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Abstract This study evaluated the therapeutic efficacy and underlying mechanisms of crisaborole combined with vitamin D in the treatment of allergic contact dermatitis. While crisaborole, a phosphodiesterase 4 inhibitor, and vitamin D analogs are commonly used in the treatment of atopic dermatitis, their combined therapeutic potential in allergic contact dermatitis (ACD) remains unexplored. Given their anti-inflammatory properties, we hypothesized that the combination of crisaborole and vitamin D could offer superior efficacy in mitigating the symptoms and underlying mechanisms of allergic contact dermatitis. In vitro, HaCaT cells stimulated with tumor necrosis factor-α and interferon-γ were treated with a combination of crisaborole and vitamin D, followed by cytokine expression analysis. In vivo, male C57BL/6 mice were divided into five groups and treated accordingly: blank control, dinitrochlorobenzene-induced model, crisaborole alone, vitamin D alone, and a combination of crisaborole and vitamin D. On day 14, dorsal skin and ear thickness were measured, followed by comprehensive pathological evaluations. In vivo and in vitro experiments showed that the expression levels of inflammatory factors were significantly lower in the DNCB + VD + Cri group than in the DNCB group. Histological analyses revealed that, compared with the DNCB group, the combined treatment group significantly reduced epidermal hyperkeratosis, improved epidermal transdermal water loss, decreased dermatitis scores, and diminished mast cell infiltration. Moreover, it lowered the expression levels of IL-6, IL-4, TNF-α, iNOS, IL-17, CC chemokine ligand 2 (CCL2), and CC chemokine receptor 2 (CCR2). CCL2 recognizes CCR2 and stimulates inflammatory cells, enhancing the inflammatory response. Increased CCL2 expression correlates with heightened inflammation and dendritic cell infiltration in ACD, while downregulation of CCL2 attenuates inflammation. Thus, the combined use of crisaborole and vitamin D demonstrates superior therapeutic efficacy over monotherapy in a mouse model of ACD. The combination of vitamin D and crisaborole significantly reduces inflammation and epidermal hyperkeratosis in a mouse model of allergic contact dermatitis, demonstrating superior therapeutic efficacy compared to either treatment alone. This suggests that the combined therapy could be a promising approach for the prevention and treatment of allergic contact dermatitis.

Background: Heat shock proteins (HSPs) play a critical role in cellular stress responses and have been implicated in numerous diseases, including Parkinson's disease (PD) and various cancers. Understanding the differential expression and functional implications of HSPs in these conditions is crucial for identifying potential therapeutic targets and biomarkers for diagnosis and prognosis. Methods: We utilized combined datasets (GSE6613 and GSE72267) to identify and analyze the heat shock-related genes differentially expressed in PD. Gene Set Variation Analysis (GSVA) was performed to explore functional profiles, while LASSO regression was employed to screen potential PD biomarkers. In glioma, prognostic value, immune infiltration, and pathway enrichment associated with HSPA1L gene expression were assessed via Kaplan-Meier plots, ssGSEA, and enrichment analyses. Results: In PD, we identified 17 differentially expressed HSPs. Enrichment analysis revealed significant pathways related to protein homeostasis and cellular stress responses. LASSO regression pinpointed 12 genes, including HSPA1L, as significant markers for PD, with nomogram and calibration plots indicating predictive accuracy. Stratification based on HSPA1L expression in PD highlighted differentially active biological processes, immune responses, and metabolic disruptions. In the pan-cancer analysis, HSPA1L showed variable expression across cancer types and a significant correlation with patient survival and immune infiltration. In glioma, low HSPA1L expression was associated with worse overall survival, distinct immune infiltration patterns, and altered pathway activities. Conclusion: This integrative study reveals the substantial role of HSPs, especially HSPA1L, in the pathogenesis and prognosis of PD and glioma. Our findings offer new perspectives on the molecular mechanisms underlying these diseases and propose HSPA1L as a potential prognostic biomarker and a target for therapeutic intervention.

A crucial measure of diabetes management is to monitor blood glucose, which often requires continuous blood collection, leading to economic burden and discomfort. Blood glucose and glycated hemoglobin A1c serve as traditional indicators of glucose monitoring. But now glycated albumin, fructosamine, and 1,5-anhydroglucitol (1,5-AG) have been gaining more attention. 1,5-AG is a chemically stable monosaccharide that exists in the human body. Its serum concentration remains stable when blood glucose levels are normal. However, it decreases when blood glucose exceeds the renal glucose threshold. Studies have shown that 1.5-AG reflects blood glucose changes in 1 to 2 weeks; therefore, decreased levels of serum 1,5-AG can serve as a clinical indicator of short-term blood glucose disturbances. Recent studies have shown that 1,5-AG can be used not only for the screening and managing of diabetes but also for predicting diabetes-related adverse events and islet β cell function in prediabetic patients. In addition, saliva 1,5-AG demonstrates potential value in the screening and diagnosis of diabetes. This review focuses on the biological characteristics, detection methods, and clinical application of 1,5-AG to promote understanding and applicable research of 1,5-AG in the future.

Drug conjugates are obtained from tumor-located vectors connected to cytotoxic agents via linkers, which are designed to deliver hyper-toxic payloads directly to targeted cancer cells. These drug conjugates include antibody-drug conjugates (ADCs), peptide-drug conjugates (PDCs), small molecule-drug conjugates (SMDCs), nucleic acid aptamer-drug conjugates (ApDCs), and virus-like drug conjugate (VDCs), which show great therapeutic value in the clinic. Drug conjugates consist of a targeting carrier, a linker, and a payload. Payloads are key therapy components. Cytotoxic molecules and their derivatives derived from natural products are commonly used in the payload portion of conjugates. The ideal payload should have sufficient toxicity, stability, coupling sites, and the ability to be released under specific conditions to kill tumor cells. Microtubule protein inhibitors, DNA damage agents, and RNA inhibitors are common cytotoxic molecules. Among these conjugates, cytotoxic molecules of natural origin are summarized based on their mechanism of action, conformational relationships, and the discovery of new derivatives. This paper also mentions some cytotoxic molecules that have the potential to be payloads. It also summarizes the latest technologies and novel conjugates developed in recent years to overcome the shortcomings of ADCs, PDCs, SMDCs, ApDCs, and VDCs. In addition, this paper summarizes the clinical trials conducted on conjugates of these cytotoxic molecules over the last five years. It provides a reference for designing and developing safer and more efficient conjugates.

Post-translational modifications play crucial roles in regulating protein functions and stabilities. PTEN is a critical tumor suppressor involved in regulating cellular proliferation, survival, and migration processes. However, dysregulation of PTEN is common in various human cancers. PTEN stability and activation/suppression have been extensively studied in the context of tumorigenesis through inhibition of the PI3K/AKT signaling pathway. PTEN undergoes various post-translational modifications, primarily including phosphorylation, acetylation, ubiquitination, SUMOylation, neddylation, and oxidation, which finely tune its activity and stability. Generally, phosphorylation modulates PTEN activity through its lipid phosphatase function, leading to altered power of the signaling pathways. Acetylation influences PTEN protein stability and degradation rate. SUMOylation has been implicated in PTEN localization and interactions with other proteins, affecting its overall function. Neddylation, as a novel modification of PTEN, is a key regulatory mechanism in the loss of tumor suppressor function of PTEN. Although current therapeutic approaches focus primarily on inhibiting PI3 kinase, understanding the post-translational modifications of PTEN could help provide new therapeutic strategies that can restore PTEN’s role in PIP3-dependent tumors. The present review summarizes the major recent developments in the regulation of PTEN protein level and activity. We expect that these insights will contribute to better understanding of this critical tumor suppressor and its potential implications for cancer therapy in the future.

Abstract Increased de novo lipogenesis (DNL) in white adipose tissue is associated with insulin sensitivity. Under both Normal-Chow-Diet and High-Fat-Diet, mice expressing a kinase inactive Cyclin-dependent kinase 6 (Cdk6) allele (K43M) display an increase in DNL in visceral white adipose tissues (VAT) as compared to wild type mice (WT), accompanied by markedly increased lipogenic transcriptional factor Carbohydrate-responsive element-binding proteins (CHREBP) and lipogenic enzymes in VAT but not in the liver. Treatment of WT mice under HFD with a CDK6 inhibitor recapitulates the phenotypes observed in K43M mice. Mechanistically, CDK6 phosphorylates AMP-activated protein kinase, leading to phosphorylation and inactivation of acetyl-CoA carboxylase, a key enzyme in DNL. CDK6 also phosphorylates CHREBP thus preventing its entry into the nucleus. Ablation of runt related transcription factor 1 in K43M mature adipocytes reverses most of the phenotypes observed in K43M mice. These results demonstrate a role of CDK6 in DNL and a strategy to alleviate metabolic syndromes.

Protein methylation, similar to DNA methylation, primarily involves post-translational modification (PTM) targeting residues of nitrogen-containing side-chains and other residues. Protein arginine methylation, occurred on arginine residue, is mainly mediated by protein arginine methyltransferases (PRMTs), which are ubiquitously present in a multitude of organisms and are intricately involved in the regulation of numerous biological processes. Specifically, PRMTs are pivotal in the process of gene transcription regulation, and protein function modulation. Abnormal arginine methylation, particularly in histones, can induce dysregulation of gene expression, thereby leading to the development of cancer. The recent advancements in modification mediated by PRMTs and cancer research have had a profound impact on our understanding of the abnormal modification involved in carcinogenesis and progression. This review will provide a defined overview of these recent progression, with the aim of augmenting our knowledge on the role of PRMTs in progression and their potential application in cancer therapy.

As a novel post-translational modification of proteins, succinylation is widely present in both prokaryotes and eukaryotes. By regulating protein translocation and activity, particularly involved in regulation of gene expression, succinylation actively participates in diverse biological processes such as cell proliferation, differentiation and metabolism. Dysregulation of succinylation is closely related to many diseases. Consequently, it has increasingly attracted attention from basic and clinical researchers. For a thorough understanding of succinylation dysregulation and its implications for disease development, such as inflammation, tumors, cardiovascular and neurological diseases, this paper provides a comprehensive review of the research progress on abnormal succinylation. This understanding of association of dysregulation of succinylation with pathological processes will provide valuable directions for disease prevention/treatment strategies as well as drug development.

Abstract Background Treatment of distal tibial fractures is a challenge due to their specific anatomical location. However, there is no appropriate mouse model to simulate a clinical distal tibial fracture for basic research. The aim of this investigation was to evaluate the feasibility of simulating a clinical fracture of the distal tibia of mice and to investigate the effect of ovariectomy (OVX)-induced osteoporosis on fracture healing in this model. Methods Sixty female 8-week-old C57BL/6 mice were randomly divided into two groups, either sham or OVX. A semi-fixation distal tibia fracture was established in the right tibia after 8 weeks of OVX. The right tibias were collected at 7, 14, 21, and 28 days post fracture. Results In the semi-fixation distal tibia fracture model, the posterior callus in the sham group showed excessive bone resorption and lower bone mass phenotype compared with the anterior site; a similar trend was not found in the OVX group. At 28 days post fracture, the posterior callus was more mineralized than the anterior callus in the OVX group. Although the fracture healing of the sham group showed a special phenotype in this mode, the progress and quality of fracture healing were still better than those of the OVX group. Conclusion A semi-fixed distal tibial closed fracture mouse model was successfully established. In this model, excess bone resorption of the posterior callus impaired normal fracture healing, but not in OVX-induced osteoporotic bone. Although the stress shielding effect was not observed in the OVX group, impaired bone healing caused by OVX was still present. Our results suggest that this fracture model may have potential for studies on distal tibial fractures and stress shielding.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. The fruits of Illicium verum, which is a medicinal and edible resource, have been shown to have anti-inflammatory properties. Methods: In this study, we investigated the effects of I. verum extracts (IVEs) on human RA fibroblasts-like synoviocytes (RA-FLS) by using a sensitive and selective ultra-high-performance liquid chromatography with high-definition mass spectrometry (UPLC-HDMS) method. We subsequently analyzed the metabolites produced after the incubation of cultured RA-FLS with IVEs. Results: IVEs inhibited the proliferation and suppressed the migration of RA-FLS, and reduced the levels of inflammatory factors including TNF-α and IL-6. Twenty differential metabolites responsible for the effects of IVEs were screened and annotated based on the UPLC-HDMS data by using a cell metabolomics approach. Discussion: Our findings suggest that treating RA-FLS with IVEs can regulate lipid and amino acid metabolism, indicating that this extract has the potential to modify the metabolic pathways that cause inflammation in RA. Conclusions: This might lead to novel therapeutic strategies for managing patients with RA.

BackgroundThe prevalence of osteoporosis and osteopenia is higher among underground coal miners than surface workers. The special underground work environment and unhealthy habits such as smoking, drinking, and a high-salt diet may lead to changes in bone metabolism, increasing the risk of fragility fractures and placing a heavy economic burden on individuals and society. ObjectiveTo identify potential factors influencing fragility fractures among coal miners in different working environments and to provide a basis for targeted preventive measures to reduce the occurrence of fragility fractures.MethodsMale participants who attended at least one of the physical examinations in Kailuan Group between June 2006 and December 2020 were included in the study. The participants were divided into two groups based on their working environment: surface or underground. A case-control study was conducted, where patients with new fragility fractures served as the case group and participants without fragility fractures served as the control group. The two groups were matched with a case:control ratio of 1:4 by age (±1 year) and the same year of physical examination. The matching process was repeated twice, once for the surface working population and once for the underground working population. The analysis of risk factors was conducted using conditional logistic regression models.ResultsAmong a total of 113138 employees in Kailuan Group, 82631 surface workers and 30507 underground workers were included, respectively. The number of individuals who suffered fragility fractures was 1375, accounting for 1.22% of the total population. The incidence of fragility fractures in underground workers was significantly higher than that in surface workers (1.63%>1.07%, P

Modifications of protein post-translation are critical modulatory processes, which alters target protein biological activity，function and/or location, even involved in pathogenesis of some diseases. So far, there are at least 16 types of post-translation modifications identified, particularly through recent mass spectrometry analysis. Among them, succinylation (Ksuc) on protein lysine residues causes a variety of biological changes. Succinylation of proteins contributes to many cellular processes such as proliferation, growth, differentiation, metabolism and even tumorigenesis. Mechanically, Succinylation leads to conformation alteration of chromatin or remodeling. As a result, transcription/expression of target genes is changed accordingly. Recent research indicated that succinylation mainly contributes to metabolism modulations, from gene expression of metabolic enzymes to their activity modulation. In this review, we will conclude roles of succinylation in metabolic regulation of glucose, fat, amino acids and related metabolic disease launched by aberrant succinylation. Our goal is to stimulate extra attention to these still not well researched perhaps important succinylation modification on proteins and cell processes.

BackgroundThe level at which cumulative blood pressure (BP) can increase the risk of ASCVD in different age groups remains unclear. This study aimed to investigate the association of 10-year cumulative BP levels with the long-term risk of ASCVD of different age groups.MethodsCumulative BP exposure was assessed using the time-weighted average (TWA) BP divided into four BP groups. The participants were also divided into four groups according to their baseline age (

ObjectiveTo systematically evaluate the safety and efficacy of antioxidant therapy in children and adolescents with attention deficit hyperactivity disorder (ADHD).MethodsRandomized controlled trials and prospective studies on antioxidant therapy in children and adolescents with ADHD were searched in PubMed, Embase, and Cochrane Library from the inception of databases to November 12, 2022. Two investigators independently screened the literature, extracted data, and evaluated the quality of the included studies. Network meta-analysis (PROSPERO registration number CRD 42023382824) was carried out by using R Studio 4.2.1.Results48 studies involving 12 antioxidant drugs (resveratrol, pycnogenol, omega-3, omega-6, quercetin, phosphatidylserine, almond, vitamin D, zinc, folic acid, ginkgo biloba, Acetyl-L-carnitine) were finally included, with 3,650 patients. Network meta-analysis showed that omega-6 (0.18), vitamin D (0.19), and quercetin (0.24) were the top three safest drugs according to SUCRA. The omega-3 (SUCRA 0.35), pycnogenol (SUCRA 0.36), and vitamin D (SUCRA 0.27) were the most effective in improving attention, hyperactivity, and total score of Conners' parent rating scale (CPRS), respectively. In terms of improving attention, hyperactivity, and total score of Conners' teacher rating scale (CTRS), pycnogenol (SUCRA 0.32), phosphatidylserine+omega-3 (SUCRA 0.26), and zinc (SUCRA 0.34) were the most effective, respectively. In terms of improving attention, hyperactivity and total score of ADHD Rating Scale-Parent, the optimal agents were phosphatidylserine (SUCRA 0.39), resveratrol+MPH (SUCRA 0.24), and phosphatidylserine (SUCRA 0.34), respectively. In terms of improving attention, hyperactivity and total score of ADHD Rating Scale-Teacher, pycnogenol (SUCRA 0.32), vitamin D (SUCRA 0.31) and vitamin D (SUCRA 0.18) were the optimal agents, respectively. The response rate of omega-3+6 was the highest in CGI (SUCRA 0.95) and CPT (SUCRA 0.42).ConclusionThe rankings of safety and efficacy of the 12 antioxidants vary. Due to the low methodological quality of the included studies, the probability ranking cannot fully explain the clinical efficacy, and the results need to be interpreted with caution. More high-quality studies are still needed to verify our findings.

Browning of white adipose tissue is a novel approach for the management of obesity and obesity-related metabolic disorders. Kaempferol (KPF) is a common dietary nutrient found abundantly in many fruits and vegetables and has been shown to have the potential to regulate lipid metabolism. However, the detailed mechanism by which it affects the browning of white adipose tissue remains unclear. In the present study, we sought to determine how KPF induces adipocytes to undergo a browning transformation by establishing a primary adipocyte model and an obese mouse model. Our results showed that KPF-treated mice were rescued from diet-induced obesity, glucose tolerance and insulin resistance, associated with increased expression of adaptive thermogenesis-related proteins. KPF-promoted white adipose browning correlated with the AMPK/SIRT1/PGC-1α pathway, as the use of an AMPK inhibitor in preadipocytes partially reversed the observed browning phenotype of KPF-treated cells. Taken together, these data suggest that KPF promotes browning of white adipose tissue through activation of the AMPK/SIRT1/PGC-1α pathway. This study demonstrates that KPF is a promising natural product for the treatment of obesity by promoting white fat browning.

Abstract Purpose Stroke is a documented risk factor for hip fracture(HF). However, no data is currently available on this issue in mainland China, we therefore assessed the risk of hip fracture after new-onset stroke using a cohort study. Methods This study included 165,670 participants without a history of stroke at baseline from the Kailuan study. All participants were followed biennially until December 31, 2021. During follow-up, a total of 8,496 new-onset stroke cases were identified. For each case subject, four control subjects was randomly selected, matched for age (± 1 years) and sex. The final analysis comprised 42,455 pair-matched cases and controls. A multivariate Cox proportional hazard regression model was used to estimate the effect of new-onset stroke on the risk of hip fracture. Results During an average follow-up of 8.87 (3.94) years, a total of 231 hip fracture cases occurred, 78 cases in the stroke group and 153 cases in the control group, with incidence rates of 1.12 and 0.50 per 1000 person-years, respectively. The cumulative incidence of the stroke group was higher than that of the controls (P

The main objective of this paper is to reduce the dimensionality of unknown coefficient vectors of finite-element (FE) solutions in two-grid (CN) FE (TGCNFE) format for the nonlinear unsaturated soil water flow problem by using a proper orthogonal decomposition (POD) and to design a new reduced-dimension iteration TGCNFE (RDITGCNFE). For this objective, a new time semi-discrete CN (TSDCN) scheme for the nonlinear unsaturated soil water flow problem is first designed and the existence, stability, and error estimates of TSDCN solutions are demonstrated. Subsequently, a new TGCNFE format for the nonlinear unsaturated soil water flow problem is designed and the existence, unconditional stability, and error estimates of TGCNFE solutions are demonstrated. Next, a new RDITGCNFE format with the same FE basis functions as the TGCNFE format is built by the POD method and the existence, unconditional stability, and error estimates of RDITGCNFE solutions are discussed. Ultimately, the rightness of theory results and the superiority of the RDITGCNFE format are verified by two sets of numerical tests. It is worth noting that the RDITGCNFE format differs completely from all previous reduced-dimension methods, including the authors’ previous works. Therefore, the study of this paper can not only provide a new theoretical method for the dimensionality reduction of numerical models for nonlinear problems but also provide an algorithm implementation technology for the numerical simulation of practical engineering problems.

ObjectiveTo investigate the association between cumulative remnant cholesterol (cumRC) and the risk of new-onset fragility fractures.MethodsThis study included individuals who participated in the 2006, 2008, and 2010 Kailuan health examinations. Baseline characteristics were compared between groups according to cumRC quartiles. The incidence density was calculated, and the log-rank test was used to compare the cumulative incidence. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI), and restricted cubic spline was used to examine the possibly non-linear relation between cumRC and the risk of fragility fractures. Additional analyses were performed with stratification by age (≥ or

This paper researches the almost sure exponential leader-following consensus (ASELFC) of linear and nonlinear multi-agent systems (MASs) under semi-Markovian switching topologies (SMSTs). Differing from existing research works of MASs under SMSTs, we remove the restriction that every topology has a directed spanning tree (DST) rooted in the leader. Only partial switching topologies are requested to have a DST. By employing Lyapunov analysis method and stochastic technique, sufficient conditions for ASELFC are obtained. Finally, the theoretical results are applied to solve the synchronization of Chaos systems by using an example of Chua’s circuits.

Background: Overweight or obesity poses a significant risk of many obesity-related metabolic diseases. Among all the potential new therapies, stem cell-based treatments hold great promise for treating many obesity-related metabolic diseases. However, the mechanisms regulating adipocyte stem cells/progenitors (precursors) are unknown. The aim of this study is to investigate if CDK6 is required for mesenchymal stem cell proliferation and adipocyte differentiation.Methods: Cyclin-dependent kinase 6 (Cdk6) mouse models together with stem cells derived from stromal vascular fraction (SVF) or mouse embryonic fibroblasts (MEFs) of Cdk6 mutant mice were used to determine if CDK6 is required for mesenchymal stem cell proliferation and adipocyte differentiation.Results: We found that mice with a kinase inactive CDK6 mutants (K43M) had fewer precursor residents in the SVF of adult white adipose tissue (WAT). Stem cells from the SVF or MEFs of K43M mice had defects in proliferation and differentiation into the functional fat cells. In contrast, mice with a constitutively active kinase CDK6 mutant (R31C) had the opposite traits. Ablation of RUNX1 in both mature and precursor K43M cells, reversed the phenotypes.Conclusion: These results represent a novel role of CDK6 in regulating precursor numbers, proliferation, and differentiation, suggesting a potential pharmacological intervention for using CDK6 inhibitors in the treatment of obesity-related metabolic diseases.

Abstract Osteoporosis is a common skeletal disease with marked bone loss, deterioration of the bone microstructure and bone fragility. An abnormal bone remodelling cycle with relatively increased bone resorption is the crucial pathophysiological mechanism. Bone remodelling is predominantly controlled by osteoblasts and osteoclasts, which are specialized cell types that are regulated by a variety of osteogenic and osteoclastic factors, including cytokines expressed within the bone microenvironment under local or systemic inflammatory conditions. Signal transducer and activator of transcription 3 (STAT3) plays a prominent role in the communication between cytokines and kinases by binding downstream gene promotors and is involved in a wide range of biological or pathological processes. Emerging evidence suggests that STAT3 and its network participate in bone remodelling and the development of osteoporosis, and this factor may be a potent target for osteoporosis treatment. This review focuses on the role and molecular mechanism of the STAT3 signalling pathway in osteogenesis, osteoclastogenesis and osteoporosis, particularly the bone-related cytokines that regulate the osteoblastic differentiation of bone marrow stromal cells and the osteoclastic differentiation of bone marrow macrophages by initiating STAT3 signalling. This review also examines the cellular interactions among immune cells, haematopoietic cells and osteoblastic/osteoclastic cells. Video abstract

ObjectiveWe report the efficacy and safety of serplulimab, a novel humanized anti–programmed death-1 antibody, plus nanoparticle albumin-bound (nab)-paclitaxel in previously treated patients with programmed death ligand-1 (PD-L1)–positive advanced cervical cancer.MethodsPatients diagnosed with PD-L1–positive (combined positive score ≥1) cervical cancer were enrolled in this single-arm, open-label, phase II study. They were given serplulimab 4.5 mg/kg for up to 2 years (35 dosing cycles) plus nab-paclitaxel 260 mg/m2 for up to six cycles once every 3 weeks. Primary endpoints were safety and objective response rate (ORR) assessed by independent radiological review committee (IRRC) per RECIST version 1.1. Secondary endpoints included ORR assessed by the investigator, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).ResultsBetween December 2019 and June 2020, 52 patients were screened and 21 were enrolled. IRRC-assessed ORR was 57.1% (95% confidence interval [CI] 34.0–78.2%); 3 (14.3%) patients achieved complete response and 9 (42.9%) partial response. The median DOR was not reached (NR) (95% CI 4.1–NR). IRRC-assessed median PFS was 5.7 months (95% CI 3.0–NR), and median OS was 15.5 months (95% CI 10.5–NR). Investigator-assessed ORR was 47.6% (95% CI 25.7–70.2%). Seventeen (81.0%) patients experienced grade ≥3 treatment-emergent adverse events. Grade ≥3 adverse drug reactions were reported in 7 (33.3%) patients. Immune-related adverse events occurred in 12 (57.1%) patients.ConclusionsIn previously treated patients with PD-L1–positive advanced cervical cancer, serplulimab plus nab-paclitaxel provided durable clinical activity and a manageable safety profile.Clinical trial registrationClinicalTrials.gov, identifier NCT04150575.

Abstract Background Hepatocellular carcinoma (HCC) is one of the most malignant tumors and the fourth leading cause of cancer-related death worldwide. Sorafenib is currently acknowledged as a standard therapy for advanced HCC. However, acquired resistance substantially limits the clinical efficacy of sorafenib. Therefore, further investigations of the associated risk factors are highly warranted. Methods We analysed a group of 78 HCC patients who received sorafenib treatment after liver resection surgery. The expression of SCAP and its correlation with sorafenib resistance in HCC clinical samples were determined by immunohistochemical analyses. Overexpression and knockdown approaches in vitro were used to characterize the functional roles of SCAP in regulating sorafenib resistance. The effects of SCAP inhibition in HCC cell lines were analysed in proliferation, apoptosis, and colony formation assays. Autophagic regulation by SCAP was assessed by immunoblotting, immunofluorescence and immunoprecipitation assays. The combinatorial effect of a SCAP inhibitor and sorafenib was tested using nude mice. Results Hypercholesterolemia was associated with sorafenib resistance in HCC treatment. The degree of sorafenib resistance was correlated with the expression of the cholesterol sensor SCAP and consequent deposition of cholesterol. SCAP is overexpressed in HCC tissues and hepatocellular carcinoma cell lines with sorafenib resistance, while SCAP inhibition could improve sorafenib sensitivity in sorafenib-resistant HCC cells. Furthermore, we found that SCAP-mediated sorafenib resistance was related to decreased autophagy, which was connected to decreased AMPK activity. A clinically significant finding was that lycorine, a specific SCAP inhibitor, could reverse acquired resistance to sorafenib in vitro and in vivo. Conclusions SCAP contributes to sorafenib resistance through AMPK-mediated autophagic regulation. The combination of sorafenib and SCAP targeted therapy provides a novel personalized treatment to enhance sensitivity in sorafenib-resistant HCC.

Background & Aims: Sterol regulatory element binding protein cleavage-activating protein (SCAP) is a cholesterol sensor that confers a broad range of functional effects in metabolic diseases. Lean nonalcoholic fatty liver disease (NAFLD) is characterized by a decrease in subcutaneous fat and ectopic fat deposition in the liver. SCAP may mediate the development of lean NAFLD, but the mechanism of action remains unclear. Methods: C57BL/6J wild-type and macrophage SCAP-specific knockout mice (SCAPΔMϕ) were subjected to Paigen diet (PD) feeding induced lean NAFLD. Inflammation and lipid metabolism of adipose and liver were evaluated. The STING–NF-κB signaling pathway was examined in vivo and in vitro to explore the underlying mechanism of macrophage SCAP on metaflammation. Results: The data showed heterogeneity of lipid metabolic processes in liver and epididymal white adipose tissue due to inflammation mediated by macrophage infiltration. Meanwhile, we found that the macrophage SCAP was abnormally increased in the adipose and liver tissues of PD-fed mice. Intriguingly, the SCAPΔMϕ mice attenuated PD-induced metaflammation and ectopic lipid deposition by reducing hepatic stimulator of interferon gene (STING)–nuclear factor kappa B (NF-κB) pathway activation. In-depth molecular analysis revealed that SCAP specifically recruits the STING and tank-binding kinase 1 onto the Golgi to activate the NF-κB in macrophages, thereby promoting the release of inflammatory factors. This process ultimately led to an increased lipolysis in adipocytes and lipid uptake and synthesis in hepatocytes. Conclusions: Our findings suggest that SCAP acts as a novel regulator of the macrophage inflammatory response and the pathogenesis of lean NAFLD by activating the STING–NF-κB signaling pathway. Inhibition of macrophage SCAP may represent a new therapeutic strategy for the treatment of lean NAFLD.

Hip fracture is the most devastating type of osteoporosis-related fracture, and is a major worldwide public health problem with a high socioeconomic burden, morbidity rate, and mortality rate. Thus, it is crucial to uncover the risk factors and protective factors to create a hip fracture prevention strategy. In addition to a briefly review of some well accepted risk and protective factors of hip fracture, this review mainly summarized the recent advances in the identification of emerging risk or protective factors for hip fracture, in terms of regional differences in medical services, diseases, drugs, mechanical load, neuromuscular mass, genes, blood types, cultural differences. This review provides a comprehensive review of the associated factors and effective prevention measures for hip fracture, and discusses issues that need further investigation. These issues include the determination of the influencing mechanism of risk factors triggering hip fracture and their interlinked correlation with other factors, as well as the confirmation or correction of emerging factors associated with hip fracture, particularly those that are still controversial. These recent findings will aid in optimizing the strategy for preventing hip fracture.

Introduction: Current treatments for patients with previously treated advanced hepatocellular carcinoma (HCC) provide modest survival benefits. We evaluated the safety and antitumor activity of serplulimab, an anti-PD-1 antibody, plus the bevacizumab biosimilar HLX04 in this patient population. Methods: In this open-label, multicenter, phase 2 study in China, patients with advanced HCC who failed prior systemic therapy received serplulimab 3 mg/kg plus HLX04 5 mg/kg (group A) or 10 mg/kg (group B) intravenously every 2 weeks. The primary endpoint was safety. Results: As of April 8, 2021, 20 and 21 patients were enrolled into group A and B, and they had received a median of 7 and 11 treatment cycles, respectively. Grade ≥3 treatment-emergent adverse events were reported by 14 (70.0%) patients in group A and 12 (57.1%) in group B. Most immune-related adverse events were grade ≤3. The objective response rate was 30.0% (95% confidence interval (CI), 11.9–54.3) in group A and 14.3% (95% CI, 3.0–36.3) in group B. Median duration of response was not reached (95% CI, 3.3–not evaluable (NE)) in group A and was 9.0 months (95% CI, 7.9–NE) in group B. Median progression-free survival was 2.2 months (95% CI, 1.4–5.5) and 4.1 months (95% CI, 1.5–NE), and median overall survival was 11.6 months (95% CI, 6.4–NE) and 14.3 months (95% CI, 8.2–NE) in group A and B, respectively. Conclusion: Serplulimab plus HLX04 showed a manageable safety profile and antitumor activity in patients with previously treated advanced HCC.

Shikonin (SHK) is a pleiotropic agent with remarkable cell growth inhibition activity against various cancer types, especially non–small cell lung cancer (NSCLC), but its molecular mechanism is still unclear. Our previous study found that miR-628-3p could inhibit the growth of A549 cells and induce its apoptosis. Bioinformatics analysis predicted that miR-628-3p promoter sequence contained p53 binding sites. Considering the regulatory effect of SHK on p53, we speculate that SHK may inhibit the growth and induce apoptosis of NSCLC cells by up-regulating miR-628-3p. CCK-8 and EdU assay confirmed the inhibitory effect of SHK on A549 and PC-9 cells. Meanwhile, quantitative reverse transcription–polymerase chain reaction and Western blot showed that SHK could promote the expression of p53 and miR-628-3p in a dose-dependent manner. Overexpression of p53 or miR-628-3p can inhibit the growth and promote apoptosis of A549 and PC-9 cells, while silencing p53 or miR-628-3p has the opposite effect. Dual luciferase reporting assay and ChIP (chromatin immunoprecipitation) assay further verified the direct interaction between p53 and the promoter of miR-628-3p. Gene knockdown for p53 or miR-628-3p confirmed that SHK inhibits the growth and induces apoptosis of A549 and PC-9 cells at least partly by up-regulating p53/miR-628-3p signaling pathway. Therefore, these novel findings provide an alternative approach to target p53/miR-628-3p axis and could be used for the development of new treatment strategies for NSCLC.

Background: Influences of fish oil supplementation on body weight and other cardiometabolic factors in overweight or obese children and adolescents remain not fully understood. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the role of fish oil for these children.Methods: Relevant studies were obtained by search of PubMed, Embase, and Cochrane's Library databases. A random-effect model, which incorporates the potential heterogeneity of the included studies, was used to pool the results.Results: Twelve RCTs including 1,028 overweight or obese children and adolescents were included. Compared to control, fish oil supplementation significantly reduced body mass index [BMI, mean difference (MD): −0.96 kg/m2, 95% confidence interval (CI): −1.69 to −0.23, P = 0.01] but did not significantly reduce body weight or waist circumference (P = 0.68 and 0.76). Moreover, fish oil supplementation significantly reduced serum triglyceride (MD: −0.24 mmol/L, 95% CI: −0.40 to −0.08, P = 0.004) but did not significantly affect serum total cholesterol and high-density or low-density lipoprotein cholesterol (P = 0.83, 0.42, and 0.31, respectively). Additionally, fish oil supplementation significantly lowered systolic blood pressure (SBP, MD: −2.46 mmHg, 95% CI: −4.93 to −0.01, P = 0.04) but did not significantly change diastolic blood pressure (P = 0.22). Supplementation with fish oil did not significantly affect fasting plasma glucose (P = 0.33).Conclusions: In overweight or obese children and adolescents, supplementation with fish oil could reduce BMI, decrease serum triglyceride, and lower SBP, while serum cholesterol and fasting glucose may not be significantly affected.

Jieduquyuziyin prescription (JP) has been used to treat systemic lupus erythematosus (SLE). Although the effectiveness of JP in the treatment of SLE has been clinically proven, the underlying mechanisms have yet to be completely understood. We observed the therapeutic actions of JP in MRL/lpr mice and their bone marrow-derived macrophages (BMDMs) and the potential mechanism of their inhibition of inflammatory activity. To estimate the effect of JP on suppressing inflammatory activity, BMDMs of MRL/lpr and MRL/MP mice were treated with JP-treated serum, and MRL/lpr mice were treated by JP for 8 weeks. Among them, JP and its treated serum were subjected to quality control, and BMDMs were separated and identified. The results showed that in the JP group of BMDMs stimulated by Lipopolysaccharide (LPS) in MRL/lpr mice, the secretion of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) reduced, and the expressions of Interleukin-1 receptor-associated kinase 1 (IRAK1) and its downstream nuclear factor κB (NF-κB) pathway decreased. Meanwhile, the alleviation of renal pathological damage, the decrease of urinary protein and serum anti-dsDNA contents, the inhibition of TNF-α level, and then the suppression of the IRAK1-NF-κB inflammatory signaling in the spleen and kidney, confirmed that the therapeutic effect of JP. These results demonstrated that JP could inhibit the inflammatory activity of MRL/lpr mice and their BMDMs by suppressing the activation of IRAK1-NF-κB signaling and was supposed to be a good choice for the treatment of SLE.

Chlamydia trachomatis and human papillomavirus (HPV) are the most common pathogens of sexually transmitted infections (STIs), which can increase the risk of cervical cancer and infertility. The purpose of this study was to evaluate the prevalence, genotype and risk factors of C. trachomatis and/or HPV infection in women attending the annual physical examination, assistant reproductive treatment and visiting the gynecology clinics from Southern Hunan province in China. Cervical-swab samples were collected from 5006 participants. We found that the overall prevalence of C. trachomatis, HPV infection and C. trachomatis/HPV coinfection was 4.7% (236/5006), 15.5% (778/5006) and 1.2% (59/5006), while the prevalence of asymptomatic infection of that was 3.8% (38/1006), 10.8% (109/1006) and 0.6% (6/1006), respectively. Furthermore, 25.0% (59/236) of C. trachomatis infection and 7.6% (59/778) of HPV infection were attributable to C. trachomatis and HPV coinfection. C. trachomatis and HPV infection were more often observed in young women of less than 25 years (10.4% and 21.3%, respectively) and in the outpatients from gynecology clinics (5.2% and 18.0%, respectively). Of note, a higher prevalence of C. trachomatis infection was observed in HPV-positive women (7.6%) than HPV- negative ones (4.2%), and vice versa. The top three C. trachomatis genotypes were E (1.4%), F (1.1%) and J (0.8%), and the counterparts of HPV genotypes were HPV52 (4.2%), HPV16 (2.3%) and HPV58 (2.2%), respectively. Among the 151 outpatients with colposcopy data, HPV infection was associated with severe cervical lesions with OR of 15.86 (95% CI 3.14–80.0, P < 0.001) while C. trachomatis infection was more likely associated with a low grade colposcopy impression (OR = 3.25, 95% CI: 1.22–8.65, P = 0.018). Our data highlight the high prevalence of asymptomatic C. trachomatis and HPV infection, particularly among women of

Beige adipocytes can arise from transdifferentiation of mature white adipocytes. Here the authors identify CDK6 as a key molecule involved in the white-to-beige adipocyte transdifferentiation and, therefore, as a regulator of organismal energy homeostasis in mice.

Two new indole alkaloids, 21-oxokoumine (1) and furanokoumine (2), were isolated from the roots of Gelsemium elegans Benth together with three known compounds. The structures of the two novel compounds were elucidated by spectroscopic methods, including NMR, HR-ESI-MS, UV, IR, CD and molecular modeling. Compound 1 is the first instance of a koumine-type alkaloid with a carbonyl at the C-21 position, while compound 2 possesses a tetrahydrofuran ring located on C-20 and C-21.

BACKGROUND: Multiplexing technologies, which allow for simultaneous detection of multiple nucleic acid sequences in a single reaction, can save a lot of time, cost and labor compared to traditional single reaction detection methods. However, the multiplexing method currently used requires precise handiwork and many complicated steps, making a new, simpler technique desirable. Oligonucleotides containing locked nucleic acid residues are an attractive tool because they have strong affinities for their complementary targets, they have been used to avoid dimer formation and mismatch hybridization and to enhance efficient priming. In this study, we aimed to investigate the use of locked nucleic acid pentamers for genomic DNA amplification and multiplex genotyping. RESULTS: We designed locked nucleic acid pentamers as universal PCR primers for genomic DNA amplification. The locked nucleic acid pentamers were able to prime amplification of the selected sequences within the investigated genomes, and the resulting products were similar in length to those obtained by restriction digest. In Real Time PCR of genomic DNA from three bacterial species, locked nucleic acid pentamers showed high priming efficiencies. Data from bias tests demonstrated that locked nucleic acid pentamers have equal affinities for each of the six genes tested from the Klebsiella pneumoniae genome. Combined with suspension array genotyping, locked nucleic acid pentamer-based PCR amplification was able to identify a total of 15 strains, including 3 species of bacteria, by gene- and species-specific probes. Among the 32 species used in the assay, 28 species and 50 different genes were clearly identified using this method. CONCLUSION: As a novel genomic DNA amplification, the use of locked nucleic acid pentamers as universal primer pairs in conjunction with suspension array genotyping, allows for the identification of multiple distinct genes or species with a single amplification procedure. This demonstrates that locked nucleic acid pentamer-based PCR can be utilized extensively in pathogen identification.

This paper analyzes the causal relationship between environmental regulation and eco-efficiency in China's understudied iron and steel industry over 2006-2019. After reviewing relevant theories and context, we construct a model assessing economic performance, sewage fees, administrative penalties, and eco-efficiency indicators using Granger causality tests on time series data. The results suggest economic performance causes tighter administrative regulation, while improved eco-efficiency reduces the need for regulatory enforcement. These findings imply environmental policy should account for feedback effects in the steel industry. Specifically, our study helps policymakers optimize regulations balancing environmental and economic objectives for sustainable development. [ABSTRACT FROM AUTHOR]

In order to improve the performance and efficiency of the rotating cylindrical shell (RCS), one of the effective ways reduces the mass of the RCS. The scientific and effective method is to design the variable thickness of RCS (VTRCS) along the axial direction in response to this demand. Then, the vibration traveling wave characteristics of VTRCS are investigated by Chebyshev–Ritz method. The displacement field of the cylindrical shell is expanded in the form of the product of the Chebyshev polynomial and the boundary function. The kinetic and potential energies of the VTRCS are calculated based on the Sanders shell theory considering the effects of Coriolis forces and centrifugal forces. Also, the frequency equation of the VTRCS is obtained according to the Ritz method. The accuracy of the modeling method is verified by comparing the present results with literature that had done, and the convergence of the calculated results is studied. Finally, the free-vibration traveling wave characteristics of the VTRCS in different thickness variations are compared, and the parameters such as the rotational speed, thickness variation parameters, and aspect ratio on the free-vibration traveling wave characteristics of the VTRCS are discussed. The influence of thickness variation on the vibration characteristics is analyzed, which has significance for the lightweight design for VTRCS. [ABSTRACT FROM AUTHOR]