Safety, efficacy, and survival outcomes of immune checkpoint inhibitors rechallenge in patients with cancer: a systematic review and meta-analysis.

BACKGROUNDS: There is little evidence on the safety, efficacy, and survival benefit of restarting immune checkpoint inhibitors (ICI) in patients with cancer after discontinuation due to immune-related adverse events (irAEs) or progressive disease (PD). Here, we performed a meta-analysis to elucidate the possible benefits of ICI rechallenge in patients with cancer. METHODS: Systematic searches were conducted using PubMed, Embase, and Cochrane Library databases. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of irAEs were the outcomes of interest. RESULTS: Thirty-six studies involving 2026 patients were analyzed. ICI rechallenge was associated with a lower incidence of all-grade (OR, 0.05; 95%CI, 0.02-0.13, P < .05) and high-grade irAEs (OR, 0.37; 95%CI, 0.21-0.64, P < .05) when compared with initial ICI treatment. Though no significant difference was observed between rechallenge and initial treatment regarding ORR (OR, 0.69; 95%CI, 0.39-1.20, P = .29) and DCR (OR, 0.85; 95%CI, 0.51-1.40, P = 0.52), patients receiving rechallenge had improved PFS (HR, 0.56; 95%CI, 0.43-0.73, P < .05) and OS (HR, 0.55; 95%CI, 0.43-0.72, P < .05) than those who discontinued ICI therapy permanently. Subgroup analysis revealed that for patients who stopped initial ICI treatment because of irAEs, rechallenge showed similar safety and efficacy with initial treatment, while for patients who discontinued ICI treatment due to PD, rechallenge caused a significant increase in the incidence of high-grade irAEs (OR, 4.97; 95%CI, 1.98-12.5, P < .05) and a decrease in ORR (OR, 0.48; 95%CI, 0.24-0.95, P < .05). CONCLUSION: ICI rechallenge is generally an active and feasible strategy that is associated with relative safety, similar efficacy, and improved survival outcomes. Rechallenge should be considered individually with circumspection, and randomized controlled trials are required to confirm these findings.

Correlation of distribution characteristics and dynamic changes of gut microbiota with the efficacy of immunotherapy in EGFR-mutated non-small cell lung cancer.

BACKGROUND: The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. METHODS: We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. RESULTS: The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients' fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. CONCLUSIONS: The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.

Comprehensive analysis of cuproptosis-related long noncoding RNA for predicting prognostic and diagnostic value and immune landscape in colorectal adenocarcinoma.

BACKGROUND: Cuproptosis, as a copper-induced mitochondrial cell death, has attracted extensive attention recently, especially in cancer. Although some key regulatory genes have been identified in cuproptosis, the related lncRNAs have not been further studied. Exploring the prognostic and diagnostic value of cuproptosis-related lncRNAs (CRLs) in colon adenocarcinoma and providing guidance for individualized immunotherapy for patients are of great significance. RESULTS: A total of 2003 lncRNAs were correlated with cuproptosis genes and considered as CRLs. We screened 33 survival-associated CRLs and established a prognostic signature base on 7 CRLs in the training group. The patients in the low-risk group had better outcomes in both training group (P < 0.001) and test group (P = 0.016). More exciting, our model showed good prognosis prediction in both stage I-II (P = 0.020) and stage III-IV (P = 0.001). The nomogram model could further improve the accuracy of prognosis prediction. Interestingly, glucose-related metabolic pathways, which were closely related to cuproptosis, were enriched in the low-risk group. Meanwhile, the immune infiltration scores were lower in the high-risk group. The high-risk group was more sensitive to OSI.906 and ABT.888, while low-risk group was more sensitive to Sorafenib. Three lncRNAs, FALEC, AC083967.1 and AC010997.4, were highly expressed in serum of COAD patients, and the AUC was 0.772, 0.726 and 0.714, respectively, indicating their valuable diagnostic value. CONCLUSIONS: Our research constructed a prognostic signature based on 7 CRLs and found three promising diagnostic markers for COAD patients. Our results provided a reference to the personalized immunotherapy strategies.

Reviving Intervertebral Discs: Treating Degeneration Using Advanced Delivery Systems.

Intervertebral disc degeneration (IVDD) is commonly associated with many spinal problems, such as low back pain, and significantly impacts a patient's quality of life. However, current treatments for IVDD, which include conservative and surgical methods, are limited in their ability to fully address degeneration. To combat IVDD, delivery-system-based therapy has received extensive attention from researchers. These delivery systems can effectively deliver therapeutic agents for IVDD, overcoming the limitations of these agents, reducing leakage and increasing local concentration to inhibit IVDD or promote intervertebral disc (IVD) regeneration. This review first briefly introduces the structure and function of the IVD, and the related pathophysiology of IVDD. Subsequently, the roles of drug-based and bioactive-substance-based delivery systems in IVDD are highlighted. The former includes natural source drugs, nonsteroidal anti-inflammatory drugs, steroid medications, and other small molecular drugs. The latter includes chemokines, growth factors, interleukin, and platelet-rich plasma. Additionally, gene-based and cell-based delivery systems are briefly involved. Finally, the limitations and future development of the combination of therapeutic agents and delivery systems in the treatment of IVDD are discussed, providing insights for future research.

Global evolving patterns and cross-country inequalities of inflammatory bowel disease burden from 1990 to 2019: a worldwide report.

AIMS: Inflammatory bowel disease (IBD) is a global disease. We aim to summarize the latest epidemiological patterns of IBD at the national, regional and global levels to give well-deserved attention and outline facilitating measures to reduce the disease burden. METHODS: We collected the incidence, prevalence, mortality and disability-adjusted life years (DALYs) of IBD in 204 countries and territories from 1990 to 2019 using data from the Global Burden of Disease Study 2019. We further calculated the estimated annual percentage change (EAPC) to qualify the temporal trends of IBD burden by sex, age and region over the past 30 years. RESULTS: Globally, a total of 404.55 thousand incident cases, 4898.56 thousand prevalent cases, 41.00 thousand deaths and 1622.50 thousand DALYs of IBD were estimated in 2019. The age-standardized DALYs decreased from 27.2 in 1990 to 20.15 per 100,000 people in 2019, with an EAPC of -1.04. The high socio-demographic index regions presented pronounced age-standardized rates (ASRs) consistently over the last 30 years. The high-income North America had the highest ASRs in 2019, followed by Western Europe and Australasia. No gender difference was observed after being stratified by sex. CONCLUSIONS: The accumulated IBD patients are expected to increase in the future due to the increased rate of IBD in developing countries, and social aging in developed countries. Understanding the changes in epidemiological patterns helps to provide evidence to mitigate the rising burden of IBD.

Tumor Environment Promotes Lnc57Rik-Mediated Suppressive Function of Myeloid-Derived Suppressor Cells.

Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes with potent immunosuppressive activity that regulate immune responses in the tumor microenvironment. We identified a novel long noncoding RNA (lncRNA), named as lnc57Rik, in the MDSCs that controls their immunosuppressive functions. Lnc57Rik was induced in in vitro and in vivo inflammatory settings and upregulated the genes related to MDSC-mediated immunosuppression, including Arg-1, NOS2, NOX2, and COX2 Furthermore, Lnc57Rik can not only bind with the C/EBPß isoform liver-enriched activator protein to activate C/EBPß but also with the methyltransferase WD repeat-containing protein 5 that enables the enrichment of histone H3 trimethylated lysine 4 marks on the promoter regions of Arg-1, NOS2, NOX2, and COX2, eventually resulting in their transcriptional activation. Furthermore, the conserved human lnc57Rik has a similar function as murine lnc57Rik Taken together, upregulation of lnc57Rik in the tumor microenvironment promotes the immunosuppressive function of MDSCs.

Relationship between the natural cessation time of umbilical cord pulsation in full-term newborns delivered vaginally and maternal-neonatal outcomes: a prospective cohort study.

BACKGROUND: To analyze the impact of the time of natural cessation of the umbilical cord on maternal and infant outcomes in order to explore the time of clamping that would be beneficial to maternal and infant outcomes. METHODS: The study was a cohort study and pregnant women who met the inclusion and exclusion criteria at the Obstetrics and Gynecology Department of Qilu Hospital of Shandong University from September 2020 to September 2021. Analysis using Kruskal-Wallis rank sum test, Pearson's Chi-squared test, generalized linear mixed model (GLMM) and repeated measures ANOVA. If the difference between groups was statistically significant, the Bonferroni test was then performed. A two-sided test of P < 0.05 was considered statistically significant. RESULTS: A total of 345 pregnants were included in this study. The subjects were divided into the ≤60 seconds group (n = 134), the 61-89 seconds group (n = 106) and the ≥90 seconds group (n = 105) according to the time of natural arrest of the umbilical cord. There was no statistically significant difference in the amount of postpartum hemorrhage and the need for iron, medication, or supplements in the postpartum period between the different cord spontaneous arrest time groups for mothers (P > 0.05). The weight of the newborns in the three groups was (3316.27 ± 356.70) g, (3387.26 ± 379.20) g, and (3455.52 ± 363.78) g, respectively, and the number of days of cord detachment was 12.00 (8.00, 15.75) days, 10.00 (7.00, 15.00) days and 9.00 (7.00, 13.00) days, respectively, as the time of natural cessation of the cord increased. The neonatal lymphocyte ratio, erythrocyte pressure, and hemoglobin reached a maximum in the 61-89 s group at (7.41 ± 2.16) %, (61.77 ± 8.17) % and (194.52 ± 25.84) g/L, respectively. Lower incidence of neonatal hyperbilirubinemia in the 61-89 s group compared to the ≥90s group 0 vs 4.8 (P < 0.05). CONCLUSIONS: In full-term singleton vaginal births, maternal and infant outcomes are better when waiting for 61-89 s after birth for the cord to stop pulsating naturally, suggesting that we can wait up to 90s for the cord to stop pulsating naturally, and if the cord does not stop pulsating after 90s, artificial weaning may be more beneficial to maternal and infant outcomes.

Association between body roundness index and overactive bladder: results from the NHANES 2005-2018.

BACKGROUND AND AIM: An increasing amount of research has indicated obesity greatly affects individuals with overactive bladder (OAB). However, traditional anthropometric methods present challenges in accurately assessing the likelihood of OAB. Hence, this study's objective was to identify the correlation between the body roundness index (BRI) and OAB. METHODS: The research included 12,401 individuals who participated in the National Health and Nutrition Examination Survey spanning 2005-2018. The correlation between BRI and OAB was explored by using weighted multiple logistic regression and weighted restricted cubic spline (RCS). Subgroup analyses showed the associations based on different population types. The study also analyzed the predictive capability of various anthropometric indices, including BRI, body mass index, waist circumference, and weight, in assessing the likelihood of OAB through Receiver-operating characteristic (ROC) curves. RESULTS: An independent positive correlation between OAB and BRI was identified after adjusting for potential confounders in weighted multivariate logistic models[odds ratio (OR) = 1.15, 95% confidence interval (CI), 1.12-1.17]. Weighted RCS analysis found a positive dose-response correlation between OAB and BRI. The effect size of BRI on OAB remained stable across all prespecified subgroups (all P for interactions > 0.05). In ROC analysis, BRI showed better discriminatory ability for OAB compared with other anthropometric measures for both genders (all P < 0.01). The best BRI cutoff for predicting OAB was lower for men (5.151) than for women (5.383), suggesting that men were more susceptible to changes in BRI than women. CONCLUSIONS: This study demonstrated that a raised BRI is correlated with a higher likelihood of OAB. Due to the effectiveness and non-invasiveness of BRI in predicting OAB, it is expected to become the preferred method for early detection and management strategies.

Burden of drug use disorders in the United States from 1990 to 2021 and its projection until 2035: results from the GBD study.

BACKGROUND: Drug use disorders (DUDs) have emerged as one of the most significant public health crises, exerting a substantial influence on both community health and socio-economic progress. The United States (US) also suffers a heavy burden, it is necessary to figure out the situation from multiple perspectives and take effective measures to deal with it. Therefore, using the data from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2021, we evaluated this topic. METHODS: Annual data on DUDs-related burden were collected from the GBD study 2021. We calculated the indicator of estimated annual percentage change (EAPC) to evaluate the changing trend of burden. The Bayesian model for age-period-cohort was introduced to forecast the burden. RESULTS: In 2021, the number and age-standardized rate of prevalence were particularly prominent, with 12,146.95 thousand and 3821.43 per 100,000, respectively. Higher burden was also observed in males, 15-45 years old populations, and opioid use disorders subtype. From 1990 to 2021, the DUDs-related burden increased in the US and all states, especially in West Virginia; and the national death-related burden with the highest increase (EAPC = 7.96). Other significant inverse associations were seen between EAPC, age-standardized rates, and socio-demographic index (SDI). Moreover, in the next 14 years, the projected DUDs burden remains exigent. CONCLUSIONS: The burden of DUDs in the US is heavy and has been enlarging. This study proposes that greater attention should be paid to the strategies in males, the younger population, opioid use disorders, and low-SDI states implemented by decision-makers to achieve goals such as reducing burden.

Notable dysthymia: evolving trends of major depressive disorders and dysthymia in China from 1990 to 2019, and projections until 2030.

BACKGROUND: Depressive disorders have been identified as a significant contributor to non-fatal health loss in China. Among the various subtypes of depressive disorders, dysthymia is gaining attention due to its similarity in clinical severity and disability to major depressive disorders (MDD). However, national epidemiological data on the burden of disease and risk factors of MDD and dysthymia in China are scarce. METHODS: This study aimed to evaluate and compare the incidence, prevalence, and disability-adjusted life-years (DALYs) caused by MDD and dysthymia in China between 1990 and 2019. The temporal trends of the depressive disorder burden were evaluated using the average annual percentage change. The comparative risk assessment framework was used to estimate the proportion of DALYs attributed to risk factors, and a Bayesian age-period-cohort model was applied to project the burden of depressive disorders. RESULTS: From 1990 to 2019, the overall age-standardized estimates of dysthymia in China remained stable, while MDD showed a decreasing trend. Since 2006, the raw prevalence of dysthymia exceeded that of MDD for the first time, and increased alternately with MDD in recent years. Moreover, while the prevalence and burden of MDD decreased in younger age groups, it increased in the aged population. In contrast, the prevalence and burden of dysthymia remained stable across different ages. In females, 11.34% of the DALYs attributable to depressive disorders in 2019 in China were caused by intimate partner violence, which has increasingly become prominent among older women. From 2020 to 2030, the age-standardized incidence, prevalence, and DALYs of dysthymia in China are projected to remain stable, while MDD is expected to continue declining. CONCLUSIONS: To reduce the burden of depressive disorders in China, more attention and targeted strategies are needed for dysthymia. It's also urgent to control potential risk factors like intimate partner violence and develop intervention strategies for older women. These efforts are crucial for improving mental health outcomes in China.

Characteristics of Clinical Isolates of Listeria monocytogenes in Sichuan, China, in 2022 Based on Whole Genome Sequencing Analysis.

Listeria monocytogenes is a foodborne pathogen. In 2022, we collected 15 strains of L. monocytogenes isolated from patients in some foodborne disease sentinel monitoring hospitals in Sichuan Province. Through whole genome sequencing (WGS), we obtained the virulence genes carried by the strains, multi-locus sequence typing (MLST), core genome MLST (cgMLST), clonal complex (CC), and serum groups and constructed a phylogenetic tree and minimum spanning tree with nonhuman strains. An analysis shows that all 15 strains of L. monocytogenes carry virulence genes LIPI-1 and LIPI-2, whereas the carrying rates of LIPI-3 and LIPI-4 virulence genes are relatively low. The MLST typing results showed a total of 10 sequence types (ST), including 10 CCs, with ST7 being the dominant type. The cgMLST clearly distinguishes strains of different lineages and CC types. The serum group is divided into three types: IIa, IIb, and IVb, with IIa being the dominant serum group. An analysis of antibiotic genes showed that all 15 strains carried FosX, lin, mprF, and norB with high carrying rates. The minimum inhibitory concentration results indicated that all were susceptible to eight antibiotics (ampicillin, penicillin, tetracycline, meropenem, erythromycin, vancomycin, ciprofloxacin, and trimethoprim-sulfamethoxazole). The analysis of strains isolated from different sources of Listeria revealed varying degrees of diversity, and the contamination of meat and environment within the province is closely related to clinical cases. L. monocytogenes isolated from clinical cases in Sichuan Province carry multiple virulence and antibiotic genes, with high potential pathogenicity. It is necessary to further strengthen the monitoring and control of food and environment by L. monocytogenes within Sichuan Province.

Molecular Characteristics of Staphylococcus aureus Isolates form Food-Poisoning Outbreaks (2011-2022) in Sichuan, China.

Staphylococcal food poisoning (SFP) is one of the most common foodborne diseases in the world. This study aimed to investigate the molecular epidemiological characteristics of Staphylococcus aureus isolated from SFP. A total of 103 S. aureus isolates were obtained during 2011-2022 in Sichuan, southwest China. All isolates were tested for the genomic characteristics and phylogenetic analysis by performing whole-genome sequencing. Multilocus sequence typing analysis showed 17 multilocus sequence types (STs), ST7 (23.30%), ST5 (22.33%), and ST6 (16.50%) being the most common. A total of 45 virulence genes were detected, 22 of which were staphylococcal enterotoxin (SE) genes. Among the identified SE genes, selX exhibited the highest prevalence (86.4%). All isolates carried at least one SE gene. The results of the antimicrobial resistance (AMR) gene detection revealed 41 AMR genes of 12 classes. ß-lactam resistance genes (blal, blaR1, blaZ) and tetracycline resistance gene (tet(38)) exhibited a higher prevalence rate. Core genome single nucleotide polymorphism showed phylogenetic clustering of the isolates with the same region, year, and ST. The results indicated that the SFP isolates in southwest of China harbored multiple toxin and resistance genes, with a high prevalence of new SEs. Therefore, it is important to monitor the antimicrobial susceptibility and SE of S. aureus to reduce the potential risks to public health.

Design, Synthesis, and Anti-Hepatocellular Carcinoma Evaluation of Sesquiterpene Lactone Epimers Trilobolide-6-O-isobutyrate Analogs.

Hepatocellular carcinoma (HCC), one of the most common malignant cancers with a low 5-year survival rate, is the third leading cause of cancer-related deaths worldwide. The finding of novel agents and strategies for the treatment of HCC is an urgent need. Sesquiterpene lactones (SLs) have attracted extensive attention because of their potent antitumor activity. In this study, a new series of SL derivatives (3-18) were synthesized using epimers 1 and 2 as parent molecules, isolated from Sphagneticola trilobata, and evaluated for their anti-HCC activity. Furthermore, the structures of 4, 6, and 14 were confirmed by X-ray single-crystal diffraction analyses. The cytotoxic activities of 3-18 on two HCC cell lines, including HepG2 and Huh7, were evaluated using the CCK-8 assay. Among them, compound 10 exhibited the best activity against the HepG2 and Huh7 cell lines. Further studies showed that 10 induced cell apoptosis, arrested the cell cycle at the S phase, and induced the inhibition of cell proliferation and migration in HepG2 and Huh7. In addition, absorption, distribution, metabolism, and excretion (ADME) properties prediction showed that 10 may possess the properties to be a drug candidate. Thus, 10 may be a promising lead compound for the treatment of HCC.

Establishing a prognostic model of chromatin modulators and identifying potential drug candidates in renal clear cell patients.

BACKGROUND: Renal carcinoma is a common malignant tumor of the urinary system. Advanced renal carcinoma has a low 5-year survival rate and a poor prognosis. More and more studies have confirmed that chromatin regulators (CRs) can regulate the occurrence and development of cancer. This article investigates the functional and prognostic value of CRs in renal carcinoma patients. METHODS: mRNA expression and clinical information were obtained from The Cancer Genome Atlas database. Univariate Cox regression analysis and LASSO regression analysis were used to select prognostic chromatin-regulated genes and use them to construct a risk model for predicting the prognosis of renal cancer. Differences in prognosis between high-risk and low-risk groups were compared using Kaplan-Meier analysis. In addition, we analyzed the relationship between chromatin regulators and tumor immune infiltration, and explored differences in drug sensitivity between risk groups. RESULTS: We constructed a model consisting of 11 CRs to predict the prognosis of renal cancer patients. We not only successfully validated its feasibility, but also found that the 11 CR-based model was an independent prognostic factor. Functional analysis showed that CRs were mainly enriched in cancer development-related signalling pathways. We also found through the TIMER database that CR-based models were also associated with immune cell infiltration and immune checkpoints. At the same time, the genomics of drug sensitivity in cancer database was used to analyze the commonly used drugs of renal clear cell carcinoma patients. It was found that patients in the low-risk group were sensitive to medicines such as axitinib, pazopanib, sorafenib, and gemcitabine. In contrast, those in the high-risk group may be sensitive to sunitinib. CONCLUSION: The chromatin regulator-related prognostic model we constructed can be used to assess the prognostic risk of patients with clear cell renal cell carcinoma. The results of this study can bring new ideas for targeted therapy of clear cell renal carcinoma, helping doctors to take corresponding measures in advance for patients with different risks.

Obesity is associated with poor outcomes of corticosteroid treatment in patients with primary immune thrombocytopenia.

Emerging evidence has demonstrated that obesity impacts multiple immune-related diseases. It remains unclear whether and how obesity alters treatment outcomes in patients with primary immune thrombocytopenia (ITP). Thus, we retrospectively investigated 214 treatment-naïve patients who received standard high-dose dexamethasone therapy in Qilu Hospital. Patients with obesity showed significantly lower overall initial response (underweight vs. normal vs. overweight vs. obese: 85.7% vs. 85.2% vs. 72.0% vs. 52.3%, p = 0.001) and initial complete response ([CR], 71.4% vs. 70.4% vs. 53.3% vs. 27.3%, p < 0.001) rates. The same trend was observed in the 6-month sustained response (63.6% vs. 52.3% vs. 35.6% vs. 22.7%, p = 0.03) and sustained CR (36.4% vs. 44.6% vs. 24.4% vs. 9.1%, p = 0.01). The Kaplan-Meier analysis revealed a shortened duration of remission in the obese group (median duration of remission, not reached vs. 16 months vs. 2 months vs. 1 month, p = 0.002). In multivariate regression analysis, obesity was independently associated with poor initial and sustained responses, and an increased risk for relapse. In conclusion, obesity is a negative predictor for outcomes of corticosteroid treatment. A stratified strategy according to body mass index status may facilitate the precision management of ITP.

Systemic inflammation indicators and risk of incident arrhythmias in 478,524 individuals: evidence from the UK Biobank cohort.

BACKGROUND: The role of systemic inflammation in promoting cardiovascular diseases has attracted attention, but its correlation with various arrhythmias remains to be clarified. We aimed to comprehensively assess the association between various indicators of systemic inflammation and atrial fibrillation/flutter (AF), ventricular arrhythmia (VA), and bradyarrhythmia in the UK Biobank cohort. METHODS: After excluding ineligible participants, a total of 478,524 eligible individuals (46.75% male, aged 40-69 years) were enrolled in the study to assess the association between systemic inflammatory indicators and each type of arrhythmia. RESULTS: After covariates were fully adjusted, CRP levels were found to have an essentially linear positive correlation with the risk of various arrhythmias; neutrophil count, monocyte count, and NLR showed a non-linear positive correlation; and lymphocyte count, SII, PLR, and LMR showed a U-shaped association. VA showed the strongest association with systemic inflammation indicators, and it was followed sequentially by AF and bradyarrhythmia. CONCLUSIONS: Multiple systemic inflammatory indicators showed strong associations with the onset of AF, VA, and bradyarrhythmia, of which the latter two have been rarely studied. Active systemic inflammation management might have favorable effects in reducing the arrhythmia burden and further randomized controlled studies are needed.

Heterogeneity in the immune microenvironment of bone metastasis in driver-positive non-small cell lung cancer.

Mutations in epidermal growth factor receptor and anaplastic lymphoma kinase are common driver events in non-small cell lung cancer (NSCLC), which are associated with a high frequency of bone metastases (BMs). While the bone marrow represents a specialized immune microenvironment, the immune repertoire of BMs remains unknown. Considering the higher incidence of BMs in driver gene-positive NSCLCs, and the unique biology of the bone, herein, we assessed the infiltrating immune cells and T cell receptor (TCR) profile of BMs in driver-positive NSCLCs. Immune profile of BMs in driver gene-positive NSCLC were assessed in 10 patients, where 6 had driver gene-positive mutation. TCR and bulk RNA sequencing were performed on malignant bone samples. The diversity and clonality of the TCR repertoire were analyzed. The cellular components were inferred from bulk gene expression profiles computationally by CIBERSORT. Although BMs were generally regarded as immune-cold tumors, immune cell composition analyses showed co-existence of cytotoxic and suppressor immune cells in driver-positive BM samples, as compared to primary lung. Analysis of the TCR repertoire indicated a trend of higher diversity and similar clonality in the driver-positive compared with the driver-negative subsets. In addition, we identified two cases that showed the opposite response to immune checkpoint blockade. A comparison of these two patients' BM samples showed more highly amplified clones, fewer M2 macrophages and more activated natural killer cells in the responder. In summary, BMs in NSCLC are heterogeneous in their immune microenvironment, which might be related to differential clinical outcomes to immune checkpoint blockade.

MATE transporter GFD1 cooperates with sugar transporters, mediates carbohydrate partitioning and controls grain-filling duration, grain size and number in rice.

More than half of the world's food is provided by cereals, as humans obtain >60% of daily calories from grains. Producing more carbohydrates is always the final target of crop cultivation. The carbohydrate partitioning pathway directly affects grain yield, but the molecular mechanisms and biological functions are poorly understood, including rice (Oryza sativa L.), one of the most important food sources. Here, we reported a prolonged grain filling duration mutant 1 (gfd1), exhibiting a long grain-filling duration, less grain number per panicle and bigger grain size without changing grain weight. Map-based cloning and molecular biological analyses revealed that GFD1 encoded a MATE transporter and expressed high in vascular tissues of the stem, spikelet hulls and rachilla, but low in the leaf, controlling carbohydrate partitioning in the stem and grain but not in the leaf. GFD1 protein was partially localized on the plasma membrane and in the Golgi apparatus, and was finally verified to interact with two sugar transporters, OsSWEET4 and OsSUT2. Genetic analyses showed that GFD1 might control grain-filling duration through OsSWEET4, adjust grain size with OsSUT2 and synergistically modulate grain number per panicle with both OsSUT2 and OsSWEET4. Together, our work proved that the three transporters, which are all initially classified in the major facilitator superfamily family, could control starch storage in both the primary sink (grain) and temporary sink (stem), and affect carbohydrate partitioning in the whole plant through physical interaction, giving a new vision of sugar transporter interactome and providing a tool for rice yield improvement.

Identification of miR-1-3p, miR-143-3p and miR-145-5p association with bone metastasis of Gleason 3+4 prostate cancer and involvement of LASP1 regulation.

Gleason Score (GS) 3 + 4 prostate cancer (PCa) is heterogeneous in clinical course and molecular features. Risk stratification of indolent and aggressive PCa with GS 3 + 4 is critical, especially those with bone metastasis (BM) potential. Microarray-based microRNA(miRNA) profiling with eight PCa cases with or without BM was used to screen the candidate miRNAs associated with BM. Transwell and MTS assays were used to characterize the function of miRNAs and target gene LASP1. RT-qPCR and immunohistochemistry assays were utilized to illustrate the clinical significance of miRNAs and target gene in a cohort of 309 Chinese PCa cases. In the current study, we identified that miR-1-3p, miR-143-3p and miR-145-5p are associated with BM of GS 3 + 4 PCa. Through functional experiments, we show that miR-1-3p/143-3p/145-5p promotes proliferation and migration of PCa in vitro. LASP1 was predicted as the common target of these three miRNAs which was further confirmed by a luciferase assay. Overexpression of LASP1 was correlated with higher GS, higher pathological stage, and the presence of metastasis by immunohistochemistry. siRNA knockdown of LASP1 significantly suppressed proliferation and migration, whereas overexpression of LASP1 promoted it. Bioinformatics analysis revealed the involvement of Wnt signaling pathway in LASP1 mediated function. LASP1 may activate Wnt signaling by interacting with ß-catenin. In all, we suggest that miR-1-3p/143-3p/145-5p are associated with BM of Gleason 3 + 4 PCa. LASP1 is the common target of these miRNAs and may active Wnt signaling by interacting with ß-catenin.

One-step assembly of a MacMillan catalyst-based phenolic-type polymer.

We report herein a "bottom-up" approach for the one-step assembly of a MacMillan catalyst-based phenolic-type polymer (Mac-CP). The resulting self-supported polymeric organocatalyst possesses homogeneously distributed and highly concentrated catalytic sites. Furthermore, Mac-CP is soluble in CH3CN but insoluble in hexane. This unique property can be used to employ the polymer as an efficient catalyst in homogeneous organocatalysis and heterogeneous recycling. As a result, Mac-CP possesses comparable catalytic activity and enantioselectivity to its homogeneous counterpart in the asymmetric Diels-Alder reaction (95% yield, 93% enantiomeric excess (ee) for endo and 92% ee for exo).