients. Restricted cubic splines were used to assess the relationship between continuous NAR and survival in CRC patients. The Kaplan-Meier method and log-rank test were used to compare survival differences between low and high NAR groups. NAR-based prognostic nomograms were constructed to predict the 1-5-year PFS and OS of CRC patients. The concordance index (C-index) and calibration curve were used to evaluate the prognostic accuracy of the nomograms. Results: A total of 1,441 CRC patients were enrolled from January 2012 to December 2016. There were 904 men (62.7%) and 537 women (37.3%), with an average age of 58.12 ± 13.15 years. High NAR was closely associated with low BMI, advanced pathological stage, colon cancer, large tumors, vascular invasion, poor differentiation, high CEA levels, long hospital stay, and recurrence and metastasis. A high NAR was an independent risk factor for postoperative complications in CRC patients (OR: 2.298, 95% CI: 1.642-3.216, p < 0.001). Patients with a high NAR had worse PFS (40.7 vs. 59.5%, p < 0.001) and OS (42.6 vs. 62.4%, p < 0.001). After adjusting for confounders, high NAR was independently associated with PFS (HR: 1.280, 95% CI: 1.031-1.589, p = 0.025) and OS (HR: 1.280; 95% CI: 1.026-1.596, p = 0.029) in CRC patients. The C-index and calibration curves showed that the NAR-based prognostic nomograms had good predictive accuracy. Conclusion: High NAR was an independent risk factor for postoperative complications and long-term prognosis of CRC patients. NAR-based research could provide references for prognostic judgment and clinical decision-making of CRC patients.

Lactobacillus johnsonii alleviates colitis by TLR1/2-STAT3 mediated CD206+ macrophagesIL-10 activation.

Imbalance of gut microbiota homeostasis is related to the occurrence of ulcerative colitis (UC), and probiotics are thought to modulate immune microenvironment and repair barrier function. Here, in order to reveal the interaction between UC and gut microbiota, we screened a new probiotic strain by 16S rRNA sequencing from Dextran Sulfate Sodium (DSS)-induced colitis mice, and explored the mechanism and clinical relevance. Lactobacillus johnsonii (L. johnsonii), as a potential anti-inflammatory bacterium was decreased colonization in colitis mice. Gavage L. johnsonii could alleviate colitis by specifically increasing the proportion of intestinal macrophages and the secretion of Il-10 with macrophages depleted model and in Il10-/- mice. We identified this subset of immune cells activated by L. johnsonii as CD206+ macrophagesIL-10. Mechanistically, L. johnsonii supplementation enhanced the mobilization of CD206+ macrophagesIL-10 through the activation of STAT3 in vivo and in vitro. In addition, we revealed that TLR1/2 was essential for the activation of STAT3 and the recognition of L. johnsonii by macrophages. Clinically, there was positive correlation between the abundance of L. johnsonii and the expression level of MRC1, IL10 and TLR1/2 in UC tissues. L. johnsonii could activate native macrophages into CD206+ macrophages and release IL-10 through TLR1/2-STAT3 pathway to relieve experimental colitis. L. johnsonii may serve as an immunomodulator and anti-inflammatory therapeutic target for UC.