The Voltage-Gated Calcium Channel α2δ Subunit in Neuropathic Pain.

Neuropathic pain (NP) is a chronic pain caused by injury or disease of the somatosensory nervous system, or it can be directly caused by disease. It often presents with clinical features like spontaneous pain, hyperalgesia, and dysesthesia. At present, voltage-gated calcium ion channels (VGCCs) are known to be closely related to the development of NP, especially the α2δ subunit. The α2δ subunit is a regulatory subunit of VGCCs. It exists mainly in the brain and peripheral nervous system, especially in nerve cells, and it plays a crucial part in regulating presynaptic and postsynaptic functions. Furthermore, the α2δ subunit influences neuronal excitation and pain signaling by promoting its expression and localization through binding to VGCC-related subunits. The α2δ subunit is widely used in the management of NP as a target of antiepileptic drugs gabapentin and pregabalin. Although drug therapy is one of the treatments for NP, its clinical application is limited due to the adverse reactions caused by drug therapy. Therefore, further research on the therapeutic target α2δ subunit is needed, and attempts are made to obtain an effective treatment for relieving NP without side effects. This review describes the current associated knowledge on the function of the α2δ subunit in perceiving and modulating NP.

Selective PI3Kδ inhibitor TYM-3-98 suppresses AKT/mTOR/SREBP1-mediated lipogenesis and promotes ferroptosis in KRAS-mutant colorectal cancer.

Colorectal cancer (CRC) is one of the most common tumors of the digestive system worldwide. KRAS mutations limit the use of anti-EGFR antibodies in combination with chemotherapy for the treatment of CRC. Therefore, novel targeted therapies are needed to overcome the KRAS-induced oncogenesis. Recent evidence suggests that inhibition of PI3K led to ferroptosis, a nonapoptotic cell death closely related to KRAS-mutant cells. Here, we showed that a selective PI3Kδ inhibitor TYM-3-98 can suppress the AKT/mTOR signaling and activate the ferroptosis pathway in KRAS-mutant CRC cells in a concentration-dependent manner. This was evidenced by the lipid peroxidation, iron accumulation, and depletion of GSH. Moreover, the overexpression of the sterol regulatory element-binding protein 1 (SREBP1), a downstream transcription factor regulating lipid metabolism, conferred CRC cells greater resistance to ferroptosis induced by TYM-3-98. In addition, the effect of TYM-3-98 was confirmed in a xenograft mouse model, which demonstrated significant tumor suppression without obvious hepatoxicity or renal toxicity. Taken together, our work demonstrated that the induction of ferroptosis contributed to the PI3Kδ inhibitor-induced cell death via the suppression of AKT/mTOR/SREBP1-mediated lipogenesis, thus displaying a promising therapeutic effect of TYM-3-98 in CRC treatment.

Developing agricultural pest management strategies with reduced-risks to surface water: An economic case study of California's Central Coast region.

Pesticides are critical for protecting agricultural crops, but the off-site transport of these materials via spray drift and runoff poses risks to surface waters and aquatic life. California's Central Coast region is a major agricultural hub in the United States characterized by year-round production and intensive use of pesticides and other chemical inputs. As a result, the quality of many waterbodies in the region has been degraded. A recent regulatory program enacted by the Central Coast Regional Water Quality Control Board set new pesticide limits for waterways and imposed enhanced enforcement mechanisms to help ensure that water quality targets are met by specific dates. This regulatory program, however, does not mandate specific changes to pest management programs. In this study, we evaluate the economic, environmental, and pest management impacts of adopting two alternative pest management programs with reduced risks to surface water: 1) replacing currently used insecticide active ingredients (AIs) that pose the greatest risk to surface water with lower-risk alternatives and 2) converting conventional arthropod pest management programs to organic ones. We utilize pesticide use and toxicity data from California's Department of Pesticide Regulation to develop our baseline and two alternative scenarios. We focus on three crop groups (cole crops, lettuce and strawberry) due to their economic importance to the Central Coast and use of high-risk AIs. For Scenario 1, we estimate that implementing the alternative program in the years 2017-2019 would have reduced annual net returns on average by $90.26 - $190.54/ha, depending on the crop. Increased material costs accounted for the greatest share of this effect (71.9%-95.6%). In contrast, Scenario 2 would have reduced annual net returns on average by $5,628.12 - $18,708.28/ha during the study period, with yield loss accounting for the greatest share (92.8-97.9%). Both alternative programs would have reduced the associated toxic units by at least 98.1% compared to the baseline scenario. Our analysis provides important guidance for policymakers and agricultural producers looking to achieve environmental protection goals while minimizing economic impacts.

Role of Exercise on Inflammation Cytokines of Neuropathic Pain in Animal Models.

Neuropathic pain (NP) resulting from a lesion or disease of the somatosensory system can lead to loss of function and reduced life quality. Neuroinflammation plays a vital role in the development and maintenance of NP. Exercise as an economical, effective, and nonpharmacological treatment, recommended by clinical practice guidelines, has been proven to alleviate chronic NP. Previous studies have shown that exercise decreases NP by modifying inflammation; however, the exact mechanisms of exercise-mediated NP are unclear. Therefore, from the perspective of neuroinflammation, this review mainly discussed the effects of exercise on inflammatory cytokines in different parts of NP conduction pathways, such as the brain, spinal cord, dorsal root ganglion, sciatic nerve, and blood in rat/mice models. Results suggested that exercise training could modulate neuroinflammation, inhibit astrocyte glial cell proliferation and microglial activation, alter the macrophage phenotype, reduce the expression of proinflammatory cytokines, increase anti-inflammatory cytokine levels, and positively modulate the state of the immune system, thereby relieving NP.

Conservative Interventions for Urinary Incontinence on Postpartum Women: A Systematic Review and Meta-Analysis.

INTRODUCTION: Urinary incontinence (UI) is common in postpartum women and can lead to a reduced quality of life and withdrawal from fitness and exercise activities. Conservative management interventions such as pelvic floor muscle training (PFMT), use of vaginal cones, and biofeedback have been recommended as first-line treatment. We aimed to explore the effects of conservative interventions on UI rate, severity, and incontinence-specific quality of life in postpartum women with UI. METHODS: Nine databases were searched from inception to August 2022: PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, CINAHL, Wanfang, China National Knowledge Infrastructure, China Biological Medicine, and VIP Journal Integration Platform. Randomized controlled trials examining the effects of conservative interventions on postpartum UI were included. RESULTS: Initial searches produced 1839 results, of which 17 studies were eligible. All included studies had a low to moderate risk of bias. Supervised PFMT and use of a vaginal cone were more effective than individual PFMT in decreasing rates of UI (odds ratio, 0.29; 95% CI, 0.14-0.61). Individual PFMT combined with acupuncture (mean difference, -1.91; 95% CI, -2.46 to -1.37) or electroacupuncture and supervised PFMT combined with moxibustion were more effective than individual supervised PFMT alone in improving the severity of symptoms. Furthermore, electrical stimulation and biofeedback combined with acupoint stimulation or core training were more effective than electrical stimulation and biofeedback alone. For improving the incontinence-specific quality of life, supervised PFMT was more efficacious than individual PFMT; electrical stimulation and biofeedback plus core training were more beneficial than electrical stimulation and biofeedback alone. DISCUSSION: Supervised PFMT and use of a vaginal cone were more beneficial in decreasing rates of UI compared with individual PFMT. Superior effects in decreasing UI severity may be achieved by combining PFMT or electrical simulation and biofeedback with other therapies. Electrical stimulation and biofeedback plus core training, as well as supervised PFMT, are most effective in improving incontinence-specific quality of life. Further research is required to provide more evidence on the efficacy of these therapies.

TYM-3-98, a novel selective inhibitor of PI3Kδ, demonstrates promising preclinical antitumor activity in B-cell lymphomas.

AIMS: PI3Kδ is expressed predominately in leukocytes and is commonly found to be aberrantly activated in human B-cell lymphomas. Although PI3Kδ has been intensively targeted for discovering anti-lymphoma drugs, the application of currently approved PI3Kδ inhibitors has been limited due to unwanted systemic toxicities, thus warranting the development of novel PI3Kδ inhibitors with new scaffolds. MAIN METHODS: We designed TYM-3-98, an indazole derivative, and evaluated its selectivity for all four PI3K isoforms, as well as its efficacy against various B-cell lymphomas both in vitro and in vivo. KEY FINDINGS: We identified TYM-3-98 as a highly selective PI3Kδ inhibitor over other PI3K isoforms at both molecular and cellular levels. It showed superior antiproliferative activity in several B-lymphoma cell lines compared with the approved first-generation PI3Kδ inhibitor idelalisib. TYM-3-98 demonstrated a concentration-dependent PI3K/AKT/mTOR signaling blockage followed by apoptosis induction. In vivo, TYM-3-98 showed good pharmaceutical properties and remarkably reduced tumor growth in a human lymphoma xenograft model and a mouse lymphoma model. SIGNIFICANCE: Our findings establish TYM-3-98 as a promising PI3Kδ inhibitor for the treatment of B-cell lymphoma.

Population Pharmacokinetic Modeling and Exposure-Efficacy and Body Weight-Response Analyses for Tezepelumab in Patients With Severe, Uncontrolled Asthma.

Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. This analysis assessed the suitability of a fixed-dose regimen of tezepelumab 210 mg every 4 weeks (Q4W) in adults and adolescents with severe, uncontrolled asthma. A population pharmacokinetic model was developed using data from 1368 patients with asthma or healthy participants enrolled in 8 clinical studies (phases 1-3). Tezepelumab exposure-efficacy relationships were analyzed in the phase 3 NAVIGATOR study (NCT03347279), using asthma exacerbation rates over 52 weeks and changes in pre-bronchodilator forced expiratory volume in 1 s at week 52. Tezepelumab pharmacokinetics were well characterized by a 2-compartment linear disposition model with first-order absorption and elimination following subcutaneous and intravenous administration at 2.1-420 and 210-700 mg, respectively. There were no clinically relevant effects on tezepelumab pharmacokinetics from age (≥12 years), sex, race/ethnicity, renal or hepatic function, disease severity (inhaled corticosteroid dose level), concomitant asthma medication use, smoking history, or anti-drug antibodies. Body weight was the most influential covariate on tezepelumab exposure, but no meaningful differences in efficacy or safety were observed across body weight quartiles in patients with asthma who received tezepelumab 210 mg subcutaneously Q4W. There was no apparent relationship between tezepelumab exposure and efficacy at this dose regimen, suggesting that it is on the plateau of the exposure-response curve of tezepelumab. In conclusion, a fixed-dose regimen of tezepelumab 210 mg subcutaneously Q4W is appropriate for eligible adults and adolescents with severe, uncontrolled asthma.

Discovery of Potent and Selective PI3Kδ Inhibitors for the Treatment of Acute Myeloid Leukemia.

PI3Kδ is an essential target correlated to the occurrence and development of acute myeloid leukemia (AML). Herein, we investigated the pyrazolo[3,4-d]pyrimidine derivatives as potent and selective PI3Kδ inhibitors with high therapeutic efficacy toward AML. There were 44 compounds designed and prepared in a four-round optimization, and the biological evaluation showed that (S)-36 exhibited potent PI3Kδ inhibitory activity, high selectivity, and high antiproliferative activities against MV-4-11 and MOLM-13 cells, coupled with high oral bioavailability (F = 59.6%). In the MOLM-13 subcutaneous xenograft model, (S)-36 could significantly suppress the tumor progression with a TGI of 67.81% at an oral administration dosage of 10 mg/kg without exhibiting obvious toxicity. Mechanistically, (S)-36 could robustly inhibit the PI3K/AKT pathway for significant suppression of cell proliferation and remarkable induction of apoptosis both in vitro and in vivo. Thus, compound (S)-36 represents a promising PI3Kδ inhibitor for the treatment of acute myeloid leukemia with high efficacy.

AIM2 regulates autophagy to mitigate oxidative stress in aged mice with acute liver injury.

The cytoplasmic pattern recognition receptor, absent in melanoma 2 (AIM2), detects cytosolic DNA, activating the inflammasome and resulting in pro-inflammatory cytokine production and pyroptotic cell death. Recent research has illuminated AIM2's contributions to PANoptosis and host defense. However, the role of AIM2 in acetaminophen (APAP)-induced hepatoxicity remains enigmatic. In this study, we unveil AIM2's novel function as a negative regulator in the pathogenesis of APAP-induced liver damage in aged mice, independently of inflammasome activation. AIM2-deficient aged mice exhibited heightened lipid accumulation and hepatic triglycerides in comparison to their wild-type counterparts. Strikingly, AIM2 knockout mice subjected to APAP overdose demonstrated intensified liver injury, compromised mitochondrial stability, exacerbated glutathione depletion, diminished autophagy, and elevated levels of phosphorylated c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). Furthermore, our investigation revealed AIM2's mitochondrial localization; its overexpression in mouse hepatocytes amplified autophagy while dampening JNK phosphorylation. Notably, induction of autophagy through rapamycin administration mitigated serum alanine aminotransferase levels and reduced the necrotic liver area in AIM2-deficient aged mice following APAP overdose. Mechanistically, AIM2 deficiency exacerbated APAP-induced acute liver damage and inflammation in aged mice by intensifying oxidative stress and augmenting the phosphorylation of JNK and ERK. Given its regulatory role in autophagy and lipid peroxidation, AIM2 emerges as a promising therapeutic target for age-related acute liver damage treatment.

Integrative analysis identifies oxidative stress biomarkers in non-alcoholic fatty liver disease via machine learning and weighted gene co-expression network analysis.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally, with the potential to progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and even hepatocellular carcinoma. Given the absence of effective treatments to halt its progression, novel molecular approaches to the NAFLD diagnosis and treatment are of paramount importance. Methods: Firstly, we downloaded oxidative stress-related genes from the GeneCards database and retrieved NAFLD-related datasets from the GEO database. Using the Limma R package and WGCNA, we identified differentially expressed genes closely associated with NAFLD. In our study, we identified 31 intersection genes by analyzing the intersection among oxidative stress-related genes, NAFLD-related genes, and genes closely associated with NAFLD as identified through Weighted Gene Co-expression Network Analysis (WGCNA). In a study of 31 intersection genes between NAFLD and Oxidative Stress (OS), we identified three hub genes using three machine learning algorithms: Least Absolute Shrinkage and Selection Operator (LASSO) regression, Support Vector Machine - Recursive Feature Elimination (SVM-RFE), and RandomForest. Subsequently, a nomogram was utilized to predict the incidence of NAFLD. The CIBERSORT algorithm was employed for immune infiltration analysis, single sample Gene Set Enrichment Analysis (ssGSEA) for functional enrichment analysis, and Protein-Protein Interaction (PPI) networks to explore the relationships between the three hub genes and other intersecting genes of NAFLD and OS. The distribution of these three hub genes across six cell clusters was determined using single-cell RNA sequencing. Finally, utilizing relevant data from the Attie Lab Diabetes Database, and liver tissues from NASH mouse model, Western Blot (WB) and Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) assays were conducted, this further validated the significant roles of CDKN1B and TFAM in NAFLD. Results: In the course of this research, we identified 31 genes with a strong association with oxidative stress in NAFLD. Subsequent machine learning analysis and external validation pinpointed two genes: CDKN1B and TFAM, as demonstrating the closest correlation to oxidative stress in NAFLD. Conclusion: This investigation found two hub genes that hold potential as novel targets for the diagnosis and treatment of NAFLD, thereby offering innovative perspectives for its clinical management.

Safety of teropavimab and zinlirvimab with lenacapavir once every 6 months for HIV treatment: a phase 1b, randomised, proof-of-concept study.

BACKGROUND: Long-acting treatment for HIV has potential to improve adherence, provide durable viral suppression, and have long-term individual and public health benefits. We evaluated treatment with two antibodies that broadly and potently neutralise HIV (broadly neutralising antibodies; bNAbs), combined with lenacapavir, a long-acting capsid inhibitor, as a long-acting regimen. METHODS: This ongoing, randomised, blind, phase 1b proof-of-concept study conducted at 11 HIV treatment centres in the USA included adults with a plasma HIV-1 RNA concentration below 50 copies per mL who had at least 18 months on oral antiretroviral therapy (ART), CD4 counts of at least 500 cells per µL, and protocol-defined susceptibility to bNAbs teropavimab (3BNC117-LS) and zinlirvimab (10-1074-LS). Participants stopped oral ART and were randomly assigned (1:1) to one dose of 927 mg subcutaneous lenacapavir plus an oral loading dose, 30 mg/kg intravenous teropavimab, and 10 mg/kg or 30 mg/kg intravenous zinlirvimab on day 1. Investigational site personnel and participants were masked to treatment assignment throughout the randomised period. The primary endpoint was incidence of serious adverse events until week 26 in all randomly assigned participants who received one dose or more of any study drug. This study is registered with ClinicalTrials.gov, NCT04811040. FINDINGS: Between June 29 and Dec 8, 2021, 21 participants were randomly assigned, ten in each group received the complete study regimen and one withdrew before completing the regimen on day 1. 18 (86%) of 21 participants were male; participants ranged in age from 25 years to 61 years and had a median CD4 cell count of 909 (IQR 687-1270) cells per µL at study entry. No serious adverse events occurred. Two grade 3 adverse events occurred (lenacapavir injection-site erythaema and injection-site cellulitis), which had both resolved. The most common adverse events were symptoms of injection-site reactions, reported in 17 (85%) of 20 participants who received subcutaneous lenacapavir; 12 (60%) of 20 were grade 1. One (10%; 95% CI 0-45) participant had viral rebound (confirmed HIV-1 RNA concentration of ≥50 copies per mL) in the zinlirvimab 10 mg/kg group, which was resuppressed on ART, and one participant in the zinlirvimab 30 mg/kg group withdrew at week 12 with HIV RNA <50 copies per mL. INTERPRETATION: Lenacapavir with teropavimab and zinlirvimab 10 mg/kg or 30 mg/kg was generally well tolerated with no serious adverse events. HIV-1 suppression for at least 26 weeks is feasible with this regimen at either zinlirvimab dose in selected people with HIV-1. FUNDING: Gilead Sciences.

Inocellia (Amurinocellia) calida (Raphidioptera, Inocelliidae) was first observed as a predator of Monochamussaltuarius (Coleoptera, Cerambycidae) in China, the vector of Bursaphelenchusxylophilus (Aphelenchida, Aphelenchoididae).

Monochamussaltuarius Gebler (Coleoptera, Cerambycidae) serves as the primary carrier of Bursaphelenchusxylophilus (Steiner & Buhrer) (Aphelenchida, Aphelenchoididae) in the middle-temperate zone of China. Pine wilt disease caused by B.xylophilus leads to serious losses to pine forestry around the world. It is necessary to study the biological control of M.saltuarius to effectively prevent the further spread of B.xylophilus. To explore the insect resources that act as natural enemies of M.saltuarius, investigations were conducted on natural enemy insects by splitting Pinuskoraiensis Siebold & Zucc (Pinales, Pinaceae) damaged by M.saltuarius and dissecting their trunks in Yingpan Village, Fushun County, Fushun City, Liaoning Province, China, in 2023. A larva of Inocellia (Amurinocellia) calida (H. Aspöck & U. Aspöck) (Raphidioptera, Inocelliidae) was discovered in the trunk of an infested P.koraiensis. Additionally, the feeding habits of I.calida were preliminarily examined under indoor conditions and a description of its morphological characteristics was provided. When placed in an indoor environment, the I.calida larva began pupating after a period of 21 days, during which time it consumed and attacked a total of 23 M.saltuarius larvae. Ultimately, after a pupal period of ten days, the I.calida larva emerged successfully as an adult. This discovery marks the first recorded presence of I.calida in Liaoning Province and the first documentation of I.calida in China, serving as a natural predatory enemy of M.saltuarius.

Distinguished biomimetic dECM system facilitates early detection of metastatic breast cancer cells.

Breast cancer is the most prevalent malignant tumor affecting women's health. Bone is the most common distant metastatic organ, worsening the quality of life and increasing the mortality of patients. Early detection of breast cancer bone metastasis is urgent for halting disease progression and improving tumor prognosis. Recently, extracellular matrix (ECM) with biomimetic tissue niches opened a new avenue for tumor models in vitro. Here, we developed a biomimetic decellularized ECM (dECM) system to recapitulate bone niches at different situations, bone mimetic dECM from osteoblasts (BM-ECM) and bone tumor mimetic dECM from osteosarcoma cells (OS-ECM). The two kinds of dECMs exhibited distinct morphology, protein composition, and distribution. Interestingly, highly metastatic breast cancer cells tended to adhere and migrate on BM-ECM, while lowly metastatic breast cancer cells preferred the OS-ECM niche. Epithelial-to-mesenchymal transition was a potential mechanism to initiate the breast cancer cell migration on different biomimetic dECMs. Importantly, in the nude mice model, the dECM system captured metastatic breast cancer cells as early as 10 days after orthotopic transplantation in mammary gland pads, with higher signal on BM-ECM than that on OS-ECM. Collectively, the biomimetic dECM system might be a promising tumor model to distinguish the metastatic ability of breast cancer cells in vitro and to facilitate early detection of metastatic breast cancer cells in vivo, contributing to the diagnosis of breast cancer bone metastasis.

CoFe Alloys Dispersed on Se, N Co-Doped Graphitic Carbon as Efficient Bifunctional Catalysts for Zn-Air Batteries.

The development of a stable and efficient non-noble metal catalyst with both oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) is paramount to achieving the widespread application of Zn-air batteries (ZABs) but remains a great challenge. Herein, a novel Co3 Fe7 alloy nanoparticle dispersed on Se, N co-doped graphitic carbon (denoted as CoFe/Se@CN) was prepared through a facile hydrothermal and pyrolysis process. The synthesized CoFe/Se@CN exhibits outstanding ORR and OER properties with an ultralow potential gap of 0.625 V, which is mainly attributed to the abundant porous structure, the rich structural defects formed by doping Se atoms, and the strong synergistic effects between the CoFe alloys and graphitic carbon nanosheet. Furthermore, the ZAB fabricated by CoFe/Se@CN shows a high peak power density of 160 mW cm-2 and a large specific capacity of 802 mA h g-1 with favorable cycling stability, outperforming that of Pt/C+RuO2 . Our study offers a plausible strategy to explore bifunctional carbon-based materials with efficient electrocatalytic properties for rechargeable ZABs.

Sn Bulk Phase Doping and Surface Modification on Ti4 O7 for Oxygen Reduction to Hydrogen Peroxide.

Developing stable and highly selective two-electron oxygen reduction reaction (2e- ORR) electrocatalysts for producing hydrogen peroxide (H2 O2 ) is considered a major challenge to replace the anthraquinone process and achieve a sustainable green economy. Here, we doped Sn into Ti4 O7 (D-Sn-Ti4 O7 ) by simple polymerization post-calcination method as a high-efficiency 2e- ORR electrocatalyst. In addition, we also applied plain calcination after the grinding method to load Sn on Ti4 O7 (L-Sn-Ti4 O7 ) as a comparison. However, the performance of L-Sn-Ti4 O7 is far inferior to that of the D-Sn-Ti4 O7 . D-Sn-Ti4 O7 exhibits a starting potential of 0.769 V (versus the reversible hydrogen electrode, RHE) and a high H2 O2 selectivity of 95.7 %. Excitingly, the catalyst can maintain a stable current density of 2.43 mA ⋅ cm-2 for 3600 s in our self-made H-type cell, and the cumulative H2 O2 production reaches 359.2 mg ⋅ L-1 within 50,000 s at 0.3 V. The performance of D-Sn-Ti4 O7 is better than that of the non-noble metal 2e- ORR catalysts reported so far. The doping of Sn not only improves the conductivity but also leads to the lattice distortion of Ti4 O7 , further forming more oxygen vacancies and Ti3+ , which greatly improves its 2e- ORR performance compared with the original Ti4 O7 . In contrast, since the Sn on the surface of L-Sn-Ti4 O7 displays a synergistic effect with Tin+ (3≤n≤4) of Ti4 O7 , the active center Tin+ dissociates the O=O bond, making it more inclined to 4e- ORR.

Association of persistent musculoskeletal pain with dementia risk score in adults aged 45 years or older: The China health and retirement longitudinal study.

BACKGROUND: Recent studies have confirmed an association between pain and dementia. Whether musculoskeletal pain in the spine, upper limbs, and lower limbs is associated with dementia risk remains unclear. The longitudinal effect of musculoskeletal pain on dementia risk also remains unclear. AIMS: This work aimed to investigate the association between musculoskeletal pain and dementia risk score. METHODS: We conducted cross-sectional and longitudinal analyses using data from the China Health and Retirement Longitudinal Study. Participants aged 45 years or older were recruited in 2011. A total of 10,759 participants with complete pain information at baseline were eligible for the cross-sectional analysis, and 5,855 were eligible for the longitudinal analyses. We utilized the Rotterdam Study Basic Dementia Risk Model (BDRM) to assess dementia risk. Generalized estimating equations were used to investigate the associations. RESULTS: Compared with participants without persistent musculoskeletal pain, those with persistent musculoskeletal pain (standardized, ß = 0.83; 95 % CI: 0.06, 1.61, p = 0.036), multisite pain (sites≧5; ß = 1.52; 95 % CI: 0.13, 2.91, p = 0.032), neck pain (ß = 2.33; 95 % CI: 0.41, 4.25, p = 0.018), back pain (ß = 2.12; 95 % CI: 0.43, 3.82, p = 0.014), waist pain (ß = 1.09; 95 % CI: 0.07, 2.11, p = 0.037), shoulder pain (ß = 1.74; 95 % CI: 0.46, 3.02, p = 0.008), wrist pain (ß = 2.72; 95 % CI: 0.42, 5.02, p = 0.021), and knee pain (ß = 1.91; 95 % CI: 0.70, 3.13, p = 0.002) had a higher BDRM score during 4 years of follow-up. CONCLUSIONS: Promoting the management of musculoskeletal pain may be beneficial in reducing the dementia risk score.

Aluminum-incorporation activates vanadium carbide with electron-rich carbon sites for efficient pH-universal hydrogen evolution reaction.

Vanadium carbide (VC) is the greatest potential hydrogen evolution reaction (HER) catalyst because of its platinum-like property and abundant earth reserves. However, it exhibits insufficient catalytic performance due to the unfavorable interaction of reaction intermediates with catalysts. In this work, using NH4VO3 as the main raw material, the flow ratio of CH4 to Ar was accurately controlled, and a non-transition metal Al-doped into VC (100) nano-flowers with carbon hybrids on nickel foams (Al-VC@C/NF) was prepared for the first time as a high-efficiency HER catalyst by chemical vapor carbonization. The overpotential of Al-VC@C/NF catalysts in 0.5 M H2SO4 and 1 M KOH at a current density of 10 mA cm-2 are only 58 mV and 97 mV, respectively, which are the best HER performance among non-noble metal vanadium carbide based catalysts. Simultaneously, Al-VC@C/NF exhibits small Tafel slope (45 mV dec-1 and 73 mV dec-1) and excellent stability in acidic and alkaline media. Theoretical calculations demonstrate that doped Al atoms can induce electron redistribution on the vanadium carbide surface to form electron-rich carbon sites, which significantly reduces the energy barrier during the HER process. This work provides a new tactic to modulate vanadium-based carbons as efficient HER catalysts through non-transition metal doping.

Oncological outcomes of conversion therapy in gastric cancer patients with peritoneal metastasis: a large-scale retrospective cohort study.

BACKGROUND: Data on the long-term oncological outcomes of patients who undergo conversion surgery (CS) in gastric cancer (GC) patients with peritoneal metastasis (PM) are limited. METHODS: GC patients with PM who received intraperitoneal (ip) and systemic chemotherapy between April 2015 and January 2021 were enrolled. Multivariate analysis was performed to identify risk factors associated with survival. Clinicopathological and survival outcomes were compared between those with CS and those without CS (NCS). The paclitaxel (PTX) plus tegafur-gimeracil-oteracil potassium capsules (S-1) (PS) + ip PTX and oxaliplatin plus S-1 (SOX) + ip PTX groups were matched in a 1:1 ratio using propensity score matching. Oncological and survival data were collected and analyzed. RESULTS: A total of 540 patients who received ip chemotherapy via subcutaneous port and systemic chemotherapy were analyzed and 268 patients were enrolled, including 113 who underwent CS and 155 who did not. Overall survival (OS) were 27.0 months and 11.8 months in the CS and NCS groups (P < 0.0001), respectively. R0 resection was an independent prognostic factor for patients who underwent CS. The OS of patients with or without ovariectomy was 21.3 or 12.0 months (P < 0.0001). No difference of clinicopathological and survival outcomes was found between the PS + ip PTX and SOX + ip PTX groups. CONCLUSION: Conversion therapy is safe and adverse events were manageable. CS improves the survival of GC patients with PM after ip and systemic chemotherapy. R0 is an important prognostic factor. Furthermore, outcomes are comparable between the PS + ip PTX and SOX + ip PTX groups.

Discovery of Highly Selective and Orally Bioavailable PI3Kδ Inhibitors with Anti-Inflammatory Activity for Treatment of Acute Lung Injury.

PI3Kδ is a promising target for the treatment of inflammatory disease; however, the application of PI3Kδ inhibitors in acute respiratory inflammatory diseases is rarely investigated. In this study, through scaffold hopping design, we report a new series of 1H-pyrazolo[3,4-d]pyrimidin-4-amine-tethered 3-methyl-1-aryl-1H-indazoles as highly selective and potent PI3Kδ inhibitors with significant anti-inflammatory activities for treatment of acute lung injury (ALI). There were 29 compounds designed, prepared, and subjected to PI3Kδ inhibitory activity evaluation and anti-inflammatory activity evaluation in macrophages. (S)-29 was identified as a candidate with high PI3Kδ inhibitory activity, isoform selectivity, and high oral bioavailability. The in vivo administration of (S)-29 at 10 mg/kg dosage could significantly ameliorate histopathological changes and attenuate lung inflammation in lung tissues of LPS-challenged mice. Molecular docking demonstrated the success of scaffold hopping design. Overall, (S)-29 is a potent PI3Kδ inhibitor which might be a promising candidate for the treatment of ALI.

Sintilimab combined neoadjuvant intraperitoneal and systemic chemotherapy in gastric cancer with peritoneal metastasis.

Intraperitoneal chemotherapy combined with systemic chemotherapy is one of the therapeutic modalities currently used for the treatment of gastric cancer patients with peritoneal metastasis. This study was designed to evaluate the efficacy and safety of sintilimab plus S-1 combined intraperitoneal and intravenous paclitaxel. This is an open-label, single-center, phase II study including 36 gastric adenocarcinoma patients with peritoneal metastases diagnosed by laparoscopy. All enrolled patients received sintilimab, intraperitoneal and intravenous paclitaxel plus oral S-1 every 3 weeks. Conversion operation should be considered when a patient responds to the regimen and the peritoneal metastasis disappears. After gastrectomy, the protocol treatment is repeated until disease progression, unacceptable toxicity, investigator decision or patient withdrawal. The primary end point is the 1-year survival rate. Clinical Trial Registration: NCT05204173 (ClinicalTrials.gov).