Subtyping and prognostic model construction based on vesicle-mediated transport-related genes in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is impacted by various environmental and genetic variables. Dysregulation of vesicle-mediated transport-related genes (VMTRGs) has been observed in many malignancies, but their effect on prognosis in CRC remains unclear. METHODS: CRC samples were clustered into varying subtypes per differential expression of VMTRGs. R package was utilized to explore differences in survival, immune, and drug sensitivity among different disease subtypes. According to differentially expressed genes (DEGs) between subtypes, regression analysis was employed to build a riskscore model and identify independent prognostic factors. The model was validated through a Gene Expression Omnibus (GEO) dataset. Immune landscape, immunophenoscore (IPS), and Tumor Immune Dysfunction and Exclusion (TIDE) scores for different risk groups were calculated. RESULTS: Two subtypes of CRC were identified based on VMTRGs, which showed significant differences in survival rates, immune cell infiltration abundance, immune functional activation levels, and immune checkpoint expression levels. Cluster2 exhibited higher sensitivity to anti-tumor drugs such as Nilotinib, Cisplatin, and Oxaliplatin compared to Cluster1. DEGs were mainly enriched in biological processes such as epidermis development, epidermal cell differentiation, and receptor-ligand activity, and signaling pathways like pancreatic secretion. The constructed 13-gene riskscore model demonstrated good predictive ability for CRC patients' prognosis. Furthermore, differences in immune landscape, IPS, and TIDE scores were observed among different risk groups. CONCLUSION: This study successfully obtained two CRC subtypes with distinct survival statuses and immune levels based on differential expression of VMTRGs. A 13-gene risk model was constructed. The findings had important implications for prognosis and treatment of CRC.

CARS senses cysteine deprivation to activate AMPK for cell survival.

Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is an important cellular metabolite-sensing enzyme that can directly sense changes not only in ATP but also in metabolites associated with carbohydrates and fatty acids. However, less is known about whether and how AMPK senses variations in cellular amino acids. Here, we show that cysteine deficiency significantly triggers calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-mediated activation of AMPK. In addition, we found that CaMKK2 directly associates with cysteinyl-tRNA synthetase (CARS), which then binds to AMPKγ2 under cysteine deficiency to activate AMPK. Interestingly, we discovered that cysteine inhibits the binding of CARS to AMPKγ2, and thus, under cysteine deficiency conditions wherein the inhibitory effect of cysteine is abrogated, CARS mediates the binding of AMPK to CaMKK2, resulting in the phosphorylation and activation of AMPK by CaMKK2. Importantly, we demonstrate that blocking AMPK activation leads to cell death under cysteine-deficient conditions. In summary, our study is the first to show that CARS senses the absence of cysteine and activates AMPK through the cysteine-CARS-CaMKK2-AMPKγ2 axis, a novel adaptation strategy for cell survival under nutrient deprivation conditions.

Mechanical force determines chimeric antigen receptor microclustering and signaling.

Chimeric antigen receptor (CAR) T cells are activated to trigger the lytic machinery after antigen engagement, and this has been successfully applied clinically as therapy. The mechanism by which antigen binding leads to the initiation of CAR signaling remains poorly understood. Here, we used a set of short double-stranded DNA (dsDNA) tethers with mechanical forces ranging from ∼12 to ∼51 pN to manipulate the mechanical force of antigen tether and decouple the microclustering and signaling events. Our results revealed that antigen-binding-induced CAR microclustering and signaling are mechanical force dependent. Additionally, the mechanical force delivered to the antigen tether by the CAR for microclustering is generated by autonomous cell contractility. Mechanistically, the mechanical-force-induced strong adhesion and CAR diffusion confinement led to CAR microclustering. Moreover, cytotoxicity may have a lower mechanical force threshold than cytokine generation. Collectively, these results support a model of mechanical-force-induced CAR microclustering for signaling.

Cancer plasticity in therapy resistance: Mechanisms and novel strategies.

Therapy resistance poses a significant obstacle to effective cancer treatment. Recent insights into cell plasticity as a new paradigm for understanding resistance to treatment: as cancer progresses, cancer cells experience phenotypic and molecular alterations, corporately known as cell plasticity. These alterations are caused by microenvironment factors, stochastic genetic and epigenetic changes, and/or selective pressure engendered by treatment, resulting in tumor heterogeneity and therapy resistance. Increasing evidence suggests that cancer cells display remarkable intrinsic plasticity and reversibly adapt to dynamic microenvironment conditions. Dynamic interactions between cell states and with the surrounding microenvironment form a flexible tumor ecosystem, which is able to quickly adapt to external pressure, especially treatment. Here, this review delineates the formation of cancer cell plasticity (CCP) as well as its manipulation of cancer escape from treatment. Furthermore, the intrinsic and extrinsic mechanisms driving CCP that promote the development of therapy resistance is summarized. Novel treatment strategies, e.g., inhibiting or reversing CCP is also proposed. Moreover, the review discusses the multiple lines of ongoing clinical trials globally aimed at ameliorating therapy resistance. Such advances provide directions for the development of new treatment modalities and combination therapies against CCP in the context of therapy resistance.

Coronin 2B Regulates Neuronal Migration via Rac1-Dependent Multipolar-Bipolar Transition.

In the developing cortex, excitatory neurons migrate along the radial fibers to their final destinations and build up synaptic connection with each other to form functional circuitry. The shaping of neuronal morphologies by actin cytoskeleton dynamics is crucial for neuronal migration. However, it is largely unknown how the distribution and assembly of the F-actin cytoskeleton are coordinated. In the present study, we found that an actin regulatory protein, coronin 2B, is indispensable for the transition from a multipolar to bipolar morphology during neuronal migration in ICR mice of either sex. Loss of coronin 2B led to heterotopic accumulation of migrating neurons in the intermediate zone along with reduced dendritic complexity and aberrant neuronal activity in the cortical plate. This was accompanied by increased seizure susceptibility, suggesting the malfunction of cortical development in coronin 2B-deficient brains. Coronin 2B knockdown disrupted the distribution of the F-actin cytoskeleton at the leading processes, while the migration defect in coronin 2B-deficient neurons was partially rescued by overexpression of Rac1 and its downstream actin-severing protein, cofilin. Our results collectively reveal the physiological function of coronin 2B during neuronal migration whereby it maintains the proper distribution of activated Rac1 and the F-actin cytoskeleton.SIGNIFICANCE STATEMENT Deficits in neuronal migration during cortical development result in various neurodevelopmental disorders (e.g., focal cortical dysplasia, periventricular heterotopia, epilepsy, etc.). Most signaling pathways that control neuronal migration process converge to regulate actin cytoskeleton dynamics. Therefore, it is important to understand how actin dynamics is coordinated in the critical processes of neuronal migration. Herein, we report that coronin 2B is a key protein that regulates neuronal migration through its ability to control the distribution of the actin cytoskeleton and its regulatory signaling protein Rac1 during the multipolar-bipolar transition in the intermediate zone, providing insights into the molecular machinery that drives the migration process of newborn neurons.

NADPH mimics the antidepressant effects of exercise in a chronic unpredictable stress rat model.

Exercise is known to be an effective intervention for depression. NADPH has been demonstrated to have neuroprotective effects in our previous studies. This study aimed to investigate if NADPH has antidepressant effects and can mimic the effects of exercise in a chronic unpredictable stress (CUS) rat model. CUS rats underwent an 8-week swimming exercise (30 min/d, 5d/w) or were intraperitoneally administered 4 mg/kg or 8 mg/kg NADPH. The open field test (OFT), sucrose preference test (SPT), novelty-suppressed feeding test (NSFT), and forced swimming test (FST) were used to examine the antidepressant-like behaviors of the rats. Exercise, 4 mg/kg, and 8 mg/kg NADPH similarly reduced anxiety, as demonstrated by the number of fecal pellets. Meanwhile, exercise and 8 mg/kg NADPH significantly increased locomotion activity in the OFT. Exercise, 4 mg/kg, and 8 mg/kg NADPH effectively reversed CUS-induced anhedonia in rats in the SPT. Exercise, 4 mg/kg, and 8 mg/kg NADPH had no impact on appetite of depressed rats; however, 8 mg/kg NADPH increased the rats' exploratory activity in the NSFT. Exercise, 4 mg/kg, and 8 mg/kg NADPH significantly reduced the immobility time of CUS model rats, while exercise and 8 mg/kg NADPH postponed the early CUS-induced "immobility" in the FST. These results demonstrated that NADPH has similar antidepressant-like effects to exercise in CUS-induced depression model rats and is a potential exercise-mimicking antidepressant.

SPI1-mediated CXCL12 expression in bladder cancer affects the recruitment of tumor-associated macrophages.

Bladder cancer (BC) originates principally from the epithelial compartment of the bladder. The immune system and its diverse players, chemokines, in particular, have been related to the responses against BC. The goal of the study here was to examine if C-X-C motif chemokine 12 (CXCL12) in BC cells could manipulate protumorigenic properties of tumor-associated macrophages (TAMs) which affects anticancer immunity supporting tumor development in the tumor microenvironment. CXCL12 was found to be overexpressed in BC and predicted poor survival. CXCL12 in BC was associated with multiple immune cell infiltrations, with TAM infiltration playing a key role. CXCL12 elevated chemotaxis of TAMs. CXCL12 downregulation inhibited cellular activity and TAM and suppressed the ability of TAMs to secrete inflammatory factors and MMP9. Furthermore, chromatin immunoprecipitation analysis revealed that SPI1 was localized to the CXCL12 promoter in BC cells, suggesting that CXCL12 serves a direct target of SPI1, which was consistent with the fact that SPI1 reversed the repressive effects of si-CXCL12 on BC cell activity and TAM recruitment in vitro and in vivo. Collectively, these findings suggest that SPI1 is involved in modulating TAM recruitment, representing a new mechanism through which it may influence tumor growth. This may be partly mediated by regulating CXCL12 expression.

Population pharmacokinetics of daptomycin in critically ill patients receiving extracorporeal membrane oxygenation.

BACKGROUND: Daptomycin is widely used in critically ill patients for Gram-positive bacterial infections. Extracorporeal membrane oxygenation (ECMO) is increasingly used in this population and can potentially alter the pharmacokinetic (PK) behaviour of antibiotics. However, the effect of ECMO has not been evaluated in daptomycin. Our study aims to explore the effect of ECMO on daptomycin in critically ill patients through population pharmacokinetic (PopPK) analysis and to determine optimal dosage regimens based on both efficacy and safety considerations. METHODS: A prospective, open-label PK study was carried out in critically ill patients with or without ECMO. The total concentration of daptomycin was determined by UPLC-MS/MS. NONMEM was used for PopPK analysis and Monte Carlo simulations. RESULTS: Two hundred and ninety-three plasma samples were collected from 36 critically ill patients, 24 of whom received ECMO support. A two-compartment model with first-order elimination can best describe the PK of daptomycin. Creatinine clearance (CLCR) significantly affects the clearance of daptomycin while ECMO has no significant effect on the PK parameters. Monte Carlo simulations showed that, when the MICs for bacteria are  ≥1 mg/L, the currently recommended dosage regimen is insufficient for critically ill patients with CLCR > 30 mL/min. Our simulations suggest 10 mg/kg for patients with CLCR between 30 and 90 mL/min, and 12 mg/kg for patients with CLCR higher than 90 mL/min. CONCLUSIONS: This is the first PopPK model of daptomycin in ECMO patients. Optimal dosage regimens considering efficacy, safety, and pathogens were provided for critical patients based on pharmacokinetic-pharmacodynamic analysis.

AKI-Pro score for predicting progression to severe acute kidney injury or death in patients with early acute kidney injury after cardiac surgery.

BACKGROUND: No reliable clinical tools exist to predict acute kidney injury (AKI) progression. We aim to explore a scoring system for predicting the composite outcome of progression to severe AKI or death within seven days among early AKI patients after cardiac surgery. METHODS: In this study, we used two independent cohorts, and patients who experienced mild/moderate AKI within 48 h after cardiac surgery were enrolled. Eventually, 3188 patients from the MIMIC-IV database were used as the derivation cohort, while 499 patients from the Zhongshan cohort were used as external validation. The primary outcome was defined by the composite outcome of progression to severe AKI or death within seven days after enrollment. The variables identified by LASSO regression analysis were entered into logistic regression models and were used to construct the risk score. RESULTS: The composite outcome accounted for 3.7% (n = 119) and 7.6% (n = 38) of the derivation and validation cohorts, respectively. Six predictors were assembled into a risk score (AKI-Pro score), including female, baseline eGFR, aortic surgery, modified furosemide responsiveness index (mFRI), SOFA, and AKI stage. And we stratified the risk score into four groups: low, moderate, high, and very high risk. The risk score displayed satisfied predictive discrimination and calibration in the derivation and validation cohort. The AKI-Pro score discriminated the composite outcome better than CRATE score, Cleveland score, AKICS score, Simplified renal index, and SRI risk score (all P < 0.05). CONCLUSIONS: The AKI-Pro score is a new clinical tool that could assist clinicians to identify early AKI patients at high risk for AKI progression or death.

Sex differences in the extent of acute axonal pathologies after experimental concussion.

Although human females appear be at a higher risk of concussion and suffer worse outcomes than males, underlying mechanisms remain unclear. With increasing recognition that damage to white matter axons is a key pathologic substrate of concussion, we used a clinically relevant swine model of concussion to explore potential sex differences in the extent of axonal pathologies. At 24 h post-injury, female swine displayed a greater number of swollen axonal profiles and more widespread loss of axonal sodium channels than males. Axon degeneration for both sexes appeared to be related to individual axon architecture, reflected by a selective loss of small caliber axons after concussion. However, female brains had a higher percentage of small caliber axons, leading to more extensive axon loss after injury compared to males. Accordingly, sexual dimorphism in axonal size is associated with more extensive axonal pathology in females after concussion, which may contribute to worse outcomes.

Real-time demonstration of two-aperture coherent digital combining free-space optical transmission with a real-valued MIMO adaptive equalizer.

Compared with the single-aperture system, the multi-aperture coherent digital combining system has the technical advantage of the effective mitigation of deep fading under strong turbulence, ease of scalability, and potential higher collected optical power. However, the tricky problem of a multi-aperture system is to efficiently combine multiple branch signals with a static skew mismatch and with time-varying characteristics of received power scintillation. In this Letter, a real-valued massive array multiple-input multiple-output (MIMO) adaptive equalizer is proposed for the first time to our knowledge to realize multi-aperture channel equalization and combining, simultaneously. In the proof-of-principle system, the feasibility of the combining technique is verified based on a MIMO 4 × 2 equalizer in a 2.5-GBaud data rate QPSK modulation FPGA-based two-aperture coherent receiver with a dynamic turbulence simulator. The results show that no reduction in combining efficiency is observed under static turbulence conditions at the hard-decision forward error correction (HD-FEC) limit of 3.8 × 0-3, and combining efficiencies of 95% and 88% are obtained for the dynamic moderate and strong turbulence.

RBP7 functions as a tumor suppressor in HR + breast cancer by inhibiting the AKT/SREBP1 pathway and reducing fatty acid.

BACKGROUND: Increasing evidence proves that RBP7 plays a significant role in breast cancer (BC). The present study was aimed to investigate the mechanism of RBP7. METHODS: Western Blotting and qRT-PCR were performed for evaluating the expression levels. CCK8, colony forming, xenograft mouse model, wound healing and transwell assays were conducted to examine cell ability of proliferation, invasion and migration. Nile red staining and Oil red O staining were used for testing the lipid. RESULTS: RBP7 was related to overall survival (OS) in patients with HR + BC. RBP7 protein was significantly decreased in HR + BC tissues and cells. RBP7 suppressed HR + BC cell proliferation in vitro and in vivo, and inhibited migration and invasion. RBP7 reduced fatty acid in HR + BC cells by inhibiting the AKT/SREBP1 pathway. CONCLUSIONS: RBP7 may function as a tumor suppressor in HR + BC by inhibiting the AKT/SREBP1 pathway and reducing fatty acid.

Pretreatment prostate-specific antigen density as a predictor of biochemical recurrence in patients with prostate cancer: a meta-analysis.

BACKGROUND: A consensus has not been reached on the value of prostate-specific antigen density (PSAD) as a predictor of biochemical recurrence of prostate cancer. This meta-analysis aimed to evaluate the association between PSAD and biochemical recurrence of prostate cancer after primary treatment. METHODS: Two authors systematically searched PubMed, Web of Science, and Embase databases (up to August September 10, 2023) to identify studies that assessed the value of pretreatment PSAD in predicting biochemical recurrence after primary treatment (radical prostatectomy or radiotherapy) of prostate cancer. A random effect model was used to pool adjusted hazard ratios (HR) with 95% confidence intervals (CI) for biochemical recurrence. RESULTS: Nine studies with 4963 patients were eligible for the meta-analysis. The reported prevalence of biochemical recurrence ranged from 4 to 55.1%. For patients with higher PSAD compared to those with low PSAD, the pooled HR of biochemical recurrence was 1.59 (95% CI 1.21-2.10). Subgroup analysis showed that the pooled HR of biochemical recurrence was 1.80 (95% CI 1.34-2.42) for patients who received radical prostatectomy, and 0.98 (95% CI 0.66-1.45) for patients who received radiotherapy. CONCLUSIONS: Elevated pretreatment PSAD may be an independent predictor for biochemical recurrence of prostate cancer after radical prostatectomy. Determining PSAD could potentially improve the prediction of biochemical recurrence in patients with prostate cancer.

Association Between Pretreatment Blood 25-Hydroxyvitamin D Level and Survival Outcomes in Patients With Clinically Localized Prostate Cancer: An Updated Meta-Analysis.

Studies on the prognostic value of the blood 25-hydroxyvitamin D level have yielded controversial results in prostate cancer (PCa) patients. This updated meta-analysis aimed to evaluate the association between pretreatment 25-hydroxyvitamin D level with survival outcomes among patients with clinically localized PCa. PubMed, Web of Science, and Embase databases were searched to identify studies evaluating the association of pretreatment 25-hydroxyvitamin D level with PCSM and all-cause mortality among clinically localized PCa patients. Ten cohort studies with 10,394 patients were identified. The meta-analysis revealed that PCa patients with the lowest 25-hydroxyvitamin D levels had an increased risk of PCSM (adjusted hazard ratio [HR] 1.52; 95% confidence interval [CI] 1.26-1.83; p < 0.001) and all-cause mortality (adjusted HR 1.31; 95% CI 1.00-1.90; p = 0.047) compared to those with higher reference 25-hydroxyvitamin D level. Subgroup analyses based on different sample sizes, follow-up duration, and adjusted times of blood draw also exhibited a significant association of vitamin D deficiency with the risk of PCSM. Lower pretreatment level of 25-hydroxyvitamin D may be an independent predictor of reduced survival in patients with clinically localized PCa. Measuring the pretreatment blood 25-hydroxyvitamin D level can provide valuable information for risk stratification of survival outcomes in these patients.

Signal enhancement ratio of multi-phase contrast-enhanced MRI: an imaging biomarker for survival in pancreatic adenocarcinoma.

OBJECTIVES: To evaluate signal enhancement ratio (SER) for tissue characterization and prognosis stratification in pancreatic adenocarcinoma (PDAC), with quantitative histopathological analysis (QHA) as the reference standard. METHODS: This retrospective study included 277 PDAC patients who underwent multi-phase contrast-enhanced (CE) MRI and whole-slide imaging (WSI) from three centers (2015-2021). SER is defined as (SIlt - SIpre)/(SIea - SIpre), where SIpre, SIea, and SIlt represent the signal intensity of the tumor in pre-contrast, early-, and late post-contrast images, respectively. Deep-learning algorithms were implemented to quantify the stroma, epithelium, and lumen of PDAC on WSIs. Correlation, regression, and Bland-Altman analyses were utilized to investigate the associations between SER and QHA. The prognostic significance of SER on overall survival (OS) was evaluated using Cox regression analysis and Kaplan-Meier curves. RESULTS: The internal dataset comprised 159 patients, which was further divided into training, validation, and internal test datasets (n = 60, 41, and 58, respectively). Sixty-five and 53 patients were included in two external test datasets. Excluding lumen, SER demonstrated significant correlations with stroma (r = 0.29-0.74, all p < 0.001) and epithelium (r = -0.23 to -0.71, all p < 0.001) across a wide post-injection time window (range, 25-300 s). Bland-Altman analysis revealed a small bias between SER and QHA for quantifying stroma/epithelium in individual training, validation (all within ± 2%), and three test datasets (all within ± 4%). Moreover, SER-predicted low stromal proportion was independently associated with worse OS (HR = 1.84 (1.17-2.91), p = 0.009) in training and validation datasets, which remained significant across three combined test datasets (HR = 1.73 (1.25-2.41), p = 0.001). CONCLUSION: SER of multi-phase CE-MRI allows for tissue characterization and prognosis stratification in PDAC. CLINICAL RELEVANCE STATEMENT: The signal enhancement ratio of multi-phase CE-MRI can serve as a novel imaging biomarker for characterizing tissue composition and holds the potential for improving patient stratification and therapy in PDAC. KEY POINTS: Imaging biomarkers are needed to better characterize tumor tissue in pancreatic adenocarcinoma. Signal enhancement ratio (SER)-predicted stromal/epithelial proportion showed good agreement with histopathology measurements across three distinct centers. Signal enhancement ratio (SER)-predicted stromal proportion was demonstrated to be an independent prognostic factor for OS in PDAC.

Cultivated alien plants with high invasion potential are more likely to be traded online in China.

Biological invasions have become a worldwide problem, and measures to efficiently prevent and control invasions are still in development. Like many other parts of the world, China is undergoing a dramatic increase in plant invasions. Most of the currently 933 established (i.e., naturalized) plant species, of which 214 are categorized as invasive, have been introduced into China for cultivation. It is likely that many of those species are still being traded, particularly online, by plant nurseries. However, studies assessing whether naturalized and invasive species are currently being traded more or less than nonnaturalized aliens are rare. We extracted online-trade information for 13,718 cultivated alien plant taxa on 1688.com, the largest website for domestic B2B in China. We analyzed how the presence in online-nursery catalogs, the number of online nurseries that offerred the species for sale, and the product type (i.e., seeds, live plants and vegetative organs) differed among nonnaturalized, naturalized noninvasive, and invasive species. Compared to nonnaturalized taxa, naturalized noninvasive and invasive taxa were 3.7-5.2 times more likely to be available for purchase. Naturalized noninvasive and invasive taxa were more frequently offered as seeds by online nurseries, whereas nonnaturalized taxa were more frequently offered as live plants. Based on these findings, we propose that, to reduce the further spread of invasive and potentially invasive plants, implementation of plant-trade regulations and a monitoring system of the online horticultural supply chain will be essential.

Advanced Glycation End Products (AGEs) Inhibit Macrophage Efferocytosis of Apoptotic ß Cells through Binding to the Receptor for AGEs.

Pancreatic ß cell apoptosis is important in the pathogenesis of type 2 diabetes mellitus (T2DM). Generally, apoptotic ß cells are phagocytosed by macrophages in a process known as "efferocytosis." Efferocytosis is critical to the resolution of inflammation and is impaired in T2DM. Advanced glycation end products (AGEs), which are increased in T2DM, are known to suppress phagocytosis function in macrophages. In this study, we found that AGEs inhibited efferocytosis of apoptotic ß cells by primary peritoneal macrophages in C57BL/6J mice or mouse macrophage cell line Raw264.7. Mechanistically, AGEs inhibit efferocytosis by blocking Ras-related C3 botulinum toxin substrate 1 activity and cytoskeletal rearrangement through receptor for advanced glycation end products/ras homolog family member A/Rho kinase signaling in macrophages. Furthermore, it was observed that AGEs decreased the secretion of anti-inflammatory factors and promoted the proinflammatory ones to modulate the inflammation function of efferocytosis. Taken together, our results indicate that AGEs inhibit efferocytosis through binding to receptor for advanced glycation end products and activating ras homolog family member A/Rho kinase signaling, thereby inhibiting the anti-inflammatory function of efferocytosis.

Repurposing ibudilast to mitigate Alzheimer's disease by targeting inflammation.

Alzheimer's disease is a multifactorial disease that exhibits cognitive deficits, neuronal loss, amyloid plaques, neurofibrillary tangles and neuroinflammation in the brain. Hence, a multi-target drug would improve treatment efficacy. We applied a new multi-scale predictive modelling framework that integrates machine learning with biophysics and systems pharmacology to screen drugs for Alzheimer's disease using patients' tissue samples. Our predictive modelling framework identified ibudilast as a drug with repurposing potential to treat Alzheimer's disease. Ibudilast is a multi-target drug, as it is a phosphodiesterase inhibitor and toll-like receptor 4 (TLR4) antagonist. In addition, we predict that ibudilast inhibits off-target kinases (e.g. IRAK1 and GSG2). In Japan and other Asian countries, ibudilast is approved for treating asthma and stroke due to its anti-inflammatory potential. Based on these previous studies and on our predictions, we tested for the first time the efficacy of ibudilast in Fisher transgenic 344-AD rats. This transgenic rat model is unique as it exhibits hippocampal-dependent spatial learning and memory deficits and Alzheimer's disease pathology, including hippocampal amyloid plaques, tau paired-helical filaments, neuronal loss and microgliosis, in a progressive age-dependent manner that mimics the pathology observed in Alzheimer's disease patients. Following long-term treatment with ibudilast, transgenic rats were evaluated at 11 months of age for spatial memory performance and Alzheimer's disease pathology. We demonstrate that ibudilast-treatment of transgenic rats mitigated hippocampal-dependent spatial memory deficits, as well as hippocampal (hilar subregion) amyloid plaque and tau paired-helical filament load, and microgliosis compared to untreated transgenic rat. Neuronal density analysed across all hippocampal regions was similar in ibudilast-treated transgenic compared to untreated transgenic rats. Interestingly, RNA sequencing analysis of hippocampal tissue showed that ibudilast-treatment affects gene expression levels of the TLR and ubiquitin-proteasome pathways differentially in male and female transgenic rats. Based on the TLR4 signalling pathway, our RNA sequencing data suggest that ibudilast-treatment inhibits IRAK1 activity by increasing expression of its negative regulator IRAK3, and/or by altering TRAF6 and other TLR-related ubiquitin ligase and conjugase levels. Our results support that ibudilast can serve as a repurposed drug that targets multiple pathways including TLR signalling and the ubiquitin/proteasome pathway to reduce cognitive deficits and pathology relevant to Alzheimer's disease.

Recent advances in small molecule Nav 1.7 inhibitors for cancer pain management.

The dorsal root ganglion (DRG) is the primary neuron responsible for transmitting peripheral pain signals to the central nervous system and plays a crucial role in pain transduction. Modulation of DRG excitability is considered a viable approach for pain management. Neuronal excitability is intricately linked to the ion channels on the neurons. The small and medium-sized DRG neurons are chiefly engaged in pain conduction and have high levels of TTX-S sodium channels, with Nav1.7 accounting for approximately 80% of the current. Voltage-gated sodium channel (VGSC or Nav) blockers are vital targets for the management of central nervous system diseases, particularly chronic pain. VGSCs play a key role in controlling cellular excitability. Clinical research has shown that Nav1.7 plays a crucial role in pain sensation, and there is strong genetic evidence linking Nav1.7 and its encoding gene SCN9A gene to painful disorders in humans. Many studies have shown that Nav1.7 plays an important role in pain management. The role of Nav1.7 in pain signaling pathways makes it an attractive target for the potential development of new pain drugs. Meanwhile, understanding the architecture of Nav1.7 may help to develop the next generation of painkillers. This review provides updates on the recently reported molecular inhibitors targeting the Nav1.7 pathway, summarizes their structure-activity relationships (SARs), and discusses their therapeutic effects on painful diseases. Pharmaceutical chemists are working to improve the therapeutic index of Nav1.7 inhibitors, achieve better analgesic effects, and reduce side effects. We hope that this review will contribute to the development of novel Nav1.7 inhibitors as potential drugs.

Baseline functioning scales of EORTC QLQ-C30 predict overall survival in patients with gastrointestinal cancer: a meta-analysis.

PURPOSE: A consensus has not been reached on the value of quality of life (QoL) as a prognostic factor for survival in gastrointestinal cancer. This meta-analysis aimed to investigate the association between functioning scales of the EORTC QoL Questionnaire Core 30 (QLQ-C30) and the overall survival (OS) in patients with gastrointestinal cancer. METHODS: A systematic literature search was conducted in PubMed, Web of Science, and Embase databases, until February 7, 2023. The studies included were those that investigated the association between baseline QoL measured by the functioning scales of EORTC QLQ-C30 and OS in patients with gastrointestinal cancer. The prognostic capacity of QoL was calculated by pooling the adjusted hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Twenty-four studies' analyses reported by 22 eligible articles involving 11,609 patients were included. When compared with good parameters of QoL, poor global QoL (HR 1.81; 95% CI 1.53-2.13), physical functioning (HR 1.51; 95% CI 1.31-1.74), social functioning (HR 1.67; 95% CI 1.30-2.15), and role functioning scale (HR 1.42; 95% CI 1.20-1.29) were significantly associated with decreased OS. For each 10-point increase in QLQ-C30 parameters, the pooled HR of OS was 0.87 (95% CI 0.83-0.92) for global QoL, 0.87 (95% CI 0.83-0.92) for physical functioning, and 0.93 (95% CI 0.88-0.97) for role functioning. However, each 10-point increase in social, emotional, or cognitive functioning scale did not significantly predict OS. CONCLUSIONS: Baseline health-related QoL defined by the physical functioning or global QoL scale of EORTC QLQ-C30 significantly predicts OS in patients with gastrointestinal cancer.