Cbl and Cbl-b ubiquitin ligases are essential for intestinal epithelial stem cell maintenance.

Receptor tyrosine kinases (RTKs) control stem cell maintenance vs. differentiation decisions. Casitas B-lineage lymphoma (CBL) family ubiquitin ligases are negative regulators of RTKs, but their stem cell regulatory roles remain unclear. Here, we show that Lgr5+ intestinal stem cell (ISC)-specific inducible Cbl-knockout (KO) on a Cblb null mouse background (iDKO) induced rapid loss of the Lgr5 Hi ISCs with transient expansion of the Lgr5 Lo transit-amplifying population. LacZ-based lineage tracing revealed increased ISC commitment toward enterocyte and goblet cell fate at the expense of Paneth cells. Functionally, Cbl/Cblb iDKO impaired the recovery from radiation-induced intestinal epithelial injury. In vitro, Cbl/Cblb iDKO led to inability to maintain intestinal organoids. Single-cell RNA sequencing in organoids identified Akt-mTOR (mammalian target of rapamycin) pathway hyperactivation upon iDKO, and pharmacological Akt-mTOR axis inhibition rescued the iDKO defects. Our results demonstrate a requirement for Cbl/Cblb in the maintenance of ISCs by fine-tuning the Akt-mTOR axis to balance stem cell maintenance vs. commitment to differentiation.

Effects of malnutrition on disease severity and adverse outcomes in idiopathic pulmonary arterial hypertension: a retrospective cohort study.

BACKGROUND: Malnutrition is common in patients with chronic cardiovascular disease and is associated with significantly higher all-cause mortality. Approximately one-third of patients with heart failure are malnourished. However, the relationship between malnutrition and idiopathic pulmonary arterial hypertension (IPAH) remains unclear. This study aimed to clarify the prognostic value of malnutrition in patients with IPAH. METHODS: A total of 432 consecutive participants with IPAH were included in this study between March 2013 and August 2021. Three common malnutrition assessment tools, including the geriatric nutritional risk index (GNRI), prognostic nutritional index (PNI), and controlling nutritional status (CONUT) score, were used to evaluate the nutritional status of patients with IPAH. The relationships between the malnutrition tools and long-term adverse outcomes were determined using restricted cubic splines and multivariate Cox regression models. RESULTS: During a mean follow-up of 3.1 years, 158 participants experienced clinical worsening or all-cause death. Patients were stratified into the low-, intermediate- and high-risk groups based on the European Society of Cardiology (ESC) risk stratification, and the PNI (55.9 ± 5.7 vs. 54.4 ± 7.2 vs. 51.1 ± 7.1, P = 0.005) and CONUT score (2.1 ± 0.9 vs. 2.5 ± 1.2 vs. 3.3 ± 1.1, P < 0.001) identified these patient groups better than the GNRI. All three malnutrition tools were associated with well-validated variables that reflected IPAH severity, such as the World Health Organization functional class, 6-min walk distance, and N-terminal pro-brain natriuretic peptide level. The CONUT score exhibited better predictive ability than both the GNRI (ΔAUC = 0.059, P < 0.001) and PNI (ΔAUC = 0.095, P < 0.001) for adverse outcomes and significantly improved reclassification and discrimination beyond the ESC risk score. Multivariable Cox regression analysis indicated that only the CONUT score (hazard ratio = 1.363, 95% confidence interval 1.147, 1.619 per 1.0-standard deviation increment, P < 0.001) independently predicted adverse outcomes. CONCLUSIONS: The malnutrition status was associated with disease severity in patients with IPAH. The CONUT score provided additional information regarding the risk of clinically worsening events, making it a meaningful risk stratification tool for these patients.

Association of non-insulin-based insulin resistance indices with disease severity and adverse outcome in idiopathic pulmonary arterial hypertension: a multi-center cohort study.

BACKGROUND: Insulin resistance (IR) plays an important role in the pathophysiology of cardiovascular disease. Recent studies have shown that diabetes mellitus and impaired lipid metabolism are associated with the severity and prognosis of idiopathic pulmonary arterial hypertension (IPAH). However, the relationship between IR and pulmonary hypertension is poorly understood. This study explored the association between four IR indices and IPAH using data from a multicenter cohort. METHODS: A total of 602 consecutive participants with IPAH were included in this study between January 2015 and December 2022. The metabolic score for IR (METS-IR), triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, triglyceride and glucose (TyG) index, and triglyceride-glucose-body mass index (TyG-BMI) were used to quantify IR levels in patients with IPAH. The correlation between non-insulin-based IR indices and long-term adverse outcomes was determined using multivariate Cox regression models and restricted cubic splines. RESULTS: During a mean of 3.6 years' follow-up, 214 participants experienced all-cause death or worsening condition. Compared with in low to intermediate-low risk patients, the TG/HDL-C ratio (2.9 ± 1.7 vs. 3.3 ± 2.1, P = 0.003) and METS-IR (34.5 ± 6.7 vs. 36.4 ± 7.5, P < 0.001) were significantly increased in high to intermediate-high risk patients. IR indices correlated with well-validated variables that reflected the severity of IPAH, such as the cardiac index and stroke volume index. Multivariate Cox regression analyses indicated that the TyG-BMI index (hazard ratio [HR] 1.179, 95% confidence interval [CI] 1.020, 1.363 per 1.0-standard deviation [SD] increment, P = 0.026) and METS-IR (HR 1.169, 95% CI 1.016, 1.345 per 1.0-SD increment, P = 0.030) independently predicted adverse outcomes. Addition of the TG/HDL-C ratio and METS-IR significantly improved the reclassification and discrimination ability beyond the European Society of Cardiology (ESC) risk score. CONCLUSIONS: IR is associated with the severity and long-term prognosis of IPAH. TyG-BMI and METS-IR can independently predict clinical worsening events, while METS-IR also provide incremental predictive performance beyond the ESC risk stratification.

TCERG1L hypermethylation is a risk factor of diabetic retinopathy in Chinese children with type 1 diabetes.

AIM: To identify the differential methylation sites (DMS) and their according genes associated with diabetic retinopathy (DR) development in type 1 diabetes (T1DM) children. METHODS: This study consists of two surveys. A total of 40 T1DM children was included in the first survey. Because no participant has DR, retina thinning was used as a surrogate indicator for DR. The lowest 25% participants with the thinnest macular retinal thickness were included into the case group, and the others were controls. The DNA methylation status was assessed by the Illumina methylation 850K array BeadChip assay, and compared between the case and control groups. Four DMS with a potential role in diabetes were identified. The second survey included 27 T1DM children, among which four had DR. The methylation patterns of the four DMS identified by 850K were compared between participants with and without DR by pyrosequencing. RESULTS: In the first survey, the 850K array revealed 751 sites significantly and differentially methylated in the case group comparing with the controls (|Δß|>0.1 and Adj.P<0.05), and 328 of these were identified with a significance of Adj.P<0.01. Among these, 319 CpG sites were hypermethylated and 432 were hypomethylated in the case group relative to the controls. Pyrosequencing revealed that the transcription elongation regulator 1 like (TCERG1L, cg07684215) gene was hypermethylated in the four T1DM children with DR (P=0.018), which was consistent with the result from the first survey. The methylation status of the other three DMS (cg26389052, cg25192647, and cg05413694) showed no difference (all P>0.05) between participants with and without DR. CONCLUSION: The hypermethylation of the TCERG1L gene is a risk factor for DR development in Chinese children with T1DM.

Tumor biomarkers in evaluating the severity and prognosis of idiopathic pulmonary arterial hypertension: A comprehensive analysis.

Inflammation contributes to development of idiopathic pulmonary arterial hypertension (IPAH), and tumor biomarkers can reflect inflammatory and immune status. We aimed to determine the value of tumor biomarkers in IPAH comprehensively. We enrolled 315 patients with IPAH retrospectively. Tumor biomarkers were correlated with established indicators of pulmonary hypertension severity. Multivariable Cox regression found that AFP (hazard ratio [HR]: 1.587, 95% confidence interval [CI]: 1.014-2.482, p = 0.043) and CA125 (HR: 2.018, 95% CI: 1.163-3.504, p = 0.013) could independently predict prognosis of IPAH. The changes of AFP over time were associated with prognosis of patients, each 1 ng/mL increase in AFP was associated with 5.4% increased risk of clinical worsening (HR: 1.054, 95% CI: 1.001-1.110, p = 0.046), enabling detection of disease progression. Moreover, beyond well-validated PH biomarkers, CA125 was still of prognostic value in the low-risk patients (HR: 1.014, 95% CI: 1.004-1.024, p = 0.004), allowing for more accurate risk stratification and prediction of disease outcomes. AFP and CA125 can serve for prognosis prediction, risk stratification, and dynamic monitor in patients with IPAH.

The Win-Win Effects of an Invasive Plant Biochar on a Soil-Crop System: Controlling a Bacterial Soilborne Disease and Stabilizing the Soil Microbial Community Network.

Biochar is increasingly being recognized as an effective soil amendment to enhance plant health and improve soil quality, but the complex relationships among biochar, plant resistance, and the soil microbial community are not clear. In this study, biochar derived from an invasive plant (Solidago canadensis L.) was used to investigate its impacts on bacterial wilt control, soil quality, and microbial regulation. The results reveal that the invasive plant biochar application significantly reduced the abundance of Ralstonia solanacearum in the soil (16.8-32.9%) and wilt disease index (14.0-49.2%) and promoted tomato growth. The biochar treatment increased the soil organic carbon, nutrient availability, soil chitinase, and sucrase activities under pathogen inoculation. The biochar did not influence the soil bacterial community diversity, but significantly increased the relative abundance of beneficial organisms, such as Bacillus and Sphingomonas. Biochar application increased the number of nodes, edges, and the average degree of soil microbial symbiotic network, thereby enhancing the stability and complexity of the bacterial community. These findings suggest that the invasive plant biochar produces win-win effects on plant-soil systems by suppressing soilborne wilt disease, enhancing the stability of the soil microbial community network, and promoting resource utilization, indicating its good potential in sustainable soil management.

A Survey of 6DoF Object Pose Estimation Methods for Different Application Scenarios.

Recently, 6DoF object pose estimation has become increasingly important for a broad range of applications in the fields of virtual reality, augmented reality, autonomous driving, and robotic operations. This task involves extracting the target area from the input data and subsequently determining the position and orientation of the objects. In recent years, many new advances have been made in pose estimation. However, existing reviews have the problem of only summarizing category-level or instance-level methods, and not comprehensively summarizing deep learning methods. This paper will provide a comprehensive review of the latest progress in 6D pose estimation to help researchers better understanding this area. In this study, the current methods about 6DoF object pose estimation are mainly categorized into two groups: instance-level and category-level groups, based on whether it is necessary to acquire the CAD model of the object. Recent advancements about learning-based 6DoF pose estimation methods are comprehensively reviewed. The study systematically explores the innovations and applicable scenarios of various methods. It provides an overview of widely used datasets, task metrics, and diverse application scenarios. Furthermore, state-of-the-art methods are compared across publicly accessible datasets, taking into account differences in input data types. Finally, we summarize the challenges of current tasks, methods for different applications, and future development directions.

Enhanced YOLOv5s-Based Algorithm for Industrial Part Detection.

In complex industrial environments, accurate recognition and localization of industrial targets are crucial. This study aims to improve the precision and accuracy of object detection in industrial scenarios by effectively fusing feature information at different scales and levels, and introducing edge detection head algorithms and attention mechanisms. We propose an improved YOLOv5-based algorithm for industrial object detection. Our improved algorithm incorporates the Crossing Bidirectional Feature Pyramid (CBiFPN), effectively addressing the information loss issue in multi-scale and multi-level feature fusion. Therefore, our method can enhance detection performance for objects of varying sizes. Concurrently, we have integrated the attention mechanism (C3_CA) into YOLOv5s to augment feature expression capabilities. Furthermore, we introduce the Edge Detection Head (EDH) method, which is adept at tackling detection challenges in scenes with occluded objects and cluttered backgrounds by merging edge information and amplifying it within the features. Experiments conducted on the modified ITODD dataset demonstrate that the original YOLOv5s algorithm achieves 82.11% and 60.98% on mAP@0.5 and mAP@0.5:0.95, respectively, with its precision and recall being 86.8% and 74.75%, respectively. The performance of the modified YOLOv5s algorithm on mAP@0.5 and mAP@0.5:0.95 has been improved by 1.23% and 1.44%, respectively, and the precision and recall have been enhanced by 3.68% and 1.06%, respectively. The results show that our method significantly boosts the accuracy and robustness of industrial target recognition and localization.

Adaptive evolution and co-evolution of chloroplast genomes in Pteridaceae species occupying different habitats: overlapping residues are always highly mutated.

BACKGROUND: The evolution of protein residues depends on the mutation rates of their encoding nucleotides, but it may also be affected by co-evolution with other residues. Chloroplasts function as environmental sensors, transforming fluctuating environmental signals into different physiological responses. We reasoned that habitat diversity may affect their rate and mode of evolution, which might be evidenced in the chloroplast genome. The Pteridaceae family of ferns occupy an unusually broad range of ecological niches, which provides an ideal system for analysis. RESULTS: We conducted adaptive evolution and intra-molecular co-evolution analyses of Pteridaceae chloroplast DNAs (cpDNAs). The results indicate that the residues undergoing adaptive evolution and co-evolution were mostly independent, with only a few residues being simultaneously involved in both processes, and these overlapping residues tend to exhibit high mutations. Additionally, our data showed that Pteridaceae chloroplast genes are under purifying selection. Regardless of whether we grouped species by lineage (which corresponded with ecological niches), we determined that positively selected residues mainly target photosynthetic genes. CONCLUSIONS: Our work provides evidence for the adaptive evolution of Pteridaceae cpDNAs, especially photosynthetic genes, to different habitats and sheds light on the adaptive evolution and co-evolution of proteins.

Impact of tectoridin on the pharmacokinetics of florfenicol via targeting cytochrome P450 and P-glycoprotein of rats.

Belamcanda chinensis (L.) DC, commonly used with florfenicol in Chinese veterinary clinics for respiratory tract infections, contains the major effective isoflavone, tectoridin (TEC). This study aimed to investigate the impact of TEC co-administration on the pharmacokinetics of florfenicol in vivo.Male rats received oral TEC (50 mg/kg BW) or sterile water for seven days, followed by a single oral dose of florfenicol (25 mg/kg BW) on the 8th day. Non-compartmental methods analysed the pharmacokinetics of florfenicol, while real-time reverse transcription polymerase chain reaction (RT-PCR), Western blot, and immunohistochemical analyses measured expression levels of cytochrome P450 (CYP) isoforms in the liver and P-glycoprotein (P-gp) in the jejunum.TEC significantly decreased florfenicol's AUC(0-∞), MRT(0-∞), t1/2z, Vz/F, and Cmax by 24.75%, 18.43%, 55.47%, 43.05%, and 19.48%, while increasing CLz/F by 33.33%. TEC also up-regulated hepatic CYP1A2 and CYP3A1 mRNA expression, as well as intestinal MDR1, by 1.39-fold, 1.85-fold, and 1.65-fold. This coincided with a respective increase in protein expression by 1.37-fold, 1.39-fold, and 1.43-fold.These findings suggest that TEC-induced alterations in the pharmacokinetics of florfenicol may be attributed to increased CYP and P-gp expression. Further investigations are warranted to understand the implications of these findings on the clinical effectiveness of florfenicol in veterinary practice.

Cbl and Cbl-b Ubiquitin Ligases are Essential for Intestinal Epithelial Stem Cell Maintenance.

Among the signaling pathways that control the stem cell self-renewal and maintenance vs. acquisition of differentiated cell fates, those mediated by receptor tyrosine kinase (RTK) activation are well established as key players. CBL family ubiquitin ligases are negative regulators of RTKs but their physiological roles in regulating stem cell behaviors are unclear. While hematopoietic Cbl/Cblb knockout (KO) leads to a myeloproliferative disease due to expansion and reduced quiescence of hematopoietic stem cells, mammary epithelial KO led to stunted mammary gland development due to mammary stem cell depletion. Here, we examined the impact of inducible Cbl/Cblb double-KO (iDKO) selectively in the Lgr5-defined intestinal stem cell (ISC) compartment. Cbl/Cblb iDKO led to rapid loss of the Lgr5 Hi ISC pool with a concomitant transient expansion of the Lgr5 Lo transit amplifying population. LacZ reporter-based lineage tracing showed increased ISC commitment to differentiation, with propensity towards enterocyte and goblet cell fate at the expense of Paneth cells. Functionally, Cbl/Cblb iDKO impaired the recovery from radiation-induced intestinal epithelial injury. In vitro , Cbl/Cblb iDKO led to inability to maintain intestinal organoids. Single cell RNAseq analysis of organoids revealed Akt-mTOR pathway hyperactivation in iDKO ISCs and progeny cells, and pharmacological inhibition of the Akt-mTOR axis rescued the organoid maintenance and propagation defects. Our results demonstrate a requirement for Cbl/Cblb in the maintenance of ISCs by fine tuning the Akt-mTOR axis to balance stem cell maintenance vs. commitment to differentiation.

Coptisine modulates the pharmacokinetics of florfenicol by targeting CYP1A2, CYP2C11 and CYP3A1 in the liver and P-gp in the jejunum of rats: a pilot study.

Coptisine (COP) is the main active ingredient of Coptis chinensis. In Chinese veterinary clinics, Coptis chinensis is commonly used alongside florfenicol to treat intestinal infections. The goal of this study was to investigate the impact of COP co-administration on the pharmacokinetics of florfenicol in rats.Male Sprague-Dawley rats were orally administered COP (50 mg/kg BW) or sterile water for 7 consecutive days, followed by a single oral dose of florfenicol (25 mg/kg BW) on the 8th day. Pharmacokinetics of florfenicol were analysed using non-compartmental methods, while expression levels of cytochrome P450 (CYP) isoforms in the liver and P-glycoprotein (P-gp) in the jejunum were measured using real-time RT-PCR, Western blot and immunohistochemical analyses.Co-administration of COP and florfenicol significantly increased AUC(0-∞), MRT(0-∞), and Cmax of florfenicol, while CLz/F was significantly decreased. COP down-regulated the expression of CYP1A2, CYP2C11, and CYP3A1 in the liver, as well as P-gp in the jejunum.These findings suggest that co-administration of COP with florfenicol alters the pharmacokinetics of florfenicol in rats. The down-regulation of CYP and P-gp expression may contribute to this effect. Therefore, the co-administration of COP with florfenicol may enhance the prophylactic or therapeutic efficacy of florfenicol in veterinary practice.

Genomic Analysis of the Deep-Sea Bacterium Shewanella sp. MTB7 Reveals Backgrounds Related to Its Deep-Sea Environment Adaptation.

Shewanella species are widely distributed in various environments, especially deep-sea sediments, due to their remarkable ability to utilize multiple electron receptors and versatile metabolic capabilities. In this study, a novel facultatively anaerobic, psychrophilic, and piezotolerant bacterium, Shewanella sp. MTB7, was isolated from the Mariana Trench at a depth of 5900 m. Here, we report its complete genome sequence and adaptation strategies for survival in deep-sea environments. MTB7 contains what is currently the third-largest genome among all isolated Shewanella strains and shows higher coding density than neighboring strains. Metabolically, MTB7 is predicted to utilize various carbon and nitrogen sources. D-amino acid utilization and HGT-derived purine-degrading genes could contribute to its oligotrophic adaptation. For respiration, the cytochrome o ubiquinol oxidase genes cyoABCDE, typically expressed at high oxygen concentrations, are missing. Conversely, a series of anaerobic respiratory genes are employed, including fumarate reductase, polysulfide reductase, trimethylamine-N-oxide reductase, crotonobetaine reductase, and Mtr subunits. The glycine reductase genes and the triplication of dimethyl sulfoxide reductase genes absent in neighboring strains could also help MTB7 survive in low-oxygen environments. Many genes encoding cold-shock proteins, glycine betaine transporters and biosynthetic enzymes, and reactive oxygen species-scavenging proteins could contribute to its low-temperature adaptation. The genomic analysis of MTB7 will deepen our understanding of microbial adaptation strategies in deep-sea environments.

Physicians' Knowledge, Attitude, and Experience of Pharmacogenomic Testing in China.

(1) Background: As prescribers, physicians play a decisive role in applying and promoting pharmacogenomic (PGx) testing in clinical practices. So far, little is known about physicians' perspectives on PGx testing in China. The aim of this study was to assess physicians' knowledge of, attitude towards, and experience of PGx testing in China. (2) Methods: A 39-question online survey was developed. Participants were physicians recruited through two platforms, MEDLINKER and "Dazhuanjia". (3) Results: A total of 450 respondents completed the survey and 366 questionnaires were eligible for analysis based on the inclusion criteria. Among all included physicians, 275 (75.1%) had heard of PGx testing before. More than half rated their knowledge of PGx testing as "Fair" (61.5%) while 20.0% chose "Excellent" or "Good" and 18.6% chose "Poor" or "Terrible". "Guidelines, consensus, and treatment paths for disease diagnosis and treatment" (72.7%) were the most preferred sources of information about PGx testing. Respondents were confident in their personal capacity to conduct PGx, with an average score of 3.30 ± 0.09 (out of 5.00). Most respondents (75.6%) believed that PGx could "help to improve efficacy and reduce the incidence of adverse reactions". Targeted cancer therapy (score 78.95 ± 1.26 out of 100) was considered the field where PGx testing had its highest value. Lack of professionals and knowledge (n = 186, 67.6%), high costs of testing (n = 170, 61.8%), and lack of hospitals to offer PGx testing (n = 166, 60.4%) were identified as the primary obstacles to increasing the uptake of PGx testing in China. Academic conference (n = 213, 72.4%) was considered the most efficient way for physicians to obtain information about PGx testing. (4) Conclusions: Physicians in China have poor knowledge about PGx testing; nonetheless, they generally had confidence in their capacity to order PGx testing and positive attitudes towards the use of PGx testing in routine clinical practices. Future efforts to promote the uptake of PGx testing should focus on foundational education and practical training.

Cardiovascular adverse events in chronic myeloid leukemia patients treated with nilotinib or imatinib: A systematic review, meta-analysis and integrative bioinformatics analysis.

Objective: The aim of this article is to assess the risk and potential mechanisms of cardiovascular adverse events in patients treated with nilotinib or imatinib by conducting a systematic review, meta-analysis and integrative bioinformatics analysis. Materials and methods: Three databases were systematically searched for studies published from inception to May 29, 2022. Differential expression analysis and weighted gene coexpression network analysis (WGCNA) were performed to search for modules of genes most associated with cardiotoxicity. Protein-protein interaction (PPI) network analysis was then performed to identify hub genes for the cardiotoxicity of nilotinib. Molecular docking was used to analyze the effects of rosuvastatin and aspirin on these targets. Results: Patients treated with nilotinib as first-line treatment were associated with a higher risk of CAE (OR = 3.43 [95% CI 2.77-4.25]), CAD (OR = 5.30 [95% CI 3.85-7.29]), ACS (OR 2.7 [95% CI 1.60-4.54]), CVA (OR 5.76 [95% CI 2.84-11.28]), PAOD (OR 5.57 [95% CI 3.26-9.50]) and arrhythmia (OR 2.34 [1.17,4.67]) than those treated with imatinib, while no significant difference was found in the risk of HF (OR 1.40 [95% CI 0.42-4.69]) between the two groups. Patients who were treated with more than 600 mg daily dosage of nilotinib or followed up for more than 5 years had a higher risk of ACS and CVA. IL6, CXCL8, CCL2, SOD2, NFKBIA, and BIRC3 were identified as the top 6 hub genes in the magenta module (human cardiomyocyte samples) and were mainly enriched in the NOD-like receptor signaling pathway, IL-17 signaling pathway, TNF signaling pathway, lipid and atherosclerosis signaling pathway. TYROBP and CSF1R were identified as hub genes in the turquoise module (liver samples from Mus musculus). GSEA results showed that type II diabetes mellitus, B-cell receptor, apoptosis, insulin, natural killer cell mediated cytotoxicity,mTOR, chemokine, and T-cell receptor signaling pathways were related to the higher risk of atherosclerosis caused by nilotinib. Rosuvastatin can effectively bind to most of the hub targets and proteins enriched in the inflammatory pathways above. Conclusion: CML patients who start with nilotinib have a higher risk of CAE than those with imatinib. Atherosclerosis caused by the inflammatory response and glycolipid metabolism disorder is the key mechanism of nilotinib cardiotoxicity. Rosuvastatin may be an effective treatment for the cardiotoxicity of nilotinib.

Prognostic value of TIGIT in East Asian patients with solid cancers: A systematic review, meta-analysis and pancancer analysis.

Background: T-cell immunoreceptor with Ig and ITIM domains (TIGIT) participates in tumor immune escape by delivering inhibitory signals to T cells. The purpose of this article was to assess the prognostic value of TIGIT and its immunological function in solid cancers. Methods: Three databases were searched for relevant articles. The main endpoints were overall survival (OS), progression-free survival (PFS), recurrence-free survival (RFS), and disease-free survival (DFS). Hazard ratios (HR) were pooled by using fixed-effects or random-effects models. Pancancer analysis of TIGIT was performed based on public online databases, mainly The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and UCSC Xena. The possible relationships between TIGIT expression and the tumor microenvironment (TME), infiltration of immune cells, immune-related genes, tumor mutation burden (TMB), and microsatellite instability (MSI) were revealed in this article. Results: Sixteen studies met the inclusion criteria. High expression of TIGIT was associated with worse OS [HR= 1.73, 95% confidence interval (CI) 1.50, 1.99], PFS (HR = 1.53, 95% CI [1.25, 1.88]), RFS (HR = 2.40, 95% CI [1.97, 2.93]), and DFS (HR= 6.57, 95% CI [0.73, 59.16]) in East Asian patients with solid cancers. TIGIT expression was positively correlated with immune infiltration scores and infiltration of CD8 T lymphocytes in all of the cancers included. TIGIT was found to be coexpressed with the genes encoding immunostimulators, immunoinhibitors, chemokines, chemokine receptors, and major histocompatibility complex (MHC), especially in gastroesophageal cancer. TMB and MSI were also associated with TIGIT upregulation in diverse kinds of cancers. Conclusion: High expression of TIGIT is associated with poorer prognosis in East Asian patients with solid cancers. TIGIT is a novel prognostic biomarker and immunotherapeutic target for various solid cancers because of its activity in cancer immunity and tumorigenesis.

Clinical Pharmacists' Knowledge of and Attitudes toward Pharmacogenomic Testing in China.

(1) Background: Uptake of pharmacogenomic testing in routine clinical practices is currently slow in China. Pharmacists might play an important role in leveraging care through applying pharmacogenomics, therefore, it is important to better understand clinical pharmacists' knowledge of and attitudes toward pharmacogenomic testing, which has not been well-studied. (2) Methods: A self-administered survey was developed based on previous knowledge of pharmacogenomic testing and its uptake in China. Participants were recruited through the Committee of Pharmaceutical Affairs Management under the Chinese Hospital Association. (3) Results: A total of 1005 clinical pharmacists completed the questionnaire, among whom 996 (99.10%) had heard of pharmacogenomic testing before participation. More than half of respondents (60.0%, n = 597) rated their knowledge of pharmacogenomic testing as "average", while 25% rated it "good" or "excellent". "Guidelines, consensus and treatment paths for disease diagnosis and treatment" (78.7%) were the most preferred sources of information about pharmacogenomic testing. Most respondents (77.0%) believed that pharmacogenomics could "help to improve efficacy and reduce the incidence of adverse reactions". Our participants also believed that patients would benefit most from pharmacogenomic testing through better prediction of individual drug responses and thus informed treatment decisions. The top challenge for the uptake of pharmacogenomic testing was its high cost or lack of insurance coverage (76.7%). (4) Conclusions: Most Chinese clinical pharmacists who participated in our study had a positive attitude toward pharmacogenomic testing, while the knowledge of pharmacogenomic testing was generally self-assessed as average.

Silica nanoparticles activate defense responses by reducing reactive oxygen species under Ralstonia solanacearum infection in tomato plants.

Silica nanoparticles (SNPs) play an important positive role in enhancing stress resistance of plants. However, their absorption and the mechanisms of resistance in plants are not yet fully understood. In this study, we investigated the uptake of SNPs in tomato plants and explored the physiological and molecular mechanisms of SNPs-mediated bacterial wilt resistance. Folia application of SNPs significantly increased silicon content in tomato leaves and roots by 5.4-fold and 1.8-fold compared with healthy control, respectively. Moreover, foliar-applied SNPs mainly accumulated in the shoots of plants. Interestingly, we found that SNPs significantly reduced wilt severity by 20.71%-87.97%. Under pathogen infection conditions, the Hydrogen peroxide (H2O2) levels and Malondialdehyde (MDA) content in SNPs treated leaves significantly decreased by 16.33%-24.84% and 22.15%-38.54%, respectively, compared to non-treated SNPs leaves. The application of SNPs remarkably increased peroxidase (78.56-157.47%), superoxide dismutase (46.02-51.68%), and catalase (1.59-1.64 fold) enzyme activities, as well as upregulated the expression of salicylic acid-related genes (PR-1, PR-5, and PAL) in tomato leaves. Taken together, our findings demonstrate that SNPs function as important nanoparticles to maintain ROS homeostasis in plants by increasing antioxidant enzyme activity in tomato plants and enhancing plant tolerance to bacterial wilt disease by regulating the expression of salicylic acid-related genes. This study expands our understanding of how plants utilize these nanoparticles to deal with pathogen infection.

Pharmacogenomics of Leukotriene Modifiers: A Systematic Review and Meta-Analysis.

Pharmacogenetics research on leukotriene modifiers (LTMs) for asthma has been developing rapidly, although pharmacogenetic testing for LTMs is not yet used in clinical practice. We performed a systematic review and meta-analysis on the impact of pharmacogenomics on LTMs response. Studies published until May 2022 were searched using PubMed, EMBASE, and Cochrane databases. Pharmacogenomics/genetics studies of patients with asthma using LTMs with or without other anti-asthmatic drugs were included. Statistical tests of the meta-analysis were performed with Review Manager (Revman, version 5.4, The Cochrane Collaboration, Copenhagen, Denmark) and R language and environment for statistical computing (version 4.1.0 for Windows, R Core Team, Vienna, Austria) software. In total, 31 studies with 8084 participants were included in the systematic review and five studies were also used to perform the meta-analysis. Two included studies were genome-wide association studies (GWAS), which showed different results. Furthermore, none of the SNPs investigated in candidate gene studies were identified in GWAS. In candidate gene studies, the most widely studied SNPs were ALOX5 (tandem repeats of the Sp1-binding domain and rs2115819), LTC4S-444A/C (rs730012), and SLCO2B1 (rs12422149), with relatively inconsistent conclusions. LTC4S-444A/C polymorphism did not show a significant effect in our meta-analysis (AA vs. AC (or AC + CC): −0.06, 95%CI: −0.16 to 0.05, p = 0.31). AA homozygotes had smaller improvements in parameters pertaining to lung functions (−0.14, 95%CI: −0.23 to −0.05, p = 0.002) in a subgroup of patients with non-selective CysLT receptor antagonists and patients without inhaled corticosteroids (ICS) (−0.11, 95%CI: −0.14 to −0.08, p < 0.00001), but not in other subgroups. Variability exists in the pharmacogenomics of LTMs treatment response. Our meta-analysis and systematic review found that LTC4S-444A/C may influence the treatment response of patients taking non-selective CysLT receptor antagonists for asthma, and patients taking LTMs not in combination with ICS for asthma. Future studies are needed to validate the pharmacogenomic influence on LTMs response.

Application effect of thoracoscopic tricuspid valvuloplasty in geriatric patients with tricuspid valve disease.

BACKGROUND: Thoracoscopic-assisted technology can ensure that doctors can implement minimally invasive treatment through the right intercostal incision or small incision of the lower sternum. This approach not only can achieve a cardiac correction effect equivalent to that of a thoracotomy but also has the benefit of a clear surgical field ensuring the safety of surgical treatment. AIM: To investigate the effect of thoracoscopic tricuspid valvuloplasty in patients with tricuspid valve disease. METHODS: A total of 41 patients with tricuspid valve disease underwent traditional thoracotomy treatment between January 2018 and June 2020. Forty-one patients with tricuspid valve disease who underwent thoracoscopic tricuspid valvuloplasty treatment between July 2020 and June 2021 in our hospital were selected as controls for our retrospective analysis. The study group underwent thoracoscopic tricuspid valvuloplasty, while traditional thoracotomy was performed in the control group. The operation conditions (the duration of extracorporeal circulation, aorta blocking, endotracheal intubation, and surgery), inflammatory response-related indices (C-reactive protein and white blood cell count) before and after surgery, parameters related to myocardial injury (myocardial troponin T, creatine kinase isoenzyme, creatine kinase, and lactate dehydrogenase), and the incidence of adverse events in the two groups was counted. RESULTS: The duration of extracorporeal circulation (109.35 ± 50.31 min), aortic occlusion (94.26 ± 59.61 min), endotracheal intubation (12.59 ± 3.54 h), and hospital stay (5.29 ± 2.34 d) in the study group were shorter than those in the control group (114.91 ± 46.98 min, 101.37 ± 61.44 min, 13.11 ± 4.01 h, 7.09 ± 3.11 d, respectively). The difference in hospital stay between the two groups was statistically significant (P < 0.05). Serum C-reactive protein level (4.69 ± 1.35 mg/L) and white blood cell count (6.21 ± 1.97 × 109/L) in the study group were found to be not significantly different than those in the control group (5.01 ± 1.18 mg/L, 5.98 ± 2.01 × 109/L, respectively; P > 0.05). Myocardial troponin T (0.04 ± 0.02 ng/mL), creatine kinase isoenzyme (4.02 ± 1.11 mg/mL), creatine kinase (91.35 ± 10.44 U/L), and lactate dehydrogenase (179.81 ± 60.04 U/L) in the study group were also not statistically significant different than those in the control group (0.05 ± 0.03 ng/mL, 3.97 ± 1.05 mg/mL, 89.69 ± 13.05 U/L, 186.35 ± 56.96 U/L; P > 0.05). After the operation, serum C-reactive protein level (7.89 ± 1.73 mg/L) and white blood cell count (10.76 ± 2.35 × 109/L) in the study group were significantly lower than those in the control group (9.96 ± 2.04 mg/L, 14.84 ± 3.07 × 109/L, respectively) (P < 0.05). In addition, myocardial troponin T (0.89 ± 0.32 ng/mL), creatine kinase isoenzyme (26.96 ± 4.95 mg/mL), creatine kinase (608.32 ± 202.33 U/L), and lactate dehydrogenase (282.56 ± 101.34 U/L) in the study group were lower than those in the control group (2.61 ± 0.69 ng/mL, 34.37 ± 6.87 mg/mL, 689.94 ± 214.64 U/L, 369.15 ± 114.46 U/L) (P < 0.05). The incidence of adverse events in the study group (4.88%) was lower than that in the control group (19.51%) (P < 0.05). CONCLUSION: Thoracoscopic tricuspid valvuloplasty can achieve good results in treating patients with tricuspid valve disease, reduce the risk of adverse events, and promote the rapid recovery of patients.