Life's Essential 8 Trajectories and Risk of Stroke: A Prospective Cohort Study.

BACKGROUND: Evidence is lacking regarding long-term patterns of change in Life's Essential 8 (LE8) and their association with the risk of stroke. We aim to evaluate LE8 trajectories and examine their association with the risk of stroke in China. METHODS: This study, conducted in a workplace setting, recruited 26 719 participants (average age, 46.02±11.27 years and a male population of 73.73%) who had no history of stroke and consecutively participated in 6 surveys from 2006 to 2016. Repeated LE8 measurements were determined by taking the unweighted average of the 8 component scores ranging from 0 to 100. People with higher scores had better overall cardiovascular health. By examining the medical records of the participants, stroke cases were identified for the period from 2016 to 2020. A latent mixture model was applied to classify the trajectory clusters of LE8 from 2006 to 2016, and Cox proportional hazard models were used to analyze the data. RESULTS: Five LE8 trajectories were detected between 2006 and 2016. Four hundred ninety-eight incident strokes including 55 (11.04%) hemorrhagic and 458 (91.97%) ischemic strokes were documented. After adjusting for covariates, the hazard ratios and 95% CIs for the association between stable-low, moderate-increasing, moderate-stable, and high-stable trajectories and incident stroke, compared with the moderate-decreasing trajectory, were 1.42 (1.11-1.84), 0.73 (0.56-0.96), 0.49 (0.39-0.62), and 0.19 (0.11-0.32), respectively. Individuals with high LE8 status (LE8≥80) exhibited a significantly reduced risk of stroke compared with those with low one (LE8≤49; P-trend <0.001). A faster annual growth in LE8 was related to a lower risk of stroke. CONCLUSIONS: Maintaining high LE8 over an extended period and high baseline LE8 status were related to a decreased risk of stroke. Despite the initial low level of LE8, improvement in LE8 attenuates or even reverses the risk of stroke.

Microbial rrn copy number is associated with soil C: N ratio and pH under long-term fertilization.

Soil microbial life-history strategies, as indicated by rRNA operon (rrn) copy numbers, strongly influence agro-ecosystem functioning. Long-term N fertilization causes strong and lasting changes in soil properties, yet its impact on microbial strategies remains largely unexplored. Using long-term field experiments across three agro-ecosystems, we consistently found that N fertilization strongly decreased soil C: N ratio and pH, further increasing the community-level rrn copy number, including both average rrn copy number and total 16S rRNA copy number. Soil C: N stoichiometry balanced by N supplement favored the growth of N-dependent copiotrophic species containing high rrn copy numbers (an average of 2.5) and increased their network connections, predominantly contributing to community-level rrn copy number increase. Decreased soil pH caused by N fertilization also favored the growth of some species whose abundances negatively correlated with pH, partially contributing to the community-level rrn copy number increase. By examining the genomes of two dominant species, we found that microorganisms with a higher rrn copy number (6), e.g., Streptomyces scabiei, possessed more genes related to C and N transport and metabolism. In contrast, the Mycobacterium simiae with a lower rrn copy number (1) has more genes associated with secondary metabolite biosynthesis and lipid transport and metabolism. Our finding challenges the concept of microbial life-strategy regulation solely by nutrient availability, highlighting the important contributions of soil stoichiometric balance and pH to microbial strategies in agro-ecosystems under long-term N inputs.

10-year trajectory of Life's Essential 8 and incident hypertension: a community-based cohort study.

BACKGROUND: The health effects of Life's Essential 8 (LE8) on chronic diseases have been disclosed, but its association with hypertension remains unknown. The current study aimed to explore the potential link between 10-year LE8 trajectory and the incidence of hypertension. METHODS: LE8 was constructed from four behaviors and four metabolic factors, ranging from 0 to 100. Latent mixture models were used to identify trajectories of LE8 scores during 2006 to 2016. Incident hypertension was diagnosed based on self-reported clinical diagnoses and physical examinations from 2016 to 2020. Cox models were employed to assess the association of LE8 trajectories with hypertension. In addition to incorporating the mean hs-CRP levels from 2006 to 2016, age, sex, monthly income, educational level, and occupation at recruitment were adjusted for as confounding factors. RESULTS: 7500 participants aged 40.28 ± 10.35 years were included in the study, of whom 2907 (38.76%) were women. Five LE8 trajectory patterns were identified. After around four-year follow-up, 667 hypertension events were observed. Compared to the Low-Stable trajectory, the hazard ratios and 95% confidence intervals for the Moderate-Increasing, Moderate-Decreasing, Moderate-Stable, and High-Stable trajectories were 0.51 (0.40, 0.65), 0.81 (0.64, 1.02), 0.45 (0.36, 0.58), 0.23 (0.16, 0.33), respectively. The risk of incident hypertension decreased as participants improved their LE8 status. The robustness of the primary results was confirmed through several sensitivity analyses. CONCLUSIONS: LE8 trajectories were associated with the incident hypertension. People who improved their LE8 scores over time experienced a decreased risk of hypertension, even if they started with lower LE8 scores initially.

Regulatory function of glycolysis-related lncRNAs in tumor progression: Mechanism, facts, and perspectives.

Altered metabolism is a hallmark of cancer, and reprogramming of energy metabolism, known as the "Warburg effect", has long been associated with cancer. Cancer cells use the process of glycolysis to quickly manufacture energy from glucose, pyruvic acid, and lactate, which in turn accelerates the growth of cancer and glycolysis becomes a key target for anti-cancer therapies. Recent groundbreaking discoveries regarding long noncoding RNAs (lncRNAs) have opened a new chapter in the mechanism of cancer occurrence. It is widely recognized that lncRNAs regulate energy metabolism through glycolysis in cancer cells. LncRNAs have been demonstrated to engage in several cancer processes such as proliferation, apoptosis, migration, invasion, and chemoresistance, whereas glycolysis is enhanced or inhibited by the dysregulation of lncRNAs. As a result, cancer survival and development are influenced by different signaling pathways. In this review, we summarize the roles of lncRNAs in a variety of cancers and describe the mechanisms underlying their role in glycolysis. Additionally, the predictive potential of glycolysis and lncRNAs in cancer therapy is discussed.

Traditional Chinese Medicine Monomers Are Potential Candidate Drugs for Cancer-Induced Cardiac Cachexia.

BACKGROUND: Cardiovascular diseases are now the second leading cause of death among cancer patients. Heart injury in patients with terminal cancer can lead to significant deterioration of left ventricular morphology and function. This specific heart condition is known as cancer-induced cardiac cachexia (CICC) and is characterized by cardiac dysfunction and wasting. However, an effective pharmacological treatment for CICC remains elusive. SUMMARY: The development and progression of CICC are closely related to pathophysiological processes, such as protein degradation, oxidative responses, and inflammation. Traditional Chinese medicine (TCM) monomers offer unique advantages in reversing heart injury, which is the end-stage manifestation of CICC except the regular treatment. This review outlines significant findings related to the impact of eleven TCM monomers, namely Astragaloside IV, Ginsenosides Rb1, Notoginsenoside R1, Salidroside, Tanshinone II A, Astragalus polysaccharides, Salvianolate, Salvianolic acids A and B, and Ginkgolide A and B, on improving heart injury. These TCM monomers are potential therapeutic agents for CICC, each with specific mechanisms that could potentially reverse the pathological processes associated with CICC. Advanced drug delivery strategies, such as nano-delivery systems and exosome-delivery systems, are discussed as targeted administration options for the therapy of CICC. KEY MESSAGE: This review summarizes the pathological mechanisms of CICC and explores the pharmacological treatment of TCM monomers that promote anti-inflammation, antioxidation, and pro-survival. It also considers pharmaceutical strategies for administering TCM monomers, highlighting their potential as therapies for CICC.

Does vertical integration increase the costs for primary care inpatients? Evidence from a national pilot programme in China.

OBJECTIVE: To assess the impact of vertical integration (VI) within County-Level Integrated Health Organisations (CIHOs) on the costs of primary care inpatients. METHODS: This study assessed Xishui, a national pilot county for CIHOs, using inpatient claims data. The treatment group comprised 10,118 inpatients from 5 vertically integrated township health centres (THCs), while the control group consisted of 21,165 inpatients from 19 non-vertically integrated THCs. The periods from July 2020 to December 2021 and January 2022 to December 2022 were defined as pre- and post-policy intervention, respectively. The primary outcome variables were total health expenditures (THS), out-of-pocket (OOP) expenditures, and the proportion of OOP expenditures. Propensity score matching was employed to align inpatient demographics and disease characteristics between the groups, followed by a difference-in-differences analysis to evaluate the outcomes. FINDINGS: VI significantly increased THS (ß = 0.1337, p < 0.01) and OOP expenditures per case (ß = 0.1661, p < 0.001), but the increase in the proportion of OOP expenditures per case was not significant (ß = 0.0029, p > 0.05). For the basic medical insurance for urban and rural residents, THS per case (ß = 0.1343, p < 0.01) and OOP expenditures (ß = 0.1714, p < 0.001) significantly increased. For the basic medical insurance system for employees, THS per case also increased significantly (ß = 0.1238, p < 0.01), but the change in OOP expenditure proportion per case was not significant (ß = 0.1020, p > 0.05). The THS per case led by Xishui County People's Hospital, the leading county medical sub-centre (CMSC), significantly increased (ß = 0.1753, p < 0.01), whereas the increase led by Xishui County Traditional Chinese Medicine Hospital was not significant (ß = 0.0742, p > 0.05). Increases in OOP expenditures per case were significant in CMSCs led by the People's Hospital and the Traditional Chinese Medicine Hospital (ß = 0.1782, p < 0.01 and ß = 0.0757, p < 0.05, respectively). CONCLUSION: VI significantly increased THS and OOP expenditures for primary care inpatients. However, VI could exacerbate economic disparities in disease burden across different insurance categories.

Bisphenol P induces increased oxidative stress in renal tissues of C57BL/6 mice and human renal cortical proximal tubular epithelial cells, resulting in kidney injury.

Bisphenol P (BPP) has been detected in human biological samples; however studies on its nephrotoxicity are scarce. Given the susceptibility of kidneys to endocrine-disrupting chemicals, there is an urgent need to investigate the renal toxicity of BPP. This study aimed to evaluate the effects of different concentrations of BPPs on the kidneys of C57BL/6 mice and elucidate the underlying mechanisms of renal damage using a combination of mouse renal transcriptomic data and human renal proximal tubular epithelial cells (HK-2). Mice were exposed to BPP (0, 0.3, 30, 3000 µg/kg bw/d) via gavage for 5 weeks. Renal injury was assessed based on changes in body and kidney weights, serum renal function indices, and histopathological examination. Transcriptomic analysis identified differentially expressed genes and pathways, whereas cellular assays were used to measure cell viability, reactive oxygen species (ROS), apoptosis, and the expression of key genes and proteins. The results show that BPP exposure induces renal injury, as evidenced by increased body weight, abnormal renal function indices, and renal tissue damage. Transcriptomic analysis revealed alterations in genes and pathways related to oxidative stress, p53 signaling, autophagy, and apoptosis. Cellular experiments confirmed that BPP induces oxidative stress and apoptosis. Furthermore, BPP exposure significantly inhibits autophagy, potentially exacerbating apoptosis and contributing to kidney injury. Treatment with a ROS inhibitor (N-Acetylcysteine, NAC) mitigated BPP-induced autophagy inhibition and apoptosis, implicating oxidative stress as a key factor. BPP exposure may lead to renal injury through excessive ROS accumulation, oxidative stress, inflammatory responses, autophagy inhibition, and increased apoptosis. The effects of NAC highlight the role of oxidative stress in BPP-induced nephrotoxicity. These findings enhance our understanding of BPP-induced nephrotoxicity and underscore the need to control BPP exposure to prevent renal disease. This study emphasized the importance of evaluating the safety of new Bisphenol A analogs, including BPP, in environmental toxicology.

Effectiveness Assessment of Bispectral Index Monitoring Compared with Conventional Monitoring in General Anesthesia: A Systematic Review and Meta-Analysis.

Background and Objective. The Bispectral Index (BIS) is utilized to guide the depth of anesthesia monitoring during surgical procedures. However, conflicting results regarding the benefits of BIS for depth of anesthesia monitoring have been reported in numerous studies. The purpose of this meta-analysis and systematic review was to assess the effectiveness of BIS for depth of anesthesia monitoring. Search Methods. A systematic search of Ovid-MEDLINE, Cochrane, and PubMed was conducted from inception to April 20, 2023. Clinical trial registers and grey literature were also searched, and reference lists of included studies, as well as related review articles, were manually reviewed. Selection Criteria. The inclusion criteria were randomized controlled trials without gender or age restrictions. The control groups used conventional monitoring, while the intervention groups utilized BIS monitoring. The exclusion criteria included duplicates, reviews, animal studies, unclear outcomes, and incomplete data. Data Collection and Analysis. Two independent reviewers screened the literature, extracted data, and assessed methodological quality, with analyses conducted using R 4.0 software. Main Results. Forty studies were included. In comparison to the conventional depth of anesthesia monitoring, BIS monitoring reduced the postoperative cognitive dysfunction risk (RR = 0.85, 95% CI: 0.73∼0.99, P = 0.04), shortened the eye-opening time (MD = -1.34, 95% CI: -2.06∼-0.61, P < 0.01), orientation recovery time (MD = -1.99, 95% CI: -3.62∼-0.36, P = 0.02), extubation time (MD = -2.54, 95% CI: -3.50∼-1.58, P < 0.01), and postanesthesia care unit stay time (MD = -7.11, 95% CI: -12.67∼-1.55, P = 0.01) and lowered the anesthesia drug dosage (SMD = -0.39, 95% CI: -0.63∼-0.15, P < 0.01). Conclusion. BIS can be used to effectively monitor the depth of anesthesia. Its use in general anesthesia enhances the effectiveness of both patient care and surgical procedures.

Influence of multiple risk factor control level on cardiovascular outcomes in hypertensive patients.

OBJECTIVE: The relationship between the level of baseline risk factor control and cardiovascular outcomes in hypertensive patients with blood pressure intervention is not well understood. It is also unclear whether the level of baseline risk factor control is persuasively associated with cardiovascular outcomes in hypertensive patients with blood pressure lowering strategy. METHOD: We performed an analysis of the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial. Participants without complete baseline risk factor data were excluded. The primary outcome was a composite of cardiovascular events and all-cause mortality. Cox proportional hazard models were used to calculate the hazard ratio (HR) and estimate association between risk factor control levels (≥6, 5, 4, and ≤ 3) and cardiovascular outcomes. RESULTS: A total of 8337 participants were involved in the analysis and the median follow-up period was 3.19 years. Each additional risk factor uncontrolled was associated with a 24% higher cardiovascular risk (HR 1.24, 95% CI 1.11-1.37). Compared with participants with optimal risk factor control, those with ≤ 3 factors control exhibited 95% higher cardiovascular risk (HR 1.95, 95% CI 1.37-2.77). The corresponding protective effects of multiple risk factor modification were not influenced by intensive or standard antihypertensive treatment (P for interaction = 0.71). CONCLUSIONS: A stepwise association was observed between cardiovascular risk and the number of risk factor control in hypertensive patients. The more risk factor was modified, the less cardiovascular risk was observed, irrespective of different blood pressure lowering strategies. Comprehensive risk factor control strategies are warranted to reduce cardiovascular disease risk in hypertensive patients. Trial registration STEP ClinicalTrials.gov number, NCT03015311. Registered 2 January 2017.

Association of Life's Essential 8 with all-cause mortality and risk of cancer: a prospective cohort study.

BACKGROUND: No study has concentrated on the association of LE8 with cancer risk and death. We aim to examine the association of LE8 with death and cancer. METHODS: A total of 94733 adults aged 51.42 ± 12.46 years and 77551 participants aged 54.09±12.06 years were enrolled in longitudinal and trajectory analysis respectively. Baseline LE8 was divided into three groups based on the American Heart Association criteria and three trajectory patterns by latent mixture models. We reviewed medical records and clinical examinations to confirm incident cancer during the period from 2006 to 2020. Death information was collected from provincial vital statistics offices. Cox models were used. RESULTS: 12807 all-cause deaths and 5060 cancers were documented during a 14-year follow-up. Relative to participants with high LE8 at baseline, participants with lower levels of LE8 have a significantly increased risk of mortality and incident cancer. All these risks have an increasing trend with LE8 level decreasing. Meanwhile, the trajectory analysis recorded 7483 all-cause deaths and 3037 incident cancers after approximately 10 years. The associations of LE8 with death and cancer were identical to the longitudinal study. In the subtype cancer analysis, LE8 has a strong effect on colorectal cancer risk. Moreover, the cut point is 56.67 in the association between LE8 and death, while the cut point altered to 64.79 in the association between LE8 and incident cancers. These associations were enhanced among younger adults. CONCLUSIONS: There was a significant association of LE8 with death and cancer risk, especially for the young population.

Pyrite from acid mine drainage promotes the removal of antibiotic resistance genes and mobile genetic elements in karst watershed with abundant calcium carbonate.

More information is needed to fully comprehend how acid mine drainage (AMD) affects the phototransformation of antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) in karst water and sewage-irrigated farmland soil with abundant carbonate rocks (CaCO3) due to increasing pollution of AMD formed from pyrite (FeS2). The results showed FeS2 accelerated the inactivation of ARB with an inactivation of 8.7 log. Notably, extracellular and intracellular ARGs and mobile genetic elements (MGEs) also experienced rapid degradation. Additionally, the pH of the solution buffered by CaCO3 significantly influenced the photo-inactivation of ARB. The Fe2+ in neutral solution was present in Fe(II) coordination with strong reducing potential and played a crucial role in generating •OH (7.0 µM), which caused severe damage to ARB, ARGs, and MGEs. The •OH induced by photo-Fenton of FeS2 posed pressure to ARB, promoting oxidative stress response and increasing generation of reactive oxygen species (ROS), ultimately damaging cell membranes, proteins and DNA. Moreover, FeS2 contributed to a decrease in MIC of ARB from 24 mg/L to 4 mg/L. These findings highlight the importance of AMD in influencing karst water and sewage-irrigated farmland soil ecosystems. They are also critical in advancing the utilization of FeS2 to inactivate pathogenic bacteria.

Difference of ventricular synchrony between LBBP, LBFP and LVSP: A speckle tracking echocardiographic study.

PURPOSE: Left bundle branch area pacing (LBBAP) has emerged as a physiological and stable form of pacing. We aim to compare the mechanical ventricular synchrony of LBBP, LBFP, and LVSP. METHODS: Proximal Left bundle branch pacing (LBBP), left bundle fascicular pacing (LBFP) and left ventricular septal pacing (LVSP) were identified in patients with bradycardia who successfully underwent LBBAP. Patients with left ventricular ejection fraction (LVEF) < 50% or QRS duration (QRSd) ≥ 120 ms were excluded. By using electrocardiograms, the left ventricular activation time (LVAT) and QRS duration (QRSd) were measured to examine electrophysiological synchrony. As indications of mechanical synchrony, global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), and peak strain dispersion (PSD) were evaluated by using 2-dimensional speckle tracking echocardiography (2D-STE). RESULTS: In 56 patients, data were collected during LBBP (n = 18), LBFP (n = 16), and LVSP (n = 22). LVSP resulted in a longer LVAT (91.3 ± 14.9 ms) than LBBP (77.1 ± 10.8 ms, P < 0.05) and LBFP (72.1 ± 9.6 ms, P < 0.05), but all three groups had similar QRSd. There were no differences in GLS, GCS, GRS, or PSD between LBBP, LBFP, and LVSP. CONCLUSIONS: In patients with normal cardiac function and narrow QRS, though LBBAP with LBB capture resulted in better electrophysiological synchrony than without, the mechanical synchrony of the three groups was comparable.

Immune landscape and prognostic immune-related signature in KRAS-mutated lung adenocarcinoma.

The heterogeneity of lung adenocarcinoma (LUAD) indicated that target therapies and immunotherapies may not be effective in all patients. The exploration of the feature of the immune landscape of different gene mutations may provide novel perspectives. In this study, we obtained LUAD samples from The Cancer Genome Atlas. By applying ESTIMATE and ssGSEA, KRAS-mutated group was discovered to be associated with lower immune infiltration, lower expression of immune checkpoints, especially, a lower abundance of B cell, CD8+ T cell, dendritic cell, natural killer cell, and macrophage, higher abundance of neutrophil and endothelial cell. Through ssGSEA, we found that the process of antigen-presenting cell co-inhibition and co-stimulation were inhibited, cytolytic activity and human leukocyte antigen molecules were downregulated in the KRAS-mutated group. And KRAS mutation is negatively related to antigen presentation and procession, cytotoxic lymphocyte activity, cytolytic activities, and cytokine interaction signaling pathway via gene function enrichment analysis. Finally, 24 immune-related genes were identified to establish an immune-related gene signature with excellent prognostic prediction capacity, whose 1-, 3- and 5-year AUCs were 0.893, 0.986, and 0.999. Our findings elucidate the features of the immune landscape of KRAS-mutated groups and successfully established a prognostic signature on the basis of immune-related genes in LUAD.

Stage 1 Hypertension and the 10-Year and Lifetime Risk of Cardiovascular Disease: A Prospective Real-World Study.

Background The 10-year and lifetime cardiovascular disease risk in the population with stage 1 hypertension and the effects of recovery from and progression of stage 1 hypertension remain undetermined. Methods and Results This prospective cohort study included 96 268 individuals with blood pressure measurements obtained in 2006 and again in 2010. The 10-year cardiovascular disease risk was estimated using the multivariable Cox proportional hazards model, and the lifetime risk was calculated using a modified survival analysis that accounted for the competing risk of death. Stage 1 hypertension was detected in 30.83% of the cohort. The 10-year cardiovascular disease risk was 2.80%, and the lifetime risk was 16.61%. Compared with the normal blood pressure group, the stage 1 hypertension group had a 35% higher 10-year risk (hazard ratio [HR], 1.35 [95% CI, 1.19-1.52]) and a 36% higher lifetime risk (HR, 1.36 [95% CI, 1.25-1.49]). By 2010, 12.57% of the participants with stage 1 hypertension had progressed to stage 2, with a significant 156% increase in 10-year risk (HR, 2.56 [95% CI, 2.11-3.11]) and an increased lifetime risk of 129% (HR, 2.29 [95% CI, 1.89-2.77]). There was no appreciable change in risk in those with stage 1 hypertension whose blood pressure returned to the normal-elevated range. Conclusions Stage 1 hypertension was associated with a significant increase in 10-year and lifetime cardiovascular disease risk. Progression to stage 2 hypertension was associated with a marked increase in lifetime risk. The current guidelines require revision to promote early detection and appropriate management of blood pressure.

Is the pacing site closer to the left ventricular septal endocardium in left bundle branch pacing or in left ventricular septal pacing?

PURPOSE: Distinguishing between left bundle branch pacing (LBBP) and left ventricular septal pacing (LVSP) is challenging. This study aimed to compare the echocardiographic distance from the pacing lead tip to the left ventricular (LV) septal endocardium between patients who underwent LBBP and those who underwent LVSP successfully. METHODS: Fifty-nine consecutive patients (age 71.9 ± 12.0 years, 35.6% male) with traditional indications for permanent cardiac pacing were included (LBBP group, n = 46; LVSP group, n = 13). Unipolar pacing from the final pacing sites generated narrow QRS complexes with a right bundle branch block pattern in all patients. After the procedure, a physician blinded to the group allocation performed echocardiographic measurements of the distance between the lead tip and the LV septal endocardium. RESULTS: The mean paced QRS duration was comparable between the LBBP group and the LVSP group (105.3 ± 15.6 ms vs. 109.2 ± 9.6 ms, P = 0.287). In the LBBP group, the interval from the left bundle branch potential to QRS onset was 28.7 ± 9.0 ms. During diastole, the mean distance between the lead tip and the LV septal endocardium was 0.6 ± 0.9 mm in the LBBP group and 3.0 ± 1.6 mm in the LVSP group (P < 0.001). During systole, the distance was 1.5 ± 1.4 mm in the LBBP group and 4.3 ± 2.6 mm in the LVSP group (P < 0.001). CONCLUSIONS: The landing zone of the lead tip was closer to the LV septal endocardium in the patients who underwent LBBP. There is a need for real-time intraprocedural monitoring of the distance between the lead tip and the LV septal endocardium when performing LBBP.

Amino acid metabolism genes associated with immunotherapy responses and clinical prognosis of colorectal cancer.

Based on amino acid metabolism-related genes (AAMRGs), this study aimed at screening out key prognosis-related genes and finding the underlying correlation between the amino acid metabolism and tumor immune microenvironment of colorectal cancer. A total of 448 amino acid metabolism-related genes were obtained from MsigDB. The risk signature was built based on differential expression genes, univariate Cox, and LASSO analyses with 403 patients' data downloaded from the TCGA database. Survival analysis and independence tests were performed to confirm the validity of the risk signature. Single-sample gene set enrichment analysis (ssGSEA), tumor mutation burden (TMB), the score of tumor immune dysfunction and exclusion (TIDE), the immunophenoscore obtained from The Cancer Immunome Atlas database, and the IC50 of drugs were used to find the relationship among the risk signature, immune status, immunotherapy response, and drug sensitivity of colorectal cancer. We identified five amino acid metabolism-related genes for the construction of the risk signature, including ENOPH1, ACAT1, ALDH4A1, FAS, and ASPG. The low-risk group was significantly associated with a better prognosis (p < 0.0001). In the entire set, the area under the curve (AUC) for 1, 3, and 5 years was 0.717, 0.734, and 0.764, respectively. We also discovered that the low-risk subgroup was related to more activity of immune cells, had higher expression of some immune checkpoints, and was more likely to benefit from immunotherapy. ssGSEA revealed that except the processes of glutamine histidine, lysine, tyrosine, and L-phenylalanine metabolism, the other amino acid metabolism pathways were more active in the samples with the low risk scores, whereas the activities of synthesis and transportation of most amino acids were similar. Hedgehog signaling, WNT/ß-catenin signaling, mitotic, notch signaling, and TGF-ß signaling were the top five pathways positively associated with the risk score. To sum up, AAMRGs were associated with the immune microenvironment of CRC patients and could be applied as biomarkers to predict the prognosis and immunotherapy response of patients.

MRG Chip: A High-Throughput qPCR-Based Tool for Assessment of the Heavy Metal(loid) Resistome.

Bacterial metal detoxification mechanisms have been well studied for centuries in pure culture systems. However, profiling metal resistance determinants at the community level is still a challenge due to the lack of comprehensive and reliable quantification tools. Here, a novel high-throughput quantitative polymerase chain reaction (HT-qPCR) chip, termed the metal resistance gene (MRG) chip, has been developed for the quantification of genes involved in the homeostasis of 9 metals. The MRG chip contains 77 newly designed degenerate primer sets and 9 published primer sets covering 56 metal resistance genes. Computational evaluation of the taxonomic coverage indicated that the MRG chip had a broad coverage matching 2 kingdoms, 29 phyla, 64 classes, 130 orders, 226 families, and 382 genera. Temperature gradient PCR and HT-qPCR verified that 57 °C was the optimal annealing temperature, with amplification efficiencies of over 94% primer sets achieving 80-110%, with R2 > 0.993. Both computational evaluation and the melting curve analysis of HT-qPCR validated a high specificity. The MRG chip has been successfully applied to characterize the distribution of diverse metal resistance determinants in natural and human-related environments, confirming its wide scope of application. Collectively, the MRG chip is a powerful and efficient high-throughput quantification tool for exploring the microbial metal resistome.

Necroptosis-Related Genes Associated With Immune Activity and Prognosis of Colorectal Cancer.

This study aims at screening out the key necroptosis-related genes in colorectal cancer and elucidating the role of necroptosis-related genes in the immune activity and prognosis of colorectal cancer (CRC). The CRC patients' data were downloaded from The Cancer Genome Atlas (TCGA). The non-negative matrix factorization method was applied to identify new molecular subgroups. Survival analysis and single sample Gene Set Enrichment Analysis were performed to determinate the differences in the overall survival time and immune status of the subgroups. Prognostic model was constructed on the basis of univariate Cox regression and LASSO analysis. Functional analyses were used to explore the potential mechanisms. Based on prognostic related necroptosis genes, we identify two molecular subgroups with significantly different survival. The better prognosis was associated with more active immune infiltration and upregulated expression of immune checkpoints. We screened nine necroptosis related genes as key prognostic genes and established a risk model, which showed a good potential for survival prediction in colorectal cancer. Nomogram assessment showed that the model had high reliability for predicting the prognosis of colorectal cancer patients. The high-risk and low-risk group also has different sensitivity to immunotherapy and commonly used drugs for colorectal cancer. Overall, necroptosis related genes were involved in the immune microenvironment of colorectal cancer patient, could be utilized to predict the prognosis of colorectal cancer and develop more individualized treatment.

The best strategy for metastatic colorectal cancer (mCRC) patients in second-line treatment: A network meta-analysis.

BACKGROUND: Varieties of systemic treatments in second-line treatment for metastatic colorectal cancer (mCRC) patients have showed an improvement on survival. In this study, we performed a systematic review with a pairwise and bayesian network meta-analysis to rank the best strategy for mCRC patients in second-line treatment. METHODS: A systematic literature search through 2007 was performed to evaluate the association between several treatment combinations and overall survival (OS), progression-free survival (PFS) and disease control rate (DCR) in mCRC patients. Data were carried out and pooled into a statistical indirect comparison with Bayesian network meta-analysis (NMA). RESULTS: 10 trials totally comprised 4183 patients were included in our study. In NMA, For PFS, Doublet+Bev showed benefits in comparing with Doublet, Doulblet+placebo and Doublet+Ramucirumab. Also, Doublet+Aflibercept demonstrated its superiority in comparing with Doulblet+placebo. For OS, Doublet+Bev represented its superiority when comparing with Double and Doublet+placebo. Doublet+Aflibercept and Doublet+Ramucirumab also done well when opposed to Doublet+placebo. For DCR, Doublet+bev showed unique superiority when compared with Doublet, And Doublet+targeted agent did not represent benefits to each other in DCR. Doublet+bev ranked highest in terms of PFS, OS and DCR followed by Doublet+panitumumab, Doublet+placebo was the lowest in terms of PFS and OS. CONCLUSIONS: Our study shows that Doublet+Bev has the major probability to provide an improvement of survival in patients with mCRC.

[In silico cloning, expression and bioinformatics analysis of NtODB from common tobacco].

It has been reported that ODB genes play an important role in homologous recombination-directed DNA repair, suggesting their potential applications in plant breeding. To analyze the expression characteristics of tobacco NtODB gene, the cDNA sequence of NtODB was obtained using in silico cloning technique. The physicochemical properties, signal peptide, and advanced structures of the predicted protein were analyzed using bioinformatics tools. The results showed that the NtODB gene has a 579-bp open reading frame which encodes a protein with 192 amino acid residues. The protein NtODB is predicted to be alkaline and hydrophilic. Real-time quantitative PCR showed that NtODB was constitutively expressed in different tissues. Subcellular localization showed that NtODB was mainly expressed in cell membrane and chloroplast. These results may help us to better understand and elucidate the roles of ODB genes in the homologous recombination-directed DNA repair.