Effects of cadmium on the intestinal health of the snail Bradybaena ravida Benson.

The heavy metal cadmium (Cd) is a toxic and bioaccumulative metal that can be enriched in the tissues and organs of living organisms through the digestive tract. However, more research is needed to determine whether food-sourced Cd affects the homeostasis of host gut microflora. In this study, the snail Bradybaena ravida (Benson) was used as a model organism fed with mulberry leaves spiked with different concentrations of Cd (0, 0.052, 0.71, and 1.94 mg kg-1). By combining 16S rRNA high-throughput sequencing with biochemical characterization, it was found that there were increases in the overall microbial diversity and abundances of pathogenic bacteria such as Corynebacterium, Enterococcus, Aeromonas, and Rickettsia in the gut of B. ravida after exposure to Cd. However, the abundances of potential Cd-resistant microbes in the host's gut, including Sphingobacterium, Lactococcus, and Chryseobacterium, decreased with increasing Cd concentrations in the mulberry leaves. In addition, there was a significant reduction in activities of energy, nutrient metabolism, and antioxidant enzymes for gut microbiota of snails treated with high concentrations of Cd compared to those with low ones. These findings highlight the interaction of snail gut microbiota with Cd exposure, indicating the potential role of terrestrial animal gut microbiota in environmental monitoring through rapid recognition and response to environmental pollution.

Multi-dimensional characterization of apoptosis in the tumor microenvironment and therapeutic relevance in melanoma.

PURPOSE: Melanoma is widely utilized as a prominent model for the development of immunotherapy, thought an inadequate immune response can occur. Moreover, the development of apoptosis-related therapies and combinations with other therapeutic strategies is impeded by the limited understanding of apoptosis's role within diverse tumor immune microenvironments (TMEs). METHODS: Here, we constructed an apoptosis-related tumor microenvironment signature (ATM) and employ multi-dimensional analysis to understand the roles of apoptosis in tumor microenvironment. We further assessed the clinical applications of ATM in nine independent cohorts, and anticipated the impact of ATM on cellular drug response in cultured cells. RESULTS: Our ATM model exhibits robust performance in survival prediction in multiple melanoma cohorts. Different ATM groups exhibited distinct molecular signatures and biological processes. The low ATM group exhibited significant enrichment in B cell activation-related pathways. What's more, plasma cells showed the lowest ATM score, highlighting their role as pivotal contributors in the ATM model. Mechanistically, the analysis of the interplay between plasma cells and other immune cells elucidated their crucial role in orchestrating an effective anti-tumor immune response. Significantly, the ATM signature exhibited associations with therapeutic efficacy of immune checkpoint blockade and the drug sensitivity of various agents, including FDA-approved and clinically utilized drugs targeting the VEGF signaling pathway. Finally, ATM was associated with tertiary lymphoid structures (TLS), exhibiting stronger patient stratification ability compared to classical "hot tumors". CONCLUSION: Our findings indicate that ATM is a prognostic factor and is associated with the immune response and drug sensitivity in melanoma.

Multiomics characterization of pyroptosis in the tumor microenvironment and therapeutic relevance in metastatic melanoma.

BACKGROUND: Pyroptosis, mediated by gasdermins with the release of multiple inflammatory cytokines, has emerged as playing an important role in targeted therapy and immunotherapy due to its effectiveness at inhibiting tumor growth. Melanoma is one of the most commonly used models for immunotherapy development, though an inadequate immune response can occur. Moreover, the development of pyroptosis-related therapy and combinations with other therapeutic strategies is limited due to insufficient understanding of the role of pyroptosis in the context of different tumor immune microenvironments (TMEs). METHODS: Here, we present a computational model (pyroptosis-related gene score, PScore) to assess the pyroptosis status. We applied PScore to 1388 melanoma samples in our in-house cohort and eight other publicly available independent cohorts and then calculated its prognostic power of and potential as a predictive marker of immunotherapy efficacy. Furthermore, we performed association analysis for PScore and the characteristics of the TME by using bulk, single-cell, and spatial transcriptomics and assessed the association of PScore with mutation status, which contributes to targeted therapy. RESULTS: Pyroptosis-related genes (PRGs) showed distinct expression patterns and prognostic predictive ability in melanoma. Most PRGs were associated with better survival in metastatic melanoma. Our PScore model based on genes associated with prognosis exhibits robust performance in survival prediction in multiple metastatic melanoma cohorts. We also found PScore to be associated with BRAF mutation and correlate positively with multiple molecular signatures, such as KRAS signaling and the IFN gamma response pathway. Based on our data, melanoma with an immune-enriched TME had a higher PScore than melanoma with an immune-depleted or fibrotic TME. Additionally, monocytes had the highest PScore and malignant cells and fibroblasts the lowest PScore based on single-cell and spatial transcriptome analyses. Finally, a higher PScore was associated with better therapeutic efficacy of immune checkpoint blockade, suggesting the potential of pyroptosis to serve as a marker of immunotherapy response. CONCLUSIONS: Collectively, our findings indicate that pyroptosis is a prognostic factor and is associated with the immune response in metastatic melanoma, as based on multiomics data. Our results provide a theoretical basis for drug combination and reveal potential immunotherapy response markers.

Association between the dietary inflammatory index and all-cause mortality in the U.S. cancer survivors: A prospective cohort study using the National Health and Nutrition Examination Survey database.

Background: Cancer remains one of the leading causes of mortality worldwide. Diet can impact inflammation and consequently affect cancer outcomes. The Dietary Inflammatory Index (DII) can serve as a tool to assess the inflammatory potential of cancer survivors' diets and further predict their survival. Objectives: To investigate the relationship between the DII and the survival of cancer survivors in National Health and Nutrition Examination Survey (NHANES). Methods: An overall sample of 2359 U.S. cancer survivors from the 2005-2014 cohorts of the NHANES were studied. The DII scores were calculated using 28 dietary components and the mortality status was ascertained until December 31, 2015. Based on the multiple analyses, the relationship between DII and all-cause mortality was examined. Results: The weighted mean age at baseline was 65.17 ± 14.46 years, 53.16 % were female and 71.30 % were non-Hispanic white. The average DII was 1.51 ± 1.97. After accounting for multiple covariates, positive associations were observed (P < 0.01). Based on Kaplan-Meier survival curves, their significant relationship remains same and the survival probability was decreased among the groups of anti-inflammatory diets (DII < 0) versus pro-inflammatory diets (DII ≥ 0) significantly (Log rank test; P = 0.03). Further analyses were conducted on subgroups and the results are still robust. Conclusions: An elevated DII was associated with a rising mortality rate among cancer survivors. DII might serve as a potential inflammatory predictor of cancer mortality prognosis, as well as guide nutritional care and even clinical treatment of cancer survivors.

Associations Between Sex-Specific Reproductive Factors and Risk of New-Onset Lung Cancer Among Female Patients.

BACKGROUND: Several characteristics distinguish lung cancer in female patients from that in male patients, with adenocarcinoma being more prevalent in female patients and occurring more frequently in female patients who do not smoke. Uncertainty surrounds the relationship between female-specific reproductive factors and lung cancer risk. RESEARCH QUESTION: Are sex-specific reproductive factors associated with risk of lung cancer in different genetic risk groups and histologic types? STUDY DESIGN AND METHODS: A Cox proportional hazard model was used to evaluate the association between multiple reproductive factors and the risk of lung cancer developing in a prospective cohort study involving 273,190 female individuals from the UK Biobank. Subgroup analyses stratified by age, smoking status, BMI, genetic risk, and histologic subtype were conducted to emphasize the modification effects further. RESULTS: A total of 1,182 cases of lung cancer in female patients were recorded over a median follow-up period of 12.0 years in the cohort study. In multivariable-adjusted models, early menarche (age ≤ 11 years: hazard ratio [HR], 1.22; 95% CI, 1.03-1.46), early menopause (age ≤ 46 years: HR, 1.49; 95% CI, 1.19-1.86), a shorter reproductive span (≤ 32 years: HR, 1.42; 95% CI, 1.18-1.71; and 33-35 years: HR, 1.24; 95% CI, 1.00-1.53), and early age at first birth (age ≤ 20 years: HR, 1.63; 95% CI, 1.33-2.01) were associated with a higher risk of lung cancer. Stratified analysis revealed that several reproductive factors, including early age at menopause, shortened reproductive span, and early age at first birth, showed a substantially stronger relationship with an elevated risk of lung cancer, particularly of lung adenocarcinoma, in populations with high genetic risk and more detrimental behaviors. INTERPRETATION: Early age at menopause, a shortened reproductive life span, and early age at first birth were associated with higher risks of lung cancer, particularly of lung adenocarcinoma, in a subpopulation with higher genetic susceptibility and detrimental behaviors. The evidence provided by this study emphasizes the significance of screening for multiple reproductive factors to prevent lung cancer among female individuals.

Vitamin D Status, Vitamin D Receptor Polymorphisms, and the Risk of Incident Rosacea: Insights from Mendelian Randomization and Cohort Study in the UK Biobank.

BACKGROUND: Previous cross-sectional studies have failed to definitively establish a causal relationship between serum 25-hydroxyvitamin D (25OHD) concentrations and the onset of rosacea. OBJECTIVE: To investigate the potential association between serum 25OHD levels, vitamin D receptor (VDR) polymorphisms, and the risk of developing incident rosacea. METHODS: This cross-sectional population-based cohort study utilizing 370,209 individuals from the UK Biobank. Cox proportional hazard regression models and two-sample Mendelian randomization (MR) analyses were applied to explore the causative relationship between 25OHD and incident rosacea. RESULTS: Our findings revealed that elevated levels of serum 25OHD were inversely correlated with the risk of incident rosacea. Specifically, compared to participants with 25OHD levels below 25 nmol/L, the multivariate-adjusted HR for incident rosacea was 0.81 (95% CI: 0.70, 0.94) in those with 25OHD levels exceeding 50 nmol/L. Further, in comparison to individuals with serum 25OHD less than 25 nmol/L and the rs731236 (TaqI) AA allele, those with serum 25OHD higher than 75 nmol/L and the TaqI GG allele had a multivariate-adjusted HR of 0.51 (95% CI 0.32 to 0.81) for developing rosacea. Results from the MR study supported a significant association, with each standard deviation increase in serum 25OHD concentrations correlating to a 23% reduced risk of rosacea (HR = 0.77, 95% CI: 0.63, 0.93). CONCLUSIONS: The findings of this cohort study indicate an inverse association between increased concentrations of serum 25OHD and the risk of developing incident rosacea. While our results highlight the potential protective role of vitamin D, the definitive efficacy of vitamin D supplementation as a preventive strategy against rosacea requires further investigation.

Adenosine 5'monophosphate-activated protein kinase activation reduces the risks of psoriasis and its comorbidities: a mendelian randomisation study in the UK Biobank.

OBJECTIVE: Whether metformin and its adenosine 5'monophosphate-activated protein kinase (AMPK) activation protect from psoriasis risk is unconcluded. We investigated the effect of AMPK, a pharmacological target of metformin, on the risk of psoriasis and its comorbidities and mortality among participants in the UK Biobank(UKB). METHODS: To avoid immortal-time-biases in pharmacoepidemiologic studies, Mendelian randomisation was used to infer the AMPK pathway-dependent effects. The cut-off age for distinguishing early-onset/late-onset psoriasis (EOP/LOP) was set at 60 years, based on the incident psoriasis peak in UKB. A genetic instrument comprising 44 single-nucleotide polymorphisms associated with HbA1c, serving as a proxy for AMPK genetic risk score (negatively associated with AMPK activation), was employed as previously reported in the literature. Log-binomial models were used to estimate the effect size of AMPK regarding relative risk (RR) and 95% confidence interval (CI). RESULTS: A total of 407 159 participants were analyzed, including 9,126 EOP and 3,324 LOP. The AMPK-genetic-risk-score was associated with a 12.4% increase in the risk of LOP in men (RR = 1.124, 95% CI: 1.022-1.236). This association was not significant for EOP or women. AMPK genetic risk score exhibited an elevated risk of ischemic heart disease (RR = 1.217, 95% CI 1.062-1.395) in male psoriasis patients. CONCLUSIONS: AMPK activation may protect against LOPs and associated ischemic heart disease in men. A sex-specific, comorbidity-targeted intervention for psoriasis is needed.

Vitamin D status, sleep patterns, genetic susceptibility, and the risk of incident adult-onset asthma: a large prospective cohort study.

Introduction: Vitamin D has been known to be associated with asthma, particularly in children, while the evidence among adults is limited and inconclusive. This study aimed to investigate the association between serum, vitamin D concentrations, and the incidence of adult-onset asthma and also the modified effect caused by sleep patterns and genetic risks. Methods: A prospective cohort study with 307,872 participants aged between 37 and 73 years was conducted based on the UK Biobank, with a median follow-up of 12 years. The Cox proportional hazard model was applied to evaluate the association between vitamin D status and incident adult-onset asthma, and the modified effect was investigated by conducting stratified analysis according to sleep pattern score and genetic risk score, and subgroup analyses were performed by sex, age, BMI, and smoking status as well. Results: Individuals with optimal vitamin D concentration were associated with 11.1% reduced risk of incident asthma compared to those participants with deficient vitamin D (HR = 0.889; 95% CI: 0.820-0.964; p = 0.005). Moreover, stratification analysis demonstrated that the protective effect of vitamin D on asthma risk was modified by sleep patterns or genetic susceptibility, with the strongest protective effect being observed in the subpopulation with a moderate sleep pattern (HR = 0.883; 95% CI: 0.797-0.977; p = 0.016) and a moderate genetic risk (HR = 0.817; 95% CI: 0.711-0.938; p = 0.004). In subgroup analyses, the protective effect of optimal vitamin D levels was only significant among men, individuals younger than 60 years of age, overweight individuals, and current or previous smokers. Conclusion: Increased serum vitamin D levels were associated with a lower risk of incident adult-onset asthma, and this association was modified by sleep patterns and genetic predisposition to some extent.

Osteoarthritis and sarcopenia-related traits: the cross-sectional study from NHANES 2011-2014 and Mendelian randomization study.

BACKGROUND: Osteoarthritis (OA) and sarcopenia are common musculoskeletal disorders in the aged population, and a growing body of evidence indicated that they mutually influence one another. Nevertheless, there was still substantial controversy and uncertainty about the causal relationship between sarcopenia and OA. We explored the complex association between sarcopenia-related traits and OA using cross-sectional analysis and Mendelian randomization (MR). METHODS: The cross-sectional study used the data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Weighted multivariable-adjusted logistic regression and subgroup analyses were used to evaluate the correlation between sarcopenia, grip, appendicular lean mass (ALM) and the risk of OA. Then, we further performed MR analysis to examine the causal effect of sarcopenia-related traits (grip strength, ALM) on OA. Instrumental variables for grip strength and ALM were from the UK Biobank, and the summary-level data for OA was derived from the Genetics of Osteoarthritis (GO) Consortium GWAS (n = 826,690). RESULTS: In this cross-sectional analysis, we observed that sarcopenia, grip were significantly linked with the risk of OA (OR 1.607, 95% CI 1.233-2.094, P < 0.001), (OR 0.972, 95% CI 0.964-0.979, P < 0.001). According to subgroup analyses stratified by gender, body mass index (BMI), and age, the significant positive relationship between sarcopenia and OA remained in males, females, the age (46-59 years) group, and the BMI (18.5-24.9 kg/m2) group (P < 0.05). Furthermore, MR analysis and sensitivity analyses showed causal associations between right grip, left grip and KOA (OR 0.668; 95% CI 0.509 to 0.877; P = 0.004), (OR 0.786; 95% CI 0.608 to 0.915; P = 0.042). Consistent directional effects for all analyses were observed in both the MR-Egger and weighted median methods. Subsequently, sensitivity analyses revealed no heterogeneity, directional pleiotropy or outliers for the causal effect of grip strength on KOA (P > 0.05). CONCLUSIONS: Our research provided evidence that sarcopenia is correlated with an increased risk of OA, and there was a protective impact of genetically predicted grip strength on OA. These findings needed to be verified in further prospective cohort studies with a large sample size.

Association between long-term exposure to wildfire-related PM2.5 and mortality: A longitudinal analysis of the UK Biobank.

Little is known about the associations between long-term exposure to wildfire-related fine particulate matter (PM2.5) and mortality. We aimed to explore theses associations using the data from the UK Biobank cohort. Long-term wildfire-related PM2.5 exposure was defined as the 3-year cumulative concentrations of wildfire-related PM2.5 within a 10-km buffer surrounding the residential address for each individual. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using the time-varying Cox regression model. We included 492,394 participants aged between 38 and 73 years. We found that after adjusting for potential covariates, a 10 µg/m3 increase of wildfire-related PM2.5 exposure was associated with a 0.4% higher risk of all-cause mortality (HR = 1.004 [95% CI: 1.001, 1.006]) and nonaccidental mortality (HR = 1.004 [95% CI: 1.002, 1.006]), and a 0.5% higher risk of neoplasm mortality (HR = 1.005 [95% CI: 1.002, 1.008]). However, no significant associations were observed between wildfire-related PM2.5 exposure and mortality from cardiovascular, respiratory, and mental diseases. Additionally, no significant modification effects of a series of modifiers were observed. Targeted health protection strategies should be adopted in response to wildfire-related PM2.5 exposure, in order to reduce the risk of premature mortality.

Association between inflammatory markers and bone mineral density: a cross-sectional study from NHANES 2007-2010.

PURPOSE: Monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) are acknowledged as novel inflammatory markers. However, studies investigating the correlation between inflammatory markers and osteoporosis (OP) remain scarce. We aimed to investigate the relationship between NLR, MLR, PLR and bone mineral density (BMD). METHODS: A total of 9054 participants from the National Health and Nutrition Examination Survey were included in the study. MLR, NLR and PLR were calculated for each patient based on routine blood tests. Given the complex study design and sample weights, the relationship between inflammatory markers and BMD was evaluated through weighted multivariable-adjusted logistic regression and smooth curve fittings. In addition, several subgroup analyses were conducted to assess the robustness of the outcomes. RESULTS: This study observed no significant relationship between MLR and lumbar spine BMD (P = 0.604). However, NLR was positively correlated with lumbar spine BMD (ß = 0.004, 95% CI: 0.001 to 0.006, P = 0.001) and PLR was negatively linked to lumbar spine BMD (ß = - 0.001, 95% CI: - 0.001 to - 0.000, P = 0.002) after accounting for covariates. When bone density measurements were changed to the total femur and femoral neck, PLR was still significantly positively correlated with total femur (ß = - 0.001, 95% CI: - 0.001, - 0.000, P = 0.001) and femoral neck BMD (ß = - 0.001, 95% CI: - 0.002, - 0.001, P < 0.001). After converting PLR to a categorical variable (quartiles), participants in the highest PLR quartile had a 0.011/cm2 lower BMD than those in the lowest PLR quartile (ß = - 0.011, 95% CI: - 0.019, - 0.004, P = 0.005). According to subgroup analyses stratified by gender and age, the negative correlation with PLR and lumbar spine BMD remained in males and age < 18 groups, but not in female and other age groups. CONCLUSIONS: NLR and PLR were positively and negatively correlated with lumbar BMD, respectively. And PLR might serve as a potential inflammatory predictor of osteoporosis outperforming MLR and NLR. The complex correlation between the inflammation markers and bone metabolism requires further evaluation in large prospective studies.

Regulation of gut bacteria in silkworm (Bombyx mori) after exposure to endogenous cadmium-polluted mulberry leaves.

Soil cadmium (Cd) pollution presents a severe pollution burden to flora and fauna due to its non-degradability and transferability. The Cd in the soil is stressing the silkworm (Bombyx mori) out through a soil-mulberry-silkworm system. The gut microbiota of B.mori are reported to shape host health. However, earlier research had not reported the effect of endogenous Cd-polluted mulberry leaves on the gut microbiota of B.mori. In the current research, we compared the phyllosphere bacteria of endogenous Cd-polluted mulberry leaves at different concentrations. The investigation of the gut bacteria of B.mori fed with the mulberry leaves was done to evaluate the impact of endogenous Cd- polluted mulberry leaves on the gut bacteria of the silkworm. The results revealed a dramatic change in the gut bacteria of B.mori whereas, the changes in the phyllosphere bacteria of mulberry leaves in response to an increased Cd concentration were insignificant. It also increased the α-diversity and altered the gut bacterial community structure of B. mori. A significant change in the abundance of dominant phyla of gut bacteria of B.mori was recorded. At the genus level, the abundance of Enterococcus, Brachybacterium and Brevibacterium group related to disease resistance, and the abundance of Sphingomonas, Glutamicibacter and Thermus related to metal detoxification was significantly increased after Cd exposure. Meanwhile, there was a significant decrease in the abundance of the pathogenic bacteria Serratia and Enterobacter. The results demonstrated that endogenous Cd-polluted mulberry leaves caused perturbations in the gut bacterial composition of B.mori, which may driven by Cd content rather than phyllosphere bacteria. A significant variation in the specific bacterial community indicated the adaptation of B. mori gut for its role in heavy metal detoxification and immune function regulation. The results of this study help to understand the bacterial community associated with endogenous Cd-polluted resistance in the gut of B.mori, which proves to be a novel addition in describing its response in activating the detoxification mechanism and promoting its growth and development. This research work will help to explore the other mechanisms and microbiota associated with the adaptations to mitigate the Cd pollution problems.

Trichosanthin Promotes Anti-Tumor Immunity through Mediating Chemokines and Granzyme B Secretion in Hepatocellular Carcinoma.

Trichosanthin (TCS) is a type I ribosome-inactivating protein extracted from the tuberous root of the plant Trichosanthes. TCS shows promising potential in clinical drug abortion, anti-tumor and immunological regulation. However, the molecular mechanisms of its anti-tumor and immune regulation properties are still not well discovered. In the present study, we investigated the anti-tumor activity of TCS in hepatocellular carcinoma (HCC), both in vitro and in vivo. Both HCC cell lines and xenograft tumor tissues showed considerable growth inhibition after they were treated with TCS. TCS provoked caspase-mediated apoptosis in HCC cells and xenograft tumor tissues. The recruitment of CD8+ T cells to HCC tissues and the expression of chemokines, CCL2 and CCL22, were promoted upon TCS treatment. In addition, TCS induced an upregulation of Granzyme B (GrzB), TNF-α and IFN-γ in HCC tissues, which are the major cytotoxic mediators produced by T cells. Furthermore, TCS also resulted in an increase of mannose-6-phosphate receptor (M6PR), the major receptor of GrzB, in HCC tissues. In summary, these results suggest that TCS perhaps increases T-cell immunity via promoting the secretion of chemokines and accelerating the entry of GrzB to HCC cells, which highlights the potential role of TCS in anti-tumor immunotherapy.

Unveil of the role of fungal taxa in iron(III) reduction in paddy soil.

Hitherto, research on iron(III)-reduction has mainly focused on bacteria rather than fungal communities. To acquire insight into fungi involved in iron(III) reduction, typical organic matters (containing cellulose, glucose, lactate, and acetate) and ferrihydrite were used as electron donors and acceptors, respectively, in the presence of antibiotics. After antibiotic addition, microbial iron(III) reduction was still detected at quite high rates. In comparison, rates of iron(III) reduction were significantly lower in cellulose-amended groups than those with glucose, lactate, and acetate under the antibiotic-added condition. Patterns of intermediate (e.g., acetate, pyruvate, glucose) turnover were markedly different between treatments with and without antibiotics during organic degradation. A total of 20 genera of potential respiratory and fermentative iron(III)-reducing fungi were discovered based on ITS sequencing and genome annotation. This study provided an insight into the diversity of iron(III)-reducing fungi, indicating the underestimated contribution of fungi to iron and the coupled carbon biogeochemical cycling in environments.

A novel nomogram based on the prognostic nutritional index for predicting postoperative outcomes in patients with stage I-III gastric cancer undergoing robotic radical gastrectomy.

Background: The inflammation and nutrition status are crucial factors influencing the outcome of patients with gastric cancer. This study aims to investigate the prognostic value of the preoperative prognostic nutritional index (PNI) in patients with stage I-III gastric cancer undergoing robotic radical gastrectomy combined with Enhanced Recovery after Surgery (ERAS), and further to create a clinical prognosis prediction model. Study: 525 patients with stage I-III gastric cancer who underwent ERAS combined with RRG from July 2010 to June 2018 were included in this work, and were divided randomly into training and validating groups in a 7-to-3 ratio. The association between PNI and overall survival (OS) was assessed by Kaplan-Meier analysis and the log-rank test. Independent risk factors impacting postoperative survival were analyzed with the Cox proportional hazards regression model. A nomogram for predicting OS was constructed based on multivariate analysis, and its predictive performance was evaluated using Harrell's concordance index (C-index), calibration plots, ROC curve, decision curve analysis (DCA), and time-dependent ROC curve analysis. Results: Survival analyses revealed the presence of a significant correlation between low preoperative PNI and shortened postoperative survival (P = 0.001). According to multivariate analysis, postoperative complications (P < 0.001), pTNM stage (II: P = 0.007; III: P < 0.001), PNI (P = 0.048) and lymph node ratio (LNR) (P = 0.003) were independent prognostic factors in patients undergoing ERAS combined with RRG. The nomogram constructed based on PNI, pTNM stage, complications, and LNR was superior to the pTNM stage model in terms of predictive performance. The C-indexes of the nomogram model were respectively 0.765 and 0.754 in the training and testing set, while AUC values for 1-year, 3-year, and 5-year OS were 0.68, 0.71, and 0.74 in the training set and 0.60, 0.67, and 0.72 in the validation set. Conclusion: Preoperative PNI is an independent prognostic factor for patients with stage I-III gastric cancer undergoing ERAS combined with robotic radical gastrectomy. Based on PNI, we constructed a nomogram for predicting postoperative outcomes of gastric cancer patients, which might be utilized clinically.

Underestimation about the Contribution of Nitrate Reducers to Iron Cycling Indicated by Enterobacter Strain.

Nitrate-reducing iron(II) oxidation (NRFO) has been intensively reported in various bacteria. Iron(II) oxidation is found to be involved in both enzymatic and chemical reactions in nitrate-reducing Fe(II)-oxidizing microorganisms (NRFOMs). However, little is known about the relative contribution of biotic and abiotic reactions to iron(II) oxidation for the common nitrate reducers during the NRFO process. In this study, the typical nitrate reducers, four Enterobacter strains E. hormaechei, E. tabaci, E. mori and E. asburiae, were utilized as the model microorganisms. The comparison of the kinetics of nitrate, iron(II) and nitrite and N2O production in setups with and without iron(II) indicates a mixture of enzymatic and abiotic oxidation of iron(II) in all four Enterobacter strains. It was estimated that 22-29% of total oxidized iron(II) was coupled to microbial nitrate reduction by E. hormaechei, E. tabaci, E. mori, and E. asburiae. Enterobacter strains displayed an metabolic inactivity with heavy iron(III) encrustation on the cell surface in the NRFOmedium during days of incubation. Moreover, both respiratory and periplasmic nitrate-reducing genes are encoded by genomes of Enterobacter strains, suggesting that cell encrustation may occur with periplasmic iron(III) oxide precipitation as well as the surface iron(II) mineral coating for nitrate reducers. Overall, this study clarified the potential role of nitrate reducers in the biochemical cycling of iron under anoxic conditions, in turn, re-shaping their activity during denitrification because of cell encrustation with iron(III) minerals.

Sphingosine kinase 1 promotes tumor immune evasion by regulating the MTA3-PD-L1 axis.

Immune checkpoint blockade (ICB) exhibits considerable benefits in malignancies, but its overall response rate is limited. Previous studies have shown that sphingosine kinases (SPHKs) are critical in the tumor microenvironment (TME), but their role in immunotherapy is unclear. We performed integrative analyses including bioinformatics analysis, functional study, and clinical validation to investigate the role of SPHK1 in tumor immunity. Functionally, we demonstrated that the inhibition of SPHK1 significantly suppressed tumor growth by promoting antitumor immunity in immunocompetent melanoma mouse models and tumor T-cell cocultures. A mechanistic analysis revealed that MTA3 functions as the downstream target of SPHK1 in transcriptionally regulating tumor PD-L1. Preclinically, we found that anti-PD-1 monoclonal antibody (mAb) treatment significantly rescued tumor SPHK1 overexpression or tumor MTA3 overexpression-mediated immune evasion. Significantly, we identified SPHK1 and MTA3 as biological markers for predicting the efficacy of anti-PD-1 mAb therapy in melanoma patients. Our findings revealed a novel role for SPHK1 in tumor evasion mediated by regulating the MTA3-PD-L1 axis, identified SPHK1 and MTA3 as predictors for assessing the efficacy of PD-1 mAb treatment, and provided a therapeutic possibility for the treatment of melanoma patients.

Development and validation of a novel nomogram to predict overall survival of patients with moderate to severe chronic kidney disease.

INTRODUCTION: The risk of death significantly increased from stage 3 chronic kidney disease (CKD) onward. We aimed to construct a novel nomogram to predict the overall survival (OS) of patients afflicted with CKD from stage 3-5. METHODS: A total of 882 patients with stage 3-5 CKD were enrolled from the NHANES 2001-2004 survey. Data sets from the 2003-2004 survey population were used to develop a nomogram that would predict the risk of OS. The 2001-2002 survey population was used to validate the nomogram. Least absolute shrinkage and selection operator (Lasso) regression was conducted to screen the significant predictors relative to all-cause death. The multivariate Cox regression based on the screened factors was applied to effectively construct the nomogram. The performance of the nomogram was evaluated according to the C-index, the area under the receiver operating characteristic curve (AUC), and the calibration curve with 1000 bootstraps resample. Kaplan-Meier's curves were used for testing the discrimination of the prediction model. RESULTS: Five variables (age, urinary albumin-to-creatinine ratio (UACR), potassium, cystatin C (Cys C), and homocysteine) were screened by the Lasso regression. The nomogram was constructed using these factors, as well as the CKD stage. The included factors (age, CKD stage, UACR, potassium, Cys C, and homocysteine) were all significantly related to the death of CKD patients, according to the multivariate Cox regression analysis. The internal validation showed that this nomogram demonstrates good discrimination and calibration (adjusted C-index: 0.70; AUC of 3-, 5-, and 10-year OS were 0.75, 0.78, and 0.77, respectively). External validation also demonstrated exceedingly similar results (C-index: 0.72, 95% CI: 0.69-0.76; AUC of 3-, 5-, and 10-year OS were 0.76, 0.79, and 0.80, respectively). CONCLUSIONS: This study effectively constructed a novel nomogram that incorporates CKD stage, age, UACR, potassium, Cys C, and homocysteine, which can be conveniently used to facilitate the individualized prediction of survival probability in patients with stage 3-5 CKD. It displays valuable potential for clinical application.

Rapid Simultaneous Determination of 43 Pesticide Residues in Schizonepeta tenuifolia by Gas Chromatography Mass Spectrometry.

A simple, fast, and reliable method was established for simultaneous determination of 43 pesticides in Schizonepeta tenuifolia. The samples were prepared using solid-phase extraction (SPE) method. Pesticides were extracted from Schizonepeta tenuifolia using acetonitrile, cleaned with Pesticarb/NH2, and eluted by mixed solvents of acetonitrile and toluene (3 : 1, v/v). Selected pesticides were identified using DB-35MS capillary column and detected by gas chromatography mass spectrometry. Samples were quantified by external standard method. Recoveries for the majority of pesticides at spike levels of 0.2, 0.5, and 1 mg kg-1 ranged between 70 and 120% (except for Chlorothalonil, Thiamethoxam, and Dicofol), and the relative standard deviations (RSDs n = 6) were 1.32%-13.91%. Limits of detection (LODs) were 0.0011-0.0135 mg kg-1, whereas limits of quantification (LOQs) were 0.0038-0.0451 mg kg-1. The satisfactory accuracy and precision, in combination with a good separation and few interferences, have demonstrated the strong potential of this technique for its application in Schizonepeta tenuifolia analysis.

Anammox Bacteria Are Potentially Involved in Anaerobic Ammonium Oxidation Coupled to Iron(III) Reduction in the Wastewater Treatment System.

Anaerobic ammonium oxidation coupled to nitrite reduction (termed as Anammox) was demonstrated as an efficient pathway to remove nitrogen from a wastewater treatment system. Recently, anaerobic ammonium oxidation was also identified to be linked to iron(III) reduction (termed Feammox) with dinitrogen, nitrite, or nitrate as end-product, reporting to enhance nitrogen removal from the wastewater treatment system. However, little is known about the role of Anammox bacteria in the Feammox process. Here, slurry from wastewater reactor amended with ferrihydrite was employed to investigate activity of Anammox bacteria in the Feammox process using the 15N isotopic tracing technique combined with 16S rRNA gene amplicon sequencing. A significantly positive relationship between rates of 15N2 production and iron(III) reduction indicated the occurrence of Feammox during incubation. Relative abundances of Anammox bacteria including Brocadia, Kuenenia, Jettenia, and unclassified Brocadiaceae were detected with low relative abundances, whereas Geobacteraceae dominated in the treatment throughout the incubation. 15N2 production rates significantly positively correlated with relative abundances of Geobacter, unclassified Geobacteraceae, and Anammox bacteria, revealing their contribution to nitrogen generation via Feammox. Overall, these findings suggested Anammox bacteria or cooperation between Anammox bacteria and iron(III) reducers serves a potential role in Feammox process.