Abstract Both tumor-associated macrophage (TAM) and tumor stiffness may support immunosuppression and limit immunotherapy response, particularly in non-small cell lung cancer (NSCLC). TAMs influence extracellular matrix (ECM) remodeling, but whether they also affect tumor stiffness, or are regulated by mechanical signals in turn, remains to be investigated. Here, we use single-cell transcriptomics of primary NSCLC samples to show that TAMs are associated with an immunosuppressive niche and are also a major source of the ECM component fibronectin (FN1). Mechanistically, macrophage-specific FN1 deficiency induces pro-inflammatory macrophages in a subcutaneous tumor mouse model, reduces ECM stiffness, increases lymphocyte infiltration into tumors, strengthens antitumor immunity, and enhances immune checkpoint blockade efficacy. Within TAMs, FN1-mediated cytoskeleton assembly and autophagy induction impair macrophage glycolysis by inhibiting the RAC1-mTOR axis, thereby limiting the antitumor activity of macrophages. Collectively, these findings highlight macrophage-derived FN1 as a mechanical cue for aggravating immunosuppression and as an intervention target to supplement immunotherapy in NSCLC.

Photodynamic therapy (PDT) boasts the advantages of high spatiotemporal selectivity and non-invasiveness, but its clinical application is still limited by the hypoxic tumor microenvironment and inherent drawbacks of traditional photosensitizers such as aggregation-induced quenching (ACQ), insufficient targeting ability, and systemic toxicity. We previously conducted a structure-activity relationship (SAR) study on a plant-derived alkaloid, berberine, and found that its derivative B12 not only significantly enhanced antitumor efficacy but also improved water solubility and bioavailability. In this study, we characterized the photodynamic properties of B12, investigated its anticancer mechanisms, and evaluated the photodynamic therapeutic efficacy and biosafety of B12 in the tumors of xenograft mouse models. We showed that B12 was a novel photosensitizer without ACQ effect, exhibited both type I and type II photodynamic activities, and generated a large amount of reactive oxygen species (ROS) under both normoxic and hypoxic conditions. In addition, B12 (12.5, 25 μM) significantly enhanced its therapeutic effect against RKO and HCT116 cells in the hypoxic microenvironment by inhibiting the AKT/mTOR signaling pathway and downregulating the expression of hypoxia-inducible factor HIF-1α. In RKO cells, B12 (2 μM) exhibited dynamic dual-organelle-targeting properties after photoactivation: it first induced the collapse of mitochondrial membrane potential, then translocated to the nucleus and bound to DNA. It improved the intersystem crossing (ISC) efficiency by narrowing the singlet-triplet energy gap, thereby amplifying the generation of ROS and damaging DNA integrity. In mice xenografted with B16 cells, intratumoral injection of B12 (5 mg/kg) followed by 10 min light irradiation daily for 9 days significantly suppressed tumor growth with good biosafety. In conclusion, the small molecule B12 simultaneously possesses type I and type II photodynamic activities, dynamic organelle-targeting and hypoxia adaptation properties. This study may provide a reference for the research and design of hypoxia-tolerant small-molecule photosensitizers and break through the clinical bottlenecks of photodynamic therapy.

BACKGROUND:Obesity remains a global health challenge, with limited therapeutic options. Berberine (BBR) shows promise as an anti-obesity agent. However, its clinical application is hampered by modest efficacy and poor bioavailability. OBJECTIVE:This study investigated the anti-obesity effects and underlying mechanisms of B12, a novel BBR derivative with enhanced solubility and bioavailability. METHODS:Mice with obesity induced by a high-fat-diet were employed to evaluate B12's effect on weight loss. Energy expenditure was assessed using metabolic cages. Adipose tissue morphology was examined through histological analysis. In vitro studies were conducted using 3T3-L1 preadipocytes and immortalized brown adipocytes. Gene and protein expression were analyzed using RT-qPCR, western blotting, and immunohistochemistry. Cell cycle progression was evaluated by flow cytometry. RESULTS:B12 demonstrated anti-obesity efficacy superior to BBR, manifesting through dual mechanisms. It enhanced energy expenditure by increasing brown adipocyte numbers and UCP1 expression through SIRT1 upregulation and AMPK phosphorylation. Furthermore, B12 markedly reduced the mass of white adipose tissue in mice with HFD-induced obesity and inhibited adipocyte differentiation and lipid accumulation in 3T3-L1 preadipocytes. This effect was achieved through intervention at multiple stages: early-stage downregulation of CyclinD1 and C/EBPβ, followed by reduced expression and heterodimerization of RXRα and PPARγ during middle and late stages of differentiation, collectively preventing matural adipocyte formation. CONCLUSIONS:Our findings establish B12 as a promising anti-obesity agent, offering significantly enhanced efficacy over its parent compound BBR. This natural product-derived therapeutic candidate, with its improved pharmacological properties and dual mechanism of action, represents a significant advance in phytomedicine-based approaches to obesity treatment.

Prostate cancer is a highly prevalent malignant tumor in men. Traditional diagnostic markers have limitations, and there is an urgent need for precise and efficient detection technologies to support the development of new biomarkers. Electrochemical sensors, with their advantages of high sensitivity, rapid response, and strong anti-interference ability, have become the core technology for clinical biomarker detection. They precisely quantify neutrophil percentage and serum albumin via electrode modification, supporting reliable NPAR calculation. This study explores NPAR's link to prostate cancer risk and mortality using electrochemical sensors, evaluating its biomarker value. Electrochemical sensors measured neutrophil percentage and albumin levels in 19,262 NHANES participants (2001-2018) and 240 Yijishan Hospital subjects to calculate NPAR. A diagnostic model was constructed in combination with machine learning, and the importance of features was analyzed through SHAP. The results show that the detection data of the electrochemical sensor is accurate and stable, highly consistent with the clinical gold standard. NPAR is significantly positively correlated with the risk of prostate cancer. Therefore, electrochemical sensors provide reliable technical support for NPAR detection. NPAR is a valuable biomarker for identifying high-risk populations of prostate cancer and evaluating prognosis. Integrating electrochemical sensors with NPAR into clinical practice can optimize the risk stratification and diagnosis and treatment strategies of prostate cancer.

Frailty is a critical geriatric syndrome associated with modifiable lifestyle factors, yet their population-level contributions remain unclear. This study aimed to quantify the proportion of frailty incidence attributable to modifiable lifestyle factors and assess temporal trends in the US. We analyzed data from 26,247 participants in the Health and Retirement Study (2004–2020) involving adults aged ≥ 50 years. Frailty was assessed using the Paulson-Lichtenberg Frailty Index. Lifestyle exposures included smoking, drinking, physical inactivity, and sleep disturbance. Associations between lifestyle factors and frailty were examined using Cox models. Population attributable fractions (PAFs) were calculated for each factor, with temporal trends assessed using generalized estimating equations with splines. From 2004 to 2020, frailty incidence declined from 55.2 to 46.6 per 1,000 person-years. Current smoking (HR = 1.46, 95

Functional precision oncology complements genomic approaches by directly testing treatment options on patient-derived models. However, existing platformssuch as patient-derived xenografts (PDXs) and patient-derived organoids (PDOs), face major barriers in clinical use due to technical challenges, including limited standardization, high costs, long assay times, scalability constraints, and incomplete recapitulation of the patient tumor microenvironment (TME). Here, we present a scalable, low-cost Organ Chip (OC) platform fabricated entirely from thermoplastics via injection molding. Leveraging a patented channel geometry and surface treatment, the device achieves barrier-free hydrogel confinement through capillary pinning without porous membranes, micropillars, or other barrier structures. This automation-compatible platform supports tissue-specific extracellular matrices and co-culture through versatile perfusion modes, with robust imaging compatibility. We demonstrate its feasibility for drug sensitivity testing using multiple cell lines and patient-derived primary cells, with imaging-based phenotypic profiling for accurate quantification of drug responses, closely aligning with clinical outcomes. Additionally, we integrated a deep learning-based image translation model that predicts fluorescence staining from bright-field images. This approach enables longitudinal, label-free phenotypic analysis with higher sensitivity than conventional endpoint staining. Together, this integrated cancer OC system overcomes key technical challenges and offers a promising framework for functional precision oncology through high-throughput, patient-relevant drug testing.

Background: For most colorectal cancer (CRC) patients, expanding the benefits of immunotherapy, particularly through blocking programmed cell death-1 (PD-1) and its ligand (PD-L1), is crucial, especially in cases with limited response to neoadjuvant therapy. This study investigates the role of Myoferlin (MYOF) as a novel target in CRC immunotherapy. Methods: Human CRC cell lines (RKO, HCT116), normal intestinal epithelial cells (HIEC-6), and the murine CRC cell line MC38 were used to study the effects of apatinib and MYOF in CRC cells. RNA sequencing, the CPTAC and TCGA databases, and other molecular and cellular methods were applied to disclose the mechanisms involved. A series of mouse models were established to assess the effects of apatinib and MYOF knockdown on tumor progression, immune cell infiltration, and immune checkpoint protein response. Results: We found that MYOF is overexpressed in CRC and linked to immune cell infiltration and checkpoint expression. Suppression of MYOF expression significantly inhibited CRC cell proliferation and migration, as well as reduced PD-L1 protein levels. Integrative analysis showed that apatinib modulates MYOF expression via VEGFR2, resulting in decreased PD-L1 expression, increased CD8+ T cell infiltration, and reduced pro-tumor M2 macrophages. Animal experiments further revealed that apatinib treatment or MYOF knockdown enhanced the efficacy of immune checkpoint blockade (ICB) in CRC. Conclusions: These findings highlight novel antitumor mechanisms of MYOF and suggest that combining apatinib with ICB therapy may improve CRC treatment outcomes, offering a promising strategy to enhance immune responses.

Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid malignancy, and its progression is closely associated with patient outcomes. This study investigated the role of the long non-coding RNA LINC02560 in the pathogenesis and aggressiveness of PTC through cell culture, transfection, RT-qPCR, Western blot analysis, and various functional assays, such as MTT, EdU, colony formation, wound healing, and Transwell migration assays. Our results revealed a significant upregulation of LINC02560 in PTC tissues, correlating with poor prognosis in affected patients. Functional analyses demonstrated that silencing of LINC02560 markedly inhibited the proliferation, migration, and invasion of the PTC cell lines, KTC-1, and BCPAP, whereas overexpression promoted these aggressive traits. Mechanistically, LINC02560 acted as a competitive endogenous RNA, sponging miR-505-5p and alleviating its suppression on PDE4C degradation, thereby activating the P-AKT and epithelial–mesenchymal transition (EMT) signaling pathways. Additionally, HNF4α was identified as a transcription factor capable of enhancing the expression of LINC02560. In conclusion, our findings elucidate the critical HNF4α/LINC02560/miR-505-5p/PDE4C axis in PTC pathology, presenting this regulatory network as a promising biomarker combination and potential therapeutic target to improve patient outcomes and survival rates, warranting further clinical investigation to validate these insights and support the development of targeted therapies in PTC management.

Berberine, an antibacterial natural product, shows promise as a theranostic agent. However, berberine exhibits moderate antibacterial efficacy and limited water solubility, restricting its clinical application. In this study, we discovered that a berberine derivative B-12 exhibits dual-state emission (DSE) characteristics, and its photodynamic antibacterial activity is significantly higher than that of berberine and methylene blue. The mechanistic studies suggested that substitution with a single methoxy group at the C-3 position reduces the intramolecular electron transfer and increases the energy gap between singlet and triplet excited states, which reduces nonradiative transition pathways and improves the fluorescence quantum yield. The C-3 methoxy group also contributes to higher ROS production due to the longer lifetime of the excited state. Through bioimaging, B-12 was able to discriminate between Gram-positive and Gram-negative bacteria. Notably, this study offers valuable insights for designing photodynamic and DSE-active berberine derivatives, highlighting the potential of these derivatives as theranostic agents.

Frailty and multimorbidity jointly drive adverse outcomes in older adults. However, their dynamic trajectories remain underexplored due to survival selection bias—where mortality systematically excludes high-risk individuals, distorting longitudinal progression patterns. This study aims to delineate joint trajectories of frailty and multimorbidity, and characterize their temporal synergies while accounting for the addressing selective survival effects. Using 12 waves (2011-2023) of the National Health and Aging Trends Study (NHATS), we annually assessed frailty (Fried phenotypic criteria) and multimorbidity (cumulative chronic conditions). To overcome survival selection bias inherent in aging cohorts, we extended group-based trajectory modeling through dual-process specification: a multivariate latent class model identifying progression typologies, coupled with a competing risks survival model. Shared parameters dynamically adjusted trajectory estimates for mortality-related attrition, ensuring unbiased characterization of temporal synergies. Among the 4,960 participants from the NHATS 2011 cohort included in this analysis, 2,931 (survey-weighted 57.2%) were female, and 2,070 died during follow-up (average annual attrition rate: 4.3%). Seven joint trajectories were identified, revealing three dominant patterns: stable phenotypes (Stable Low Risk, Persistent High Multimorbidity), progressive escalators (Late-Onset Frailty, Early Accelerated Frailty, Delayed Escalation), and nonlinear progressors (High Baseline Attenuation, Critical-State Reversal). Notably, Critical-State Reversal demonstrated frailty decline despite extreme multimorbidity progression, while Early Accelerated Frailty and Late-Onset Frailty diverged in progression timing despite comparable multimorbidity burdens, challenging assumptions of unidirectional frailty trajectories in aging. This study identifies seven distinct trajectories, and reveals unexpected heterogeneity in aging processes. These mortality-adjusted trajectories may offer a clinically actionable framework for risk stratification and personalized care planning.

Introduction:Crohn's disease (CD) is a chronic inflammatory condition of the intestines with a rising global incidence. Traditional diagnostic and therapeutic methods have limitations, necessitating the exploration of more effective strategies. Methods:In this study, we employed the Gene Expression Omnibus database to identify genes that are differentially expressed in CD. RT-PCR and immunohistochemical analysis were used to SLC6A14 RNA and protein expression in the colons of CD mice and CD tissues from patients. The mouse model of CD was induced by dextran sodium sulfate (DSS). Infiltrating immune cells in mouse model were screened by flow cytometry. Results:We discovered that SLC6A14 is significantly overexpressed in CD samples, and its expression is positively correlated with the degree of infiltration by CD4+ and CD8+ T cells. The elevated levels of SLC6A14 RNA and protein were confirmed in clinical CD tissues. The SLC6A14 inhibitor α-methyl-tryptophan (α-MT) significantly decreased the expression of SLC6A14 RNA and protein in the colons of CD mice. The α-MT treatment group also exhibited reduced levels of cytokines involved in T cell differentiation (IFN-γ and TNF-α) and the expression of immune cell surface markers CXCR-3 and LAG-3. Flow cytometry analysis revealed a significant increase in the infiltration of CD4+ and CD8+ T cells in the DSS-treated group compared to the control group. Conversely, the α-MT treatment group showed a significant reduction in CD4+ and CD8+ T cell infiltration and the restoration of intestinal parameters in CD mice. These findings underscore the role of SLC6A14 in regulating intestinal immune cell infiltration during CD progression. Discussion:Our findings suggest that SLC6A14 could serve as a potential diagnostic biomarker and therapeutic target for CD. Furthermore, α-MT offers a novel approach for the clinical diagnosis and treatment of CD by targeting SLC6A14 for therapeutic intervention.

Ubiquitin-Specific Protease 39 (USP39) has been implicated in numerous malignancies, however, its pathogenic mechanisms and impact on the tumor immune microenvironment (TIME) remain incompletely characterized. Based on The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases, we investigated the diagnostic and prognostic values of USP39 across various cancer types. Additionally, we examined the correlation between USP39 expression and immune-related gene signature, immune cell infiltration pattern, tumor microsatellite instability (MSI), and tumor mutation burden (TMB). This study specifically focused on exploring the clinical relevance and molecular functions of USP39 in pancreatic adenocarcinoma (PAAD), with particularly emphasis on its role in shaping the TIME and modulating responses to immunotherapy. The results demonstrated that evaluated USP39 expression significantly correlated with advanced tumor stage and unfavorable clinical outcomes across multiple cancer types, most notably in PAAD. Functional enrichment analysis indicated that USP39 potentially promotes tumor progression through multiple oncogenic signaling cascades. In vitro experimental validation confirmed that USP39 knockdown inhibited migration and proliferation of pancreatic cancer cells while inducing apoptosis. Additionally, we identified significant positive correlations between USP39 expression and immune checkpoint molecules, particularly prominent in PAAD. Furthermore, we observed associations between USP39 expression and TMB in 16 cancer types and MSI in 11 cancer types, suggesting that heightened USP39 expression may enhance responsiveness to immunotherapeutic interventions. Collectively, our findings establish USP39 as a valuable immune-related biomarker with both diagnostic and prognostic utility across multiple cancer types, especially PAAD, underscoring its potential as a promising therapeutic target for cancer immunotherapy. Clinical trial number Not applicable.

BACKGROUND:Breast cancer (BC) remains one of the most prevalent cancers affecting women globally, imposing significant health and economic burdens on both patients and society. This study aims to investigate the relationship between the neutrophil percentage-to-albumin ratio (NPAR) and BC risk and mortality. MATERIALS AND METHODS:Clinical data from 13 540 participants in the NHANES database were analyzed, including 331 individuals with a documented history of BC. Survival analysis and advanced machine learning (ML) techniques were applied to assess the data. RESULTS:Higher NPAR levels were significantly associated with increased BC risk in the unadjusted model, with quartile comparisons revealing an odds ratio (OR) of 1.51 (95% CI: 0.99-2.29, P = 0.057). After adjustment, the OR increased to 1.70 (95% CI: 1.12-2.57, P < 0.05), indicating the robustness of this association. Elevated NPAR levels were also linked to higher all-cause mortality (ACM). Multivariate Cox regression models showed that a one-unit increase in NPAR was associated with adjusted hazard ratios of 1.09 (95% CI: 1.07-1.12) for overall mortality and 1.17 (95% CI: 1.13-1.22) for cardiovascular disease mortality, both with P values <0.001. Restricted cubic splines analysis revealed a linear correlation between NPAR and BC risk ( P for nonlinearity = 0.15), while a nonlinear relationship was observed for ACM ( P for nonlinearity < 0.01). Among nine ML models evaluated, the LightGBM model exhibited the best diagnostic performance, achieving an area under the receiver operating characteristic curve of 0.995, outperforming models such as CATBoost, Naive Bayes, logistic regression, random forest, K-nearest neighbors, support vector machine, decision tree, and XGBoost. After model selection, an online calculator was built for use in the clinic, and the web-service is available at https://fast.statsape.com/tool/detail?id=11 . CONCLUSION:NPAR emerged as a crucial biomarker in BC risk assessment. This study suggests that NPAR may serve as a dual-purpose biomarker for both BC risk evaluation and prognostic assessment, potentially aiding in early screening and personalized treatment strategies.

Generating effective live vaccines from intact viruses remains challenging owing to considerations of safety and immunogenicity. Approaches that can be applied in a systematic manner are needed. Here we created a library of live attenuated influenza vaccines by using diverse cellular E3 ubiquitin ligases to generate proteolysis-targeting (PROTAR) influenza A viruses. PROTAR viruses were engineered to be attenuated by the ubiquitin–proteasome system, which mediates viral protein degradation in conventional host cells, but allows efficient replication in engineered cell lines for large-scale manufacturing. Depending on the degron–E3 ligase pairs, viruses showed varying degrees of attenuation. In animal models, PROTAR viruses were highly attenuated and elicited robust, broad, strain-dependent humoral, mucosal and cellular immunity. In addition, they provided cross-reactive protection against homologous and heterologous viral challenges. This study provides a systematic approach for developing safe and effective vaccines, with potential applications in designing live attenuated vaccines against other pathogens. Diverse cellular E3 ubiquitin ligase–degron pairs are used to generate live attenuated influenza vaccines. Attenuation and humoral, mucosal and cellular immune responses were characterized in mouse and ferret models.

Delayed diagnosis can adversely impact outcomes, leading to increased complication risks. This study aimed to investigate the influence of sociodemographic factors on diagnostic delay and associations between diagnostic delay and mortality among adults aged 37-73 years. A total of 130,843 hypertension-free individuals with abnormal blood pressure (BP) biomarker and 9,909 diabetes-free individuals with abnormal diabetes-related biomarkers, aged 37-73, from the UK Biobank, were included in two cohorts. Diagnoses were obtained through linked database, coded by ICD-10, and supplemented by self-report diagnoses or medications. Abnormal BP biomarker was defined as ≥ 140/90 mmHg; abnormal diabetes-related biomarkers included fasting glucose >7.0 mmol/L or HbA1C >48.0 mmol/mol. Logistic regression models were employed to examine the associations. During follow-up, there were 40,055 and 4,603 participants who had hypertension and diabetes diagnosis, respectively. The median diagnostic delay was 6.67 years for hypertension and 4.47 years for diabetes. Compared to individuals without cardiometabolic diseases (CMD) at baseline, those with abnormal blood pressure biomarker who had any disease of diabetes, cerebral vascular disease, and other 10 CMDs, and those with abnormal diabetes-related biomarkers who had any disease of obesity, hypertension and other 3 diseases were more likely to experience diagnostic delay. Additionally, higher levels of abnormal biomarker, older age, male, higher BMI, higher annual income, and former smoking were positively associated with diagnostic delay for both cohorts. Longer diagnostic delay, older age, higher annual income, and smoking were significantly associated with increased mortality. Baseline health conditions, age, income, and lifestyles may contribute to diagnostic delays and mortality.

Triple-negative breast cancer (TNBC) is a highly heterogeneous and aggressive subtype of breast cancer that faces therapeutic challenges due to a shortage of effective targeted therapies. The complex biology of TNBC renders its clinical management fraught with difficulties, especially regarding the immune microenvironment of the tumor. In recent years, long non-coding RNAs (lncRNAs) have been recognized as important gene regulators with key roles in tumor development and microenvironmental regulation. Previous studies have shown that lncRNAs play important roles in the immune microenvironment of TNBC, including the regulation of tumor immune escape and the function of tumor-infiltrating immune cells. However, despite the increasing research on lncRNAs, there are still many unanswered questions, such as their specific mechanism of action and how to effectively utilize them as therapeutic targets. Therefore, the aim of this study was to review the mechanisms of lncRNAs in the TNBC immune microenvironment, explore their regulatory roles in tumor immune escape and immune cell infiltration, and explore their prospects as potential therapeutic targets. By integrating the latest research results, this study aims to provide new ideas and directions for future TNBC treatment.

Observational studies suggest nonlinear mortality patterns in cardiometabolic diseases (CMDs): acute events show early risk spikes, while chronic conditions exhibit gradual risk accumulation. These trends superficially align with the bathtub curve—an engineering model describing triphasic failure rates. However, systematic validation of this framework in chronic disease epidemiology remains limited. This study aims to explore and validate the nonlinear temporal dynamics of mortality risk in CMD patients based on bathtub curve theory. Using data from the UK Biobank (n = 502,130), we analyzed 17 CMDs with linked primary care, inpatient and death records among 73,908 patients. A piecewise exponential survival model segmented mortality risk into intervals to capture time-dependent hazard rates. Chronic (e.g., diabetes) and acute diseases (e.g., myocardial infarction) were analyzed separately. Models were adjusted for age, sex, BMI, education, and smoking/alcohol status. Chronic diseases, such as diabetes, exhibited a bathtub-shaped mortality risk: elevated initially, declining in mid-term, and rising again long-term. Each phase showed increased risk with older age at diagnosis. Acute conditions (e.g., heart failure) demonstrated rapidly declining risks over time. Heterogeneity in high-risk time windows was observed across diseases, with hypertension and diabetes consistently following the bathtub curve. Using the piecewise exponential model, we validate the bathtub curve framework could provide a novel nonlinear perspective for understanding mortality risk evolution in CMDs. This approach supports stratified patient management, intensive early intervention, stable-phase monitoring, and late-phase complication control, enhancing precision in public health strategies. The findings underscore the theory’s potential in optimizing lifecycle management of CMDs and guiding personalized interventions.

Immune checkpoint blockade has led to breakthroughs in the treatment of advanced gastric cancer. However, the prominent heterogeneity in gastric cancer, notably the heterogeneity of the tumor microenvironment, highlights the idea that the antitumor response is a reflection of multifactorial interactions. Through transcriptomic analysis and dynamic plasma sample analysis, we identified a metabolic "face-off" mechanism within the tumor microenvironment, as shown by the dual prognostic significance of nicotinamide metabolism. Specifically, macrophages and fibroblasts expressing the rate-limiting enzymes nicotinamide phosphoribosyltransferase and nicotinamide N-methyltransferase, respectively, regulate the nicotinamide/1-methylnicotinamide ratio and CD8+ T cell function. Mechanistically, nicotinamide N-methyltransferase is transcriptionally activated by the NOTCH pathway transcription factor RBP-J and is further inhibited by macrophage-derived extracellular vesicles containing nicotinamide phosphoribosyltransferase via the SIRT1/NICD axis. Manipulating nicotinamide metabolism through autologous injection of extracellular vesicles restored CD8+ T cell cytotoxicity and the anti-PD-1 response in gastric cancer.

Colorectal cancer (CRC) has been becoming one of the most common causes of cancer mortality worldwide. Accumulating studies suggest that the progressive up-regulation of Wnt/β-catenin signaling is a crucial hallmark of CRC, and suppressing it is a promising strategy to treat CRC. Herein, we reported our latest efforts in the discovery of novel fused tetrahydroisoquinoline derivatives with good anti-CRC activities by screening our in-house berberine-like library and further structure-activity relationship (SAR) studies, in which we identified compound 10 is a potent lead compound with significant antiproliferation potencies. By the biotinylated probe and LC-MS/MS study, Hsp90 was identified as its molecular target, which is a fully different mechanism of action from what we reported before. Further studies showed compound 10 directly engaged the N-terminal site of Hsp90 and promoted the degradation of β-catenin, thereby suppressing the Wnt/β-catenin signaling. More importantly, compound 10 exhibits favorable pharmacokinetic parameters and significant anti-tumor efficacies in the HCT116 xenograft model. Taken together, this study furnished the discovery of candidate drug compound 10 possessing a novel fused tetrahydroisoquinoline scaffold with excellent in vitro and in vivo anti-CRC activities by targeting Hsp90 to disturb Wnt/β-catenin signaling pathway, which lay a foundation for discovering more effective CRC-targeted therapies.

Background: The optimal multimorbidity measures for predicting disability trajectories are not universally agreed upon. We developed a multimorbidity index among middle-aged and older community-dwelling Chinese adults and compare its predictive ability of disability trajectories with other multimorbidity measures.Methods: This study included 17,649 participants aged >= 50 years from the China Health and Retirement Longitudinal Survey 2011-2018. Two disability trajectory groups were estimated using the total disability score differences calculated between each follow-up visit and baseline. A weighted index was constructed using logistic regression models for disability trajectories based on the training set (70 %). The index and the condition count were used, along with the pattern identified by the latent class analysis to measure multimorbidity at baseline. Logistic regression models were used in the training set to examine associations between each multimorbidity measure and disability trajectories. C-statistics, integrated discrimination improvements, and net reclassification indices were applied to compare the performance of different multimorbidity measures in predicting disability trajectories in the testing set (30 %).Results: In the newly developed multimorbidity index, the weights of the chronic conditions varied from 1.04 to 2.55. The multimorbidity index had a higher predictive performance than the condition count. The condition count performed better than the multimorbidity pattern in predicting disability trajectories. Limitation: Self-reported chronic conditions.Conclusions: The multimorbidity index may be considered an ideal measurement in predicting disability trajectories among middle-aged and older community-dwelling Chinese adults. The condition count is also suggested due to its simplicity and superior predictive performance.