Background: Non-radiographic axial spondyloarthritis is a progressive and disabling inflammatory disease affecting young adults, with limited treatment options. TNFi are more efficacious than JAKi and IL1-7i in nr-ax ...Background: Non-radiographic axial spondyloarthritis is a progressive and disabling inflammatory disease affecting young adults, with limited treatment options. TNFi are more efficacious than JAKi and IL1-7i in nr-ax SPA and it has a well-known safety profile over a longer duration. Recently, many IL-17i and JAKi were approved for the treatment of nr-ax SPA;however, data comparing IL1-7i and JAKi in terms of efficacy and safety is lacking. This systematized review aimed to compare the existing efficacy and safety data of JAKi vs IL-17i in the treatment of patients with nr-ax SPA. Methods: A systematic literature search was performed using relevant keywords in many databases. According to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA, 2020), relevant articles were included and evaluated in this review. Efficacy and safety data were collected, analyzed and compared through week 52. The first check was done by the end of week 14 and week 16 for upadacitinib and IL-17i respectively. Results: Data from four RCTs evaluating upadacitinib, secukinumab, ixekizumab, and bimekizumab comprising 1425 patients were analyzed. Overall, a comparable efficacy and safety profile were observed across different treatment arms through week 52;however, non-significant variations were encountered in some outcome measures. The primary endpoint among these RCTs (ASAS40 response rate) was met and it was higher in patients treated with bimekizumab 160 mg sc Q 4 weeks in TNFi non responders (48%) and lowest in ixekizumab 80 mg sc Q 4 weeks treated patients, (35%) (p Conclusion: The above-mentioned three IL-17i and the only one JAKi demonstrated comparable safety and efficacy profiles with some minor variations. A head-to-head trial comparing the effectiveness and safety characteristics of JAKi vs IL-17i may be needed in patients with active nr-ax SpA.展开更多
Histone deacetylase inhibitors(HDACis),such as trichostatin A(TSA),have been recognized as promising anti-cancer agents due to their capacity to restore epigenetic regulation and reactivate tumor suppressor genes.Howe...Histone deacetylase inhibitors(HDACis),such as trichostatin A(TSA),have been recognized as promising anti-cancer agents due to their capacity to restore epigenetic regulation and reactivate tumor suppressor genes.However,emerging evidence indicates that unintended pro-metastatic effects may offset the therapeutic benefits of HDACis.Chen et al elucidate this paradox,demonstrating that TSA-induced hyperacetylation activates the BRD4/c-Myc/ER-stress axis,thereby promoting epithelial-mesenchymal transition and metastasis in esophageal squamous cell carcinoma(ESCC).Furthermore,they clarify the clinical significance of histone acetylation in the prognostic evaluation of ESCC.Their findings underscore the complexity of epigenetic therapies and highlight the necessity of reevaluating the associated risks and combinatorial therapeutic strategies with HDACi-based treatments.Here,we summarize the potential risks of HDACis therapy and discuss feasible combination therapeutic strategies.展开更多
BACKGROUND Acute variceal bleeding(AVB)represents a life-threatening complication in hepatocellular carcinoma(HCC)patients undergoing systemic therapy,mainly including immune checkpoint inhibitors(ICIs)and antivascula...BACKGROUND Acute variceal bleeding(AVB)represents a life-threatening complication in hepatocellular carcinoma(HCC)patients undergoing systemic therapy,mainly including immune checkpoint inhibitors(ICIs)and antivascular drugs used alone or in combination.The pathogenesis of AVB in this population may involve tumor-related factors,treatment-induced effects,or progression of underlying portal hypertension.Identifying high-risk factors for AVB is crucial for the management of this patient population.AIM To develop and validate a risk prediction model for AVB occurrence in cirrhotic HCC patients receiving ICI-based systemic therapy.METHODS This retrospective study analyzed 286 HCC patients(2021-2022)receiving ICIs(mono-/combination therapy),randomly split into training(n=184)and validation(n=102)cohorts.In the training cohort,bleeding vs nonbleeding groups were compared for general information,etiological data,laboratory indicators,tumor staging,systemic treatment drugs,variceal bleeding history,and endoscopic treatment history.Risk factors for AVB were identified and used to establish a logistic regression model for predicting bleeding,which was further validated in the validation cohort.RESULTS The bleeding group had significantly higher proportions of patients with platelet count≥100×10^(9)/L,alphafetoprotein≥400 ng/mL,tumor diameter≥5 cm,portal vein tumor thrombosis,ascites,bleeding history,prior endoscopic treatment,albumin-bilirubin grade level 2-3,fibrosis-4 index(FIB-4)≥4.57,and prognostic nutritional index<45 compared to the non-bleeding group.Multivariate analysis identified tumor diameter≥5 cm,portal vein thrombosis,bleeding history,and elevated FIB-4 as independent risk factors for bleeding(P<0.05).A predictive model based on these factors showed good discrimination,with area under the receiver operating characteristic curve values of 0.861(training)and 0.816(validation).CONCLUSION A history of pre-ICI bleeding significantly increases recurrent bleeding risk,necessitating close monitoring.The FIB-4 fibrosis model,combined with tumor features,can also serve as a predictive factor for bleeding.展开更多
Severe acute respiratory coronavirus-2(SARS-CoV-2)infection course differs between the young and healthy and the elderly with co-morbidities.In the latter a potentially lethal coronavirus disease 2019(COVID-19)cytokin...Severe acute respiratory coronavirus-2(SARS-CoV-2)infection course differs between the young and healthy and the elderly with co-morbidities.In the latter a potentially lethal coronavirus disease 2019(COVID-19)cytokine storm has been described with an unrestrained renin-angiotensin(Ang)system(RAS).RAS inhibitors[Ang converting enzyme inhibitors and Ang II type 1 receptor(AT1R)blockers]while appearing appropriate in COVID-19,display enigmatic effects ranging from protection to harm.MicroRNA-155(miR-155)-induced translational repression of key cardiovascular(CV)genes(i.e.,AT1R)restrains SARS-CoV-2-engendered RAS hyperactivity to tolerable and SARS-CoV-2-protective CV phenotypes supporting a protective erythropoietin(EPO)evolutionary landscape.MiR-155’s disrupted repression of the AT1R 1166C-allele associates with adverse CV and COVID-19 outcomes,confirming its decisive role in RAS modulation.RAS inhibition disrupts this miR-155-EPO network by further lowering EPO and miR-155 in COVID-19 with co-morbidities,thereby allowing unimpeded RAS hyperactivity to progress precariously.Current pharmacological interventions in COVID-19 employing RAS inhibition should consider these complex but potentially detrimental miR-155/EPO-related effects.展开更多
BACKGROUND Chemotherapy,targeted therapy,and immunotherapy have all been shown to achieve some efficacy in treating intrahepatic cholangiocarcinoma(ICC).How-ever,these systemic treatments have not provided optimal res...BACKGROUND Chemotherapy,targeted therapy,and immunotherapy have all been shown to achieve some efficacy in treating intrahepatic cholangiocarcinoma(ICC).How-ever,these systemic treatments have not provided optimal results for some patients.Therefore,the combination of transarterial chemoembolization(TACE)and hepatic artery infusion chemotherapy or other local interventional therapy methods is being considered for the treatment of liver tumors.AIM To evaluate the efficacy and safety of combining chemotherapy,targeted therapy,and immunotherapy,with or without TACE,in patients with ICC.METHODS We recruited 83 patients with unresectable ICC from July 2021 to December 2023 at the Affiliated Hospital of Xuzhou Medical University.Forty-one patients received TACE combined with chemotherapy,tyrosine kinase inhibitors,and pro-grammed death 1(PD-1)/programmed cell death ligand 1(PD-L1)inhibitors(ex-perimental group),whereas 42 patients were treated with chemotherapy,tyrosine kinase inhibitors,and PD-1/PD-L1 inhibitors(control group).Short-term efficacy was assessed using the modified response evaluation criterion,and the objective response rate,disease control rate,progression-free survival,and incidence of adverse events were compared between groups.RESULTS The objective response rate in the experimental group was greater than that in the control group(39.0%vs 19.0%,P<0.05).The disease control rate in the experimental group was significantly greater than that in the control group(75.6%vs 52.4%,P<0.05).The median progression-free survival times were 14.3 months in the experimental group and 12.7 months in the control group(P<0.05).All 41 patients in the experimental group developed postembol-ization syndrome.Among the symptoms,fever and pain were significantly more common in the experimental group than in the control group(85.4%vs 11.9%,P<0.001 and 58.5%vs 9.5%,P<0.001).No grade 4 or 5 treatment-related adverse events were observed in either group.CONCLUSION In patients with unresectable ICC,TACE combined with chemotherapy,tyrosine kinase inhibitors,and PD-1/PD-L1 inhibitors has good efficacy and high safety,indicating potential benefits for these patients.展开更多
Numerous c-mesenchymal-epithelial transition(c-MET)inhibitors have been reported as potential anticancer agents.However,most fail to enter clinical trials owing to poor efficacy or drug resistance.To date,the scaffold...Numerous c-mesenchymal-epithelial transition(c-MET)inhibitors have been reported as potential anticancer agents.However,most fail to enter clinical trials owing to poor efficacy or drug resistance.To date,the scaffold-based chemical space of small-molecule c-MET inhibitors has not been analyzed.In this study,we constructed the largest c-MET dataset,which included 2,278 molecules with different struc-tures,by inhibiting the half maximal inhibitory concentration(IC_(50))of kinase activity.No significant differences in drug-like properties were observed between active molecules(1,228)and inactive mol-ecules(1,050),including chemical space coverage,physicochemical properties,and absorption,distri-bution,metabolism,excretion,and toxicity(ADMET)profiles.The higher chemical diversity of the active molecules was downscaled using t-distributed stochastic neighbor embedding(t-SNE)high-dimensional data.Further clustering and chemical space networks(CSNs)analyses revealed commonly used scaffolds for c-MET inhibitors,such as M5,M7,and M8.Activity cliffs and structural alerts were used to reveal“dead ends”and“safe bets”for c-MET,as well as dominant structural fragments consisting of pyr-idazinones,triazoles,and pyrazines.Finally,the decision tree model precisely indicated the key structural features required to constitute active c-MET inhibitor molecules,including at least three aromatic het-erocycles,five aromatic nitrogen atoms,and eight nitrogeneoxygen atoms.Overall,our analyses revealed potential structure-activity relationship(SAR)patterns for c-MET inhibitors,which can inform the screening of new compounds and guide future optimization efforts.展开更多
This article discusses the study by GrubićRotkvićet al on the mechanisms of action of sodium-glucose cotransporter 2 inhibitors(SGLT2i)in patients with type 2 diabetes mellitus(T2DM)and heart failure(HF).T2DM and HF a...This article discusses the study by GrubićRotkvićet al on the mechanisms of action of sodium-glucose cotransporter 2 inhibitors(SGLT2i)in patients with type 2 diabetes mellitus(T2DM)and heart failure(HF).T2DM and HF are highly comorbid,with a significantly increased prevalence of HF in patients with T2DM.SGLT2i exhibit potential in reducing hospitalization rates for HF and cardiovascular mortality through multiple mechanisms,including improving blood glucose control,promoting urinary sodium excretion,reducing sympathetic nervous system activity,lowering both preload and afterload on the heart,alleviating inflammation and oxidative stress,enhancing endothelial function,improving myocardial energy metabolism,and stabilizing cardiac ion homeostasis.Further research and clinical practice will help optimize the use of SGLT2i in HF patients.展开更多
BACKGROUND Proton pump inhibitors(PPIs)are widely used,including among cancer patients,to manage gastroesophageal reflux and other gastric acid-related disorders.Recent evidence suggests associations between long-term...BACKGROUND Proton pump inhibitors(PPIs)are widely used,including among cancer patients,to manage gastroesophageal reflux and other gastric acid-related disorders.Recent evidence suggests associations between long-term PPI use and higher risks for various adverse health outcomes,including greater mortality.AIM To investigate the association between PPI use and all-cause mortality among cancer patients by a comprehensive analysis after adjustment for various confounders and a robust methodological approach to minimize bias.METHODS This retrospective cohort study used data from the TriNetX research network,with electronic health records from multiple healthcare organizations.The study employed a new-user,active comparator design,which compared newly treated PPI users with non-users and newly treated histamine2 receptor antagonists(H2RA)users among adult cancer patients.Newly prescribed PPIs(esomeprazole,lansoprazole,omeprazole,pantoprazole,or rabeprazole)users were compared to non-users or newly prescribed H2RAs(cimetidine,famotidine,nizatidine,or ranitidine)users.The primary outcome was all-cause mortality.Each patient in the main group was matched to a patient in the control group using 1:1 propensity score matching to reduce confounding effects.Multivariable Cox regression models were used to estimate hazard ratios(HRs)and 95% confidence interval(CI).RESULTS During the follow-up period(median 5.4±1.8 years for PPI users and 6.5±1.0 years for non-users),PPI users demonstrated a higher all-cause mortality rate than non-users after 1 year,2 years,and at the end of follow up(HRs:2.34-2.72).Compared with H2RA users,PPI users demonstrated a higher rate of all-cause mortality HR:1.51(95%CI:1.41-1.69).Similar results were observed across sensitivity analyses by excluding deaths from the first 9 months and 1-year post-exposure,confirming the robustness of these findings.In a sensitivity analysis,we analyzed all-cause mortality outcomes between former PPI users and individuals who have never used PPIs,providing insights into the long-term effects of past PPI use.In addition,at 1-year follow-up,the analysis revealed a significant difference in mortality rates between former PPI users and non-users(HR:1.84;95%CI:1.82-1.96).CONCLUSION PPI use among cancer patients was associated with a higher risk of all-cause mortality compared to non-users or H2RA users.These findings emphasize the need for cautious use of PPIs in cancer patients and suggest that alternative treatments should be considered when clinically feasible.However,further studies are needed to corroborate our findings,given the significant adverse outcomes in cancer patients.展开更多
Treatment with immune checkpoint inhibitors(ICIs)is an innovative therapy for managing certain types of malignancy and has the potential to improve overall patient survival significantly.The most widely used ICIs sele...Treatment with immune checkpoint inhibitors(ICIs)is an innovative therapy for managing certain types of malignancy and has the potential to improve overall patient survival significantly.The most widely used ICIs selectively target different receptors comprising programmed cell death-1 receptor,programmed cell death-ligand 1 receptor,and cytotoxic T lymphocyte antigen 4 receptor.The widespread utilization of ICIs over the past several years,however,is frequently accompanied by immune-related adverse events(irAEs)that substantially impact the patient’s quality of life,particularly those affecting the digestive system,including both the upper and lower gastrointestinal tract.Based on a literature search covering databases such as PubMed,Web of Science,Embase,and the Cochrane Library,we present an insight into primary gastrointestinal irAEs,with a special focus on endoscopic manifestations.Additionally,we analyze data regarding the pathogenetic mechanisms,diagnostic approaches,histological characteristics,and proposed therapeutic interventions for managing irAEs involving the gastrointestinal tract.展开更多
Trehalose is an autophagy-promoting disaccharide,which can improve and delay chronic diseases like neurodegenerative diseases and atherosclerosis,but its bioavailability is severely restricted by endogenous trehalase ...Trehalose is an autophagy-promoting disaccharide,which can improve and delay chronic diseases like neurodegenerative diseases and atherosclerosis,but its bioavailability is severely restricted by endogenous trehalase in mammals.Trehalase inhibitor is a promising and effective way to enhance trehalose bioavailability by preventing trehalose from hydrolyzing.However,previously reported trehalase inhibitors still face safety of long-term use and promiscuous inhibition on intestinal glycosidases.This study carried out a high-throughput virtual screening through molecular pool-based molecular docking combined with in vitro inhibition experiments to screen trehalase inhibitors naturally derived from foods.Out of 1769 small molecules,which include 115 analogs of trehalose,natural monosaccharides,disaccharides,trisaccharides,imidazoles and their derivatives,as well as 20 natural amino acids and their 400 dipeptides,isomaltose,α-isomaltulose,and isomaltitol exhibited the best inhibitory activities,beyond as traditional sweetener and prebiotic.Best of all,isomaltose showed the half maximal inhibitory concentration(IC50)and inhibition constant(Ki)values on trehalase of 5.59 and(2.1760±0.3431)mmol/L,respectively.Moreover,isomaltose was resistant to the simulated digestive environment and did not affect intestinal glycosidases such asα-glucosidase and glucoamylase,making it a reliable edible candidate for a trehalase inhibitor.This study provides new insights into the virtual screening-based identification of new food-derived trehalase inhibitors for enhanced integrity and bioavailability of orally administered trehalose,especially repurposing a prebiotic for another new use as trehalase inhibitor.展开更多
To comprehensively analyze the current research landscape and emerging trends in the application of pro-protein convertase subtilisin/kexin type 9(PCSK9)inhibitors for treating cardiovascular diseases,a bibliometric a...To comprehensively analyze the current research landscape and emerging trends in the application of pro-protein convertase subtilisin/kexin type 9(PCSK9)inhibitors for treating cardiovascular diseases,a bibliometric analysis was conducted.Relevant English-language literature on PCSK9 inhibitors in cardiovascular treatment,published between January 1,2013,and December 31,2023,was retrieved from the Web of Science core collection database.Utilizing tools such as VOSviewer 1.6.20,CiteSpace 6.2.R6,and Excel 2021,the study examined key features of the literature,including annual publication trends,contributing countries/regions,institutions,authors,journals,and key research themes.The analysis identified a total of 1383 articles,revealing a general upward trend in annual publication output.Research in this field has been conducted by 78 countries/regions,with the United States leading in the number of publications(563 articles).The United States also demonstrates strong collaborative networks with other leading countries,including the United Kingdom,Canada,the Netherlands,Australia,Italy,Germany,and Switzerland.In terms of institutional contributions,2379 institutions have published relevant studies,with Amgen Inc.producing the most publications(n=70).Among individual contributors,Professor Giugliano from the Thrombolysis in Myocardial Infarction(TIMI)Study Group at Brigham and Women’s Hospital and Harvard Medical School is the most prolific author,with 37 publications.Meanwhile,Professor Sabatine,also from the TIMI Study Group,holds the highest number of co-citations,underscoring his influence in the field.The analysis also identified 436 journals publishing research on PCSK9 inhibitors,with the Journal of Clinical Lipidology being the most productive(n=54).However,the New England Journal of Medicine is noted as the journal with the highest co-citation count,indicating its significant impact on this research area.Research hotspots have focused on the efficacy and safety of PCSK9 inhibitors,alongside the clinical application of conventional lipid-lowering therapies such as statins and ezetimibe.Notably,the development of monoclonal antibodies and siRNA-based therapies targeting PCSK9 has gained considerable attention over the past decade due to their superior ability to lower low-density lipoprotein cholesterol(LDL-C).The effectiveness and long-term safety profiles of these novel agents are of growing interest,prompting updates to lipid management guidelines and offering new perspectives for the prevention and treatment of cardiovascular diseases.展开更多
Dear Editor,Rosacea is characterized by persistent or transient erythema,papules,pustules,telangiectasia,and/or phymatous lesions[1].Although multiple treatments are available for rosacea,the advent of biological agen...Dear Editor,Rosacea is characterized by persistent or transient erythema,papules,pustules,telangiectasia,and/or phymatous lesions[1].Although multiple treatments are available for rosacea,the advent of biological agents and small-molecule agents has significantly advanced our ability to target the disease more effectively[2].In the current review,we summarize the outcomes of targeted therapies in rosacea,mainly focusing on interleukin(IL)-17 inhibitors and Janus kinase(JAK)inhibitors.展开更多
Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challengin...Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challenging.In this research,a database-assisted liquid chromatography-tandem mass spectrometry(LC-MS/MS)strategy was developed to quickly discover potential cysteine-targeting compounds.First,compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes.And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database.Second,substrate-independent product ions produced from N-acetyl-cysteine moiety were selected.Third,multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds.This strategy showed broad applicability,and covalent compounds with diverse structures were screened out,offering structural resources for covalent inhibitors development.Moreover,the screened compounds,norketamine and hydroxynorketamine,could modify synaptic transmission-related proteins in vivo,indicating their potential as covalent inhibitors.This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.展开更多
BACKGROUND The CRAFITY score is mainly utilized for hepatocellular carcinoma(HCC)patients receiving atezolizumab and bevacizumab,with little investigation in its predictive capacity for alternative regimens,such as le...BACKGROUND The CRAFITY score is mainly utilized for hepatocellular carcinoma(HCC)patients receiving atezolizumab and bevacizumab,with little investigation in its predictive capacity for alternative regimens,such as lenvatinib and programmed cell death protein 1(PD-1)inhibitors,which are widely utilized in Chinese clinical practice.AIM To look at the predictive significance of the CRAFITY score in HCC patients taking lenvatinib and PD-1 inhibitors.METHODS The retrospective investigation consisted of 192 patients with incurable HCC who received lenvatinib and PD-1 inhibitors between January 2018 and January 2022.Patients were stratified according to CRAFITY score(based on baseline alphafetoprotein and C-reactive protein levels)into CRAFITY-low,CRAFITY-intermediate,and CRAFITY-high groups.Overall survival(OS)and progressionfree survival(PFS)were assessed using Kaplan-Meier analysis,and independent prognostic factors were identified through Cox regression analysis.Nomograms were created to forecast survival for a year.RESULTS The median PFS and OS were the longest for patients in the CRAFITY-low group,followed by those in the CRAFITY-intermediate and CRAFITY-high groups(median PFS:8.4 months,6.0 months,and 3.1 months,P<0.0001;median OS:33.4 months,19.2 months,and 6.6 months,P<0.0001).Both the objective response rate(5%,19.6%,and 22%,P=0.0669)and the disease control rate(50%,76.5%,and 80%,P=0.0023)were considerably lower in the CRAFITY-high group.The findings from the multivariate analysis showed that a nomogram which included the tumor number,prior transarterial chemoembolization history,and CRAFITY score predicted 12-month survival with an area under the curve of 0.788(95%confidence interval:0.718-0.859),which was in good agreement with actual data.CONCLUSION The CRAFITY score is a valuable predictor of survival and treatment outcomes in patients receiving lenvatinib and PD-1 inhibitors.展开更多
BACKGROUND Traumatic brain injury(TBI)poses a considerable risk to human health.After TBI,individuals are susceptible to a range of psychiatric disorders,with depression being a primary complication.Selective serotoni...BACKGROUND Traumatic brain injury(TBI)poses a considerable risk to human health.After TBI,individuals are susceptible to a range of psychiatric disorders,with depression being a primary complication.Selective serotonin reuptake inhibitors(SSRIs)are frequently used in the treatment of depression;however,their efficacy in addressing major depressive disorder(MDD)in adults following TBI remains uncertain.AIM To investigate the efficacy of SSRIs in the treatment of MDD after TBI.METHODS A comprehensive search across multiple databases was conducted following the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement,encompassing studies published until May 2024.This review focused on studies that examined the efficacy of SSRIs in the treatment of MDD following TBI.Studies were assessed based sample size,treatment duration,treatment methodologies,severity of brain injury,assessment techniques,and drug response.A random-effects model was used to derive the summary effect size.RESULTS Eight studies compared the reduction in depression scores in patients with MDD after TBI and SSRI treatment.The eight studies did not exhibit heterogeneity(I^(2)=38%).The depression score for MDD after TBI in the SSRI group decreased more than that in the control group[odds ratio(OR)1.68,95%CI:1.09-2.58,P=0.02].The adverse reactions after treatment included diarrhea,dizziness,dry mouth,nausea,or vomiting.There was no difference in the incidence of adverse reactions after treatment between the two groups(OR 1.16,95%CI:0.78-1.73,P=0.46).These studies did not show significant heterogeneity(I^(2)=44%).CONCLUSION SSRIs may be effective in treating patients with MDD after TBI.Adequately powered,randomized,controlled trials are required to confirm these findings.展开更多
Gastric cancer(GC)is one of the most common malignant tumors globally.The screening rate of GC is low,and the early symptoms are not obvious,which affects early diagnosis,and most patients have a poor prognosis.Variou...Gastric cancer(GC)is one of the most common malignant tumors globally.The screening rate of GC is low,and the early symptoms are not obvious,which affects early diagnosis,and most patients have a poor prognosis.Various treatments are available for GC,mainly surgery,chemotherapy,radiotherapy,targeted therapy and immunotherapy.Immunotherapy has made significant progress in recent years,especially for unresectable and metastatic GC.Immune checkpoints are proteins which can regulate the congenital and adaptive immu-nity,and are mainly expressed on immune cells.Immune checkpoints are crucial molecules that regulate the immune system,maintaining immune balance through positive or negative modulation.Tumors exploit negative immune checkpoint molecules to suppress immune responses,thereby evading immune surveillance.Immune checkpoint inhibitors(ICIs)can undo this inhibition,reactivating immune cells to destroy tumor cells.The prospects for the treatment of GC with ICIs are promising,but it also faces many difficulties and challenges.This minireview summarizes the progress of immune ICIs in GC,discusses current individualized strategies,and explores future development directions.展开更多
Hepatocellular carcinoma(HCC),a primary malignancy of the liver and leading cause of cancer-related mortality worldwide,poses substantial therapeutic challenges,particularly in advanced and unresectable stages.Immune ...Hepatocellular carcinoma(HCC),a primary malignancy of the liver and leading cause of cancer-related mortality worldwide,poses substantial therapeutic challenges,particularly in advanced and unresectable stages.Immune checkpoint inhibitors(ICIs)have emerged as critical therapeutic agents,targeting immune checkpoint pathways to restore antitumor immune responses.Combinations such as atezolizumab(anti-programmed cell death ligand 1 with bevacizumab antivascular endothelial growth factor),as well as antibodies directed against cytotoxic T-lymphocyte associated protein 4 and programmed cell death protein 1(e.g.,ipilimumab and nivolumab),have demonstrated improved clinical outcome in selected patients.However,the overall efficacy of ICIs remains hindered by variable response rate and primary or acquired resistance.Recent evidence suggests that the gut microbiome plays a pivotal role in modulating host immune responses and may significantly influence the therapeutic efficacy of ICIs.Dysbiosis within the gut-liver axis has been implicated not only in pathogenesis and progression of HCC but also diminishing immunotherapy effectiveness.Emerging studies highlight the potential of microbiome-targeted interventions including dietary modulation,prebiotics,probiotics,and fecal microbiota transplantation to enhance ICIs responsiveness.This review explores the evolving interplay between the gut microbiota and immunotherapy in HCC,with a focus on microbiome-based strategies aimed at optimizing clinical outcomes.展开更多
Genetic disruption of the RAS binding domain(RBD)of Phosphoinositide 3-kinase alpha(PI3Kα)impairs the growth of tumors driven by the small guanosine triphosphatase RAS in mice and does not impact PI3Kα's role in...Genetic disruption of the RAS binding domain(RBD)of Phosphoinositide 3-kinase alpha(PI3Kα)impairs the growth of tumors driven by the small guanosine triphosphatase RAS in mice and does not impact PI3Kα's role in insulin mediated control of glucose homeostasis.Selectively blocking the RAS-PI3Kαinteraction may represent a strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3Kαlipid kinase activity.We developed compounds that bind covalently to cysteine 242 in the RBD of PI3K p110αand block RAS activation of PI3Kαactivity.In mice,inhibitors slow the growth of RAS mutant tumors and Human Epidermal Growth Factor Receptor 2(HER2)overexpressing tumors,particularly when combined with other inhibitors of the RAS/Mitogen-activated protein kinase pathway,without causing hyperglycemia.Oncogenic mutations in the small guanosine triphosphatase RAS occur in 20%of human cancers,with RAS proteins activating both the mitogen-activated protein kinase(MAPK)and Phosphoinositide 3-kinase(PI3K)pathways(1-3).As each of these pathways has oncogenic potential,simultaneous activation,as occurs in mutant RAS driven cancers,generates aggressive disease.In RAS-driven cell and animal models,inhibition of both the MAPK and PI3K pathways is more efficacious than targeting the individual pathways(4);however,dose-limiting toxicities in humans prevent clinical success of this strategy.展开更多
BACKGROUND Long-term use of proton pump inhibitors(PPIs)has been associated with poten-tial adverse effects,including an increased risk of gastric cancer.Despite wide-spread use awareness of these risks among physicia...BACKGROUND Long-term use of proton pump inhibitors(PPIs)has been associated with poten-tial adverse effects,including an increased risk of gastric cancer.Despite wide-spread use awareness of these risks among physicians varies considerably.Under-standing physicians’perceptions and prescribing behaviors is critical to impro-ving patient safety and promoting evidence-based practices.This study aimed to assess the level of awareness and risk perception among gastroenterologists and non-gastroenterologists regarding prolonged PPI use and its association with gastric malignancy.AIM To assess physicians’awareness of gastric cancer risk associated with long-term PPI use and compare perceptions between specialties.METHODS A cross-sectional observational study was conducted among 33 physicians(15 gastroenterologists and 18 non-gastroenterologists)in Israel.Participants com-pleted a structured questionnaire evaluating knowledge,attitudes,and prescri-bing behaviors related to PPI use.Data were analyzed using descriptive statistics and nonparametric tests to assess differences between groups and correlation patterns.Ethical approval and informed consent were obtained.RESULTS Gastroenterologists demonstrated significantly higher awareness of the potential gastric cancer risks linked to prolonged PPI use(mean awareness score:6.9±1.2)compared with non-gastroenterologists(4.1±1.3,P<0.01).Despite their awa-reness 80%of gastroenterologists reported frequent long-term prescribing.Non-parametric correlation analysis revealed associations between specialty,know-ledge level,and prescribing habits.Several misconceptions about cancer risk mechanisms were identified across specialties.CONCLUSION Physician awareness regarding gastric cancer risk of long-term PPI use remains inconsistent,especially among non-specialists,emphasizing the need for targeted educational programs and clearer prescribing guidelines.展开更多
Signal transducer and activator of transcription 3(STAT3)is a member of the transcription factors involved in regulating many physiological and pathological processes,such as cell proliferation,angiogenesis and immune...Signal transducer and activator of transcription 3(STAT3)is a member of the transcription factors involved in regulating many physiological and pathological processes,such as cell proliferation,angiogenesis and immune escape.STAT3 has been identified as a potential therapeutic target for various cancers.Although numerous STAT3 inhibitors have been discovered and optimized to directly inhibit STAT3 activity,they are not yet authorized for clinical use and only a few have entered clinical trials.Furthermore,several proteolysis-targeting chimera(PROTAC)molecules with STAT3 degrading effects have been developed.The event-driven action of PROTAC overcome the drawbacks of STAT3,a traditional undruggable target,and addressed possible resistance to small-molecule inhibitors by degrading the entire STAT3 protein.In this review,we presented a brief introduction to STAT3 and its functions in various cancers,and systematically overviewed the pharmacological effects of inhibitors targeting different domains of STAT3 in the last three years,the structural characterization of the main scaffold,the design strategies,and the pharmacological activities of the substituents.Also,the binding patterns and interactions of some inhibitors with STAT3 were analyzed in detail and the recent advances in STAT3 degraders are also summarized.We anticipate that this perspective will contribute to the design and optimize more novel effective and specific STAT3 inhibitors or degraders for carcinoma treatment.展开更多
文摘Background: Non-radiographic axial spondyloarthritis is a progressive and disabling inflammatory disease affecting young adults, with limited treatment options. TNFi are more efficacious than JAKi and IL1-7i in nr-ax SPA and it has a well-known safety profile over a longer duration. Recently, many IL-17i and JAKi were approved for the treatment of nr-ax SPA;however, data comparing IL1-7i and JAKi in terms of efficacy and safety is lacking. This systematized review aimed to compare the existing efficacy and safety data of JAKi vs IL-17i in the treatment of patients with nr-ax SPA. Methods: A systematic literature search was performed using relevant keywords in many databases. According to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA, 2020), relevant articles were included and evaluated in this review. Efficacy and safety data were collected, analyzed and compared through week 52. The first check was done by the end of week 14 and week 16 for upadacitinib and IL-17i respectively. Results: Data from four RCTs evaluating upadacitinib, secukinumab, ixekizumab, and bimekizumab comprising 1425 patients were analyzed. Overall, a comparable efficacy and safety profile were observed across different treatment arms through week 52;however, non-significant variations were encountered in some outcome measures. The primary endpoint among these RCTs (ASAS40 response rate) was met and it was higher in patients treated with bimekizumab 160 mg sc Q 4 weeks in TNFi non responders (48%) and lowest in ixekizumab 80 mg sc Q 4 weeks treated patients, (35%) (p Conclusion: The above-mentioned three IL-17i and the only one JAKi demonstrated comparable safety and efficacy profiles with some minor variations. A head-to-head trial comparing the effectiveness and safety characteristics of JAKi vs IL-17i may be needed in patients with active nr-ax SpA.
基金Supported by National Natural Science Foundation of China,No.32270768,No.82273970,No.32070726 and No.82370715Hubei Natural Science Foundation of China,No.2024AFB218+1 种基金National Key R&D Program of China,No.2023YFC2507904Doctoral Startup Foundation of Hubei University of Technology,No.XJ2022003901.
文摘Histone deacetylase inhibitors(HDACis),such as trichostatin A(TSA),have been recognized as promising anti-cancer agents due to their capacity to restore epigenetic regulation and reactivate tumor suppressor genes.However,emerging evidence indicates that unintended pro-metastatic effects may offset the therapeutic benefits of HDACis.Chen et al elucidate this paradox,demonstrating that TSA-induced hyperacetylation activates the BRD4/c-Myc/ER-stress axis,thereby promoting epithelial-mesenchymal transition and metastasis in esophageal squamous cell carcinoma(ESCC).Furthermore,they clarify the clinical significance of histone acetylation in the prognostic evaluation of ESCC.Their findings underscore the complexity of epigenetic therapies and highlight the necessity of reevaluating the associated risks and combinatorial therapeutic strategies with HDACi-based treatments.Here,we summarize the potential risks of HDACis therapy and discuss feasible combination therapeutic strategies.
基金Supported by Tianjin Key Medical Discipline(Specialty)Construction Project,No.TJYXZDXK-034AHebei Province 2025 Traditional Chinese Medicine Scientific Research Project Plan,No.T2025008.
文摘BACKGROUND Acute variceal bleeding(AVB)represents a life-threatening complication in hepatocellular carcinoma(HCC)patients undergoing systemic therapy,mainly including immune checkpoint inhibitors(ICIs)and antivascular drugs used alone or in combination.The pathogenesis of AVB in this population may involve tumor-related factors,treatment-induced effects,or progression of underlying portal hypertension.Identifying high-risk factors for AVB is crucial for the management of this patient population.AIM To develop and validate a risk prediction model for AVB occurrence in cirrhotic HCC patients receiving ICI-based systemic therapy.METHODS This retrospective study analyzed 286 HCC patients(2021-2022)receiving ICIs(mono-/combination therapy),randomly split into training(n=184)and validation(n=102)cohorts.In the training cohort,bleeding vs nonbleeding groups were compared for general information,etiological data,laboratory indicators,tumor staging,systemic treatment drugs,variceal bleeding history,and endoscopic treatment history.Risk factors for AVB were identified and used to establish a logistic regression model for predicting bleeding,which was further validated in the validation cohort.RESULTS The bleeding group had significantly higher proportions of patients with platelet count≥100×10^(9)/L,alphafetoprotein≥400 ng/mL,tumor diameter≥5 cm,portal vein tumor thrombosis,ascites,bleeding history,prior endoscopic treatment,albumin-bilirubin grade level 2-3,fibrosis-4 index(FIB-4)≥4.57,and prognostic nutritional index<45 compared to the non-bleeding group.Multivariate analysis identified tumor diameter≥5 cm,portal vein thrombosis,bleeding history,and elevated FIB-4 as independent risk factors for bleeding(P<0.05).A predictive model based on these factors showed good discrimination,with area under the receiver operating characteristic curve values of 0.861(training)and 0.816(validation).CONCLUSION A history of pre-ICI bleeding significantly increases recurrent bleeding risk,necessitating close monitoring.The FIB-4 fibrosis model,combined with tumor features,can also serve as a predictive factor for bleeding.
文摘Severe acute respiratory coronavirus-2(SARS-CoV-2)infection course differs between the young and healthy and the elderly with co-morbidities.In the latter a potentially lethal coronavirus disease 2019(COVID-19)cytokine storm has been described with an unrestrained renin-angiotensin(Ang)system(RAS).RAS inhibitors[Ang converting enzyme inhibitors and Ang II type 1 receptor(AT1R)blockers]while appearing appropriate in COVID-19,display enigmatic effects ranging from protection to harm.MicroRNA-155(miR-155)-induced translational repression of key cardiovascular(CV)genes(i.e.,AT1R)restrains SARS-CoV-2-engendered RAS hyperactivity to tolerable and SARS-CoV-2-protective CV phenotypes supporting a protective erythropoietin(EPO)evolutionary landscape.MiR-155’s disrupted repression of the AT1R 1166C-allele associates with adverse CV and COVID-19 outcomes,confirming its decisive role in RAS modulation.RAS inhibition disrupts this miR-155-EPO network by further lowering EPO and miR-155 in COVID-19 with co-morbidities,thereby allowing unimpeded RAS hyperactivity to progress precariously.Current pharmacological interventions in COVID-19 employing RAS inhibition should consider these complex but potentially detrimental miR-155/EPO-related effects.
文摘BACKGROUND Chemotherapy,targeted therapy,and immunotherapy have all been shown to achieve some efficacy in treating intrahepatic cholangiocarcinoma(ICC).How-ever,these systemic treatments have not provided optimal results for some patients.Therefore,the combination of transarterial chemoembolization(TACE)and hepatic artery infusion chemotherapy or other local interventional therapy methods is being considered for the treatment of liver tumors.AIM To evaluate the efficacy and safety of combining chemotherapy,targeted therapy,and immunotherapy,with or without TACE,in patients with ICC.METHODS We recruited 83 patients with unresectable ICC from July 2021 to December 2023 at the Affiliated Hospital of Xuzhou Medical University.Forty-one patients received TACE combined with chemotherapy,tyrosine kinase inhibitors,and pro-grammed death 1(PD-1)/programmed cell death ligand 1(PD-L1)inhibitors(ex-perimental group),whereas 42 patients were treated with chemotherapy,tyrosine kinase inhibitors,and PD-1/PD-L1 inhibitors(control group).Short-term efficacy was assessed using the modified response evaluation criterion,and the objective response rate,disease control rate,progression-free survival,and incidence of adverse events were compared between groups.RESULTS The objective response rate in the experimental group was greater than that in the control group(39.0%vs 19.0%,P<0.05).The disease control rate in the experimental group was significantly greater than that in the control group(75.6%vs 52.4%,P<0.05).The median progression-free survival times were 14.3 months in the experimental group and 12.7 months in the control group(P<0.05).All 41 patients in the experimental group developed postembol-ization syndrome.Among the symptoms,fever and pain were significantly more common in the experimental group than in the control group(85.4%vs 11.9%,P<0.001 and 58.5%vs 9.5%,P<0.001).No grade 4 or 5 treatment-related adverse events were observed in either group.CONCLUSION In patients with unresectable ICC,TACE combined with chemotherapy,tyrosine kinase inhibitors,and PD-1/PD-L1 inhibitors has good efficacy and high safety,indicating potential benefits for these patients.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82173699 and 32200531)Shanghai Jiao Tong University Trans-Med Awards Research,China(STAR Project No.:20230101)Shanghai Science and Technol-ogy Commission,China(Grant No.:23DZ2290600).
文摘Numerous c-mesenchymal-epithelial transition(c-MET)inhibitors have been reported as potential anticancer agents.However,most fail to enter clinical trials owing to poor efficacy or drug resistance.To date,the scaffold-based chemical space of small-molecule c-MET inhibitors has not been analyzed.In this study,we constructed the largest c-MET dataset,which included 2,278 molecules with different struc-tures,by inhibiting the half maximal inhibitory concentration(IC_(50))of kinase activity.No significant differences in drug-like properties were observed between active molecules(1,228)and inactive mol-ecules(1,050),including chemical space coverage,physicochemical properties,and absorption,distri-bution,metabolism,excretion,and toxicity(ADMET)profiles.The higher chemical diversity of the active molecules was downscaled using t-distributed stochastic neighbor embedding(t-SNE)high-dimensional data.Further clustering and chemical space networks(CSNs)analyses revealed commonly used scaffolds for c-MET inhibitors,such as M5,M7,and M8.Activity cliffs and structural alerts were used to reveal“dead ends”and“safe bets”for c-MET,as well as dominant structural fragments consisting of pyr-idazinones,triazoles,and pyrazines.Finally,the decision tree model precisely indicated the key structural features required to constitute active c-MET inhibitor molecules,including at least three aromatic het-erocycles,five aromatic nitrogen atoms,and eight nitrogeneoxygen atoms.Overall,our analyses revealed potential structure-activity relationship(SAR)patterns for c-MET inhibitors,which can inform the screening of new compounds and guide future optimization efforts.
文摘This article discusses the study by GrubićRotkvićet al on the mechanisms of action of sodium-glucose cotransporter 2 inhibitors(SGLT2i)in patients with type 2 diabetes mellitus(T2DM)and heart failure(HF).T2DM and HF are highly comorbid,with a significantly increased prevalence of HF in patients with T2DM.SGLT2i exhibit potential in reducing hospitalization rates for HF and cardiovascular mortality through multiple mechanisms,including improving blood glucose control,promoting urinary sodium excretion,reducing sympathetic nervous system activity,lowering both preload and afterload on the heart,alleviating inflammation and oxidative stress,enhancing endothelial function,improving myocardial energy metabolism,and stabilizing cardiac ion homeostasis.Further research and clinical practice will help optimize the use of SGLT2i in HF patients.
文摘BACKGROUND Proton pump inhibitors(PPIs)are widely used,including among cancer patients,to manage gastroesophageal reflux and other gastric acid-related disorders.Recent evidence suggests associations between long-term PPI use and higher risks for various adverse health outcomes,including greater mortality.AIM To investigate the association between PPI use and all-cause mortality among cancer patients by a comprehensive analysis after adjustment for various confounders and a robust methodological approach to minimize bias.METHODS This retrospective cohort study used data from the TriNetX research network,with electronic health records from multiple healthcare organizations.The study employed a new-user,active comparator design,which compared newly treated PPI users with non-users and newly treated histamine2 receptor antagonists(H2RA)users among adult cancer patients.Newly prescribed PPIs(esomeprazole,lansoprazole,omeprazole,pantoprazole,or rabeprazole)users were compared to non-users or newly prescribed H2RAs(cimetidine,famotidine,nizatidine,or ranitidine)users.The primary outcome was all-cause mortality.Each patient in the main group was matched to a patient in the control group using 1:1 propensity score matching to reduce confounding effects.Multivariable Cox regression models were used to estimate hazard ratios(HRs)and 95% confidence interval(CI).RESULTS During the follow-up period(median 5.4±1.8 years for PPI users and 6.5±1.0 years for non-users),PPI users demonstrated a higher all-cause mortality rate than non-users after 1 year,2 years,and at the end of follow up(HRs:2.34-2.72).Compared with H2RA users,PPI users demonstrated a higher rate of all-cause mortality HR:1.51(95%CI:1.41-1.69).Similar results were observed across sensitivity analyses by excluding deaths from the first 9 months and 1-year post-exposure,confirming the robustness of these findings.In a sensitivity analysis,we analyzed all-cause mortality outcomes between former PPI users and individuals who have never used PPIs,providing insights into the long-term effects of past PPI use.In addition,at 1-year follow-up,the analysis revealed a significant difference in mortality rates between former PPI users and non-users(HR:1.84;95%CI:1.82-1.96).CONCLUSION PPI use among cancer patients was associated with a higher risk of all-cause mortality compared to non-users or H2RA users.These findings emphasize the need for cautious use of PPIs in cancer patients and suggest that alternative treatments should be considered when clinically feasible.However,further studies are needed to corroborate our findings,given the significant adverse outcomes in cancer patients.
文摘Treatment with immune checkpoint inhibitors(ICIs)is an innovative therapy for managing certain types of malignancy and has the potential to improve overall patient survival significantly.The most widely used ICIs selectively target different receptors comprising programmed cell death-1 receptor,programmed cell death-ligand 1 receptor,and cytotoxic T lymphocyte antigen 4 receptor.The widespread utilization of ICIs over the past several years,however,is frequently accompanied by immune-related adverse events(irAEs)that substantially impact the patient’s quality of life,particularly those affecting the digestive system,including both the upper and lower gastrointestinal tract.Based on a literature search covering databases such as PubMed,Web of Science,Embase,and the Cochrane Library,we present an insight into primary gastrointestinal irAEs,with a special focus on endoscopic manifestations.Additionally,we analyze data regarding the pathogenetic mechanisms,diagnostic approaches,histological characteristics,and proposed therapeutic interventions for managing irAEs involving the gastrointestinal tract.
基金supported by the National Natural Science Foundation of China(32360564)the Guangxi Science and Technology Major Project(2021AA17011)the Nanning Government Specially-invited Expert Program,and Guangxi University Natural Science and Technological Innovation Development Multiplication Plan Project(2022BZRC010).
文摘Trehalose is an autophagy-promoting disaccharide,which can improve and delay chronic diseases like neurodegenerative diseases and atherosclerosis,but its bioavailability is severely restricted by endogenous trehalase in mammals.Trehalase inhibitor is a promising and effective way to enhance trehalose bioavailability by preventing trehalose from hydrolyzing.However,previously reported trehalase inhibitors still face safety of long-term use and promiscuous inhibition on intestinal glycosidases.This study carried out a high-throughput virtual screening through molecular pool-based molecular docking combined with in vitro inhibition experiments to screen trehalase inhibitors naturally derived from foods.Out of 1769 small molecules,which include 115 analogs of trehalose,natural monosaccharides,disaccharides,trisaccharides,imidazoles and their derivatives,as well as 20 natural amino acids and their 400 dipeptides,isomaltose,α-isomaltulose,and isomaltitol exhibited the best inhibitory activities,beyond as traditional sweetener and prebiotic.Best of all,isomaltose showed the half maximal inhibitory concentration(IC50)and inhibition constant(Ki)values on trehalase of 5.59 and(2.1760±0.3431)mmol/L,respectively.Moreover,isomaltose was resistant to the simulated digestive environment and did not affect intestinal glycosidases such asα-glucosidase and glucoamylase,making it a reliable edible candidate for a trehalase inhibitor.This study provides new insights into the virtual screening-based identification of new food-derived trehalase inhibitors for enhanced integrity and bioavailability of orally administered trehalose,especially repurposing a prebiotic for another new use as trehalase inhibitor.
基金supported by the National Natural Science Foundation of China(Grant No.81903685).
文摘To comprehensively analyze the current research landscape and emerging trends in the application of pro-protein convertase subtilisin/kexin type 9(PCSK9)inhibitors for treating cardiovascular diseases,a bibliometric analysis was conducted.Relevant English-language literature on PCSK9 inhibitors in cardiovascular treatment,published between January 1,2013,and December 31,2023,was retrieved from the Web of Science core collection database.Utilizing tools such as VOSviewer 1.6.20,CiteSpace 6.2.R6,and Excel 2021,the study examined key features of the literature,including annual publication trends,contributing countries/regions,institutions,authors,journals,and key research themes.The analysis identified a total of 1383 articles,revealing a general upward trend in annual publication output.Research in this field has been conducted by 78 countries/regions,with the United States leading in the number of publications(563 articles).The United States also demonstrates strong collaborative networks with other leading countries,including the United Kingdom,Canada,the Netherlands,Australia,Italy,Germany,and Switzerland.In terms of institutional contributions,2379 institutions have published relevant studies,with Amgen Inc.producing the most publications(n=70).Among individual contributors,Professor Giugliano from the Thrombolysis in Myocardial Infarction(TIMI)Study Group at Brigham and Women’s Hospital and Harvard Medical School is the most prolific author,with 37 publications.Meanwhile,Professor Sabatine,also from the TIMI Study Group,holds the highest number of co-citations,underscoring his influence in the field.The analysis also identified 436 journals publishing research on PCSK9 inhibitors,with the Journal of Clinical Lipidology being the most productive(n=54).However,the New England Journal of Medicine is noted as the journal with the highest co-citation count,indicating its significant impact on this research area.Research hotspots have focused on the efficacy and safety of PCSK9 inhibitors,alongside the clinical application of conventional lipid-lowering therapies such as statins and ezetimibe.Notably,the development of monoclonal antibodies and siRNA-based therapies targeting PCSK9 has gained considerable attention over the past decade due to their superior ability to lower low-density lipoprotein cholesterol(LDL-C).The effectiveness and long-term safety profiles of these novel agents are of growing interest,prompting updates to lipid management guidelines and offering new perspectives for the prevention and treatment of cardiovascular diseases.
文摘Dear Editor,Rosacea is characterized by persistent or transient erythema,papules,pustules,telangiectasia,and/or phymatous lesions[1].Although multiple treatments are available for rosacea,the advent of biological agents and small-molecule agents has significantly advanced our ability to target the disease more effectively[2].In the current review,we summarize the outcomes of targeted therapies in rosacea,mainly focusing on interleukin(IL)-17 inhibitors and Janus kinase(JAK)inhibitors.
基金supported by the Science and Technology Development Fund,Macao SAR,China(Grant Nos.:FDCT 0001/2020/AKP and 006/2023/SKL)Guangxi Science and Technology Major Program,China(Program No.:Guike AA22096022).
文摘Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challenging.In this research,a database-assisted liquid chromatography-tandem mass spectrometry(LC-MS/MS)strategy was developed to quickly discover potential cysteine-targeting compounds.First,compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes.And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database.Second,substrate-independent product ions produced from N-acetyl-cysteine moiety were selected.Third,multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds.This strategy showed broad applicability,and covalent compounds with diverse structures were screened out,offering structural resources for covalent inhibitors development.Moreover,the screened compounds,norketamine and hydroxynorketamine,could modify synaptic transmission-related proteins in vivo,indicating their potential as covalent inhibitors.This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.
基金Supported by the Capital’s Funds for Health Improvement and Research,No.SF202222175.
文摘BACKGROUND The CRAFITY score is mainly utilized for hepatocellular carcinoma(HCC)patients receiving atezolizumab and bevacizumab,with little investigation in its predictive capacity for alternative regimens,such as lenvatinib and programmed cell death protein 1(PD-1)inhibitors,which are widely utilized in Chinese clinical practice.AIM To look at the predictive significance of the CRAFITY score in HCC patients taking lenvatinib and PD-1 inhibitors.METHODS The retrospective investigation consisted of 192 patients with incurable HCC who received lenvatinib and PD-1 inhibitors between January 2018 and January 2022.Patients were stratified according to CRAFITY score(based on baseline alphafetoprotein and C-reactive protein levels)into CRAFITY-low,CRAFITY-intermediate,and CRAFITY-high groups.Overall survival(OS)and progressionfree survival(PFS)were assessed using Kaplan-Meier analysis,and independent prognostic factors were identified through Cox regression analysis.Nomograms were created to forecast survival for a year.RESULTS The median PFS and OS were the longest for patients in the CRAFITY-low group,followed by those in the CRAFITY-intermediate and CRAFITY-high groups(median PFS:8.4 months,6.0 months,and 3.1 months,P<0.0001;median OS:33.4 months,19.2 months,and 6.6 months,P<0.0001).Both the objective response rate(5%,19.6%,and 22%,P=0.0669)and the disease control rate(50%,76.5%,and 80%,P=0.0023)were considerably lower in the CRAFITY-high group.The findings from the multivariate analysis showed that a nomogram which included the tumor number,prior transarterial chemoembolization history,and CRAFITY score predicted 12-month survival with an area under the curve of 0.788(95%confidence interval:0.718-0.859),which was in good agreement with actual data.CONCLUSION The CRAFITY score is a valuable predictor of survival and treatment outcomes in patients receiving lenvatinib and PD-1 inhibitors.
文摘BACKGROUND Traumatic brain injury(TBI)poses a considerable risk to human health.After TBI,individuals are susceptible to a range of psychiatric disorders,with depression being a primary complication.Selective serotonin reuptake inhibitors(SSRIs)are frequently used in the treatment of depression;however,their efficacy in addressing major depressive disorder(MDD)in adults following TBI remains uncertain.AIM To investigate the efficacy of SSRIs in the treatment of MDD after TBI.METHODS A comprehensive search across multiple databases was conducted following the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement,encompassing studies published until May 2024.This review focused on studies that examined the efficacy of SSRIs in the treatment of MDD following TBI.Studies were assessed based sample size,treatment duration,treatment methodologies,severity of brain injury,assessment techniques,and drug response.A random-effects model was used to derive the summary effect size.RESULTS Eight studies compared the reduction in depression scores in patients with MDD after TBI and SSRI treatment.The eight studies did not exhibit heterogeneity(I^(2)=38%).The depression score for MDD after TBI in the SSRI group decreased more than that in the control group[odds ratio(OR)1.68,95%CI:1.09-2.58,P=0.02].The adverse reactions after treatment included diarrhea,dizziness,dry mouth,nausea,or vomiting.There was no difference in the incidence of adverse reactions after treatment between the two groups(OR 1.16,95%CI:0.78-1.73,P=0.46).These studies did not show significant heterogeneity(I^(2)=44%).CONCLUSION SSRIs may be effective in treating patients with MDD after TBI.Adequately powered,randomized,controlled trials are required to confirm these findings.
文摘Gastric cancer(GC)is one of the most common malignant tumors globally.The screening rate of GC is low,and the early symptoms are not obvious,which affects early diagnosis,and most patients have a poor prognosis.Various treatments are available for GC,mainly surgery,chemotherapy,radiotherapy,targeted therapy and immunotherapy.Immunotherapy has made significant progress in recent years,especially for unresectable and metastatic GC.Immune checkpoints are proteins which can regulate the congenital and adaptive immu-nity,and are mainly expressed on immune cells.Immune checkpoints are crucial molecules that regulate the immune system,maintaining immune balance through positive or negative modulation.Tumors exploit negative immune checkpoint molecules to suppress immune responses,thereby evading immune surveillance.Immune checkpoint inhibitors(ICIs)can undo this inhibition,reactivating immune cells to destroy tumor cells.The prospects for the treatment of GC with ICIs are promising,but it also faces many difficulties and challenges.This minireview summarizes the progress of immune ICIs in GC,discusses current individualized strategies,and explores future development directions.
文摘Hepatocellular carcinoma(HCC),a primary malignancy of the liver and leading cause of cancer-related mortality worldwide,poses substantial therapeutic challenges,particularly in advanced and unresectable stages.Immune checkpoint inhibitors(ICIs)have emerged as critical therapeutic agents,targeting immune checkpoint pathways to restore antitumor immune responses.Combinations such as atezolizumab(anti-programmed cell death ligand 1 with bevacizumab antivascular endothelial growth factor),as well as antibodies directed against cytotoxic T-lymphocyte associated protein 4 and programmed cell death protein 1(e.g.,ipilimumab and nivolumab),have demonstrated improved clinical outcome in selected patients.However,the overall efficacy of ICIs remains hindered by variable response rate and primary or acquired resistance.Recent evidence suggests that the gut microbiome plays a pivotal role in modulating host immune responses and may significantly influence the therapeutic efficacy of ICIs.Dysbiosis within the gut-liver axis has been implicated not only in pathogenesis and progression of HCC but also diminishing immunotherapy effectiveness.Emerging studies highlight the potential of microbiome-targeted interventions including dietary modulation,prebiotics,probiotics,and fecal microbiota transplantation to enhance ICIs responsiveness.This review explores the evolving interplay between the gut microbiota and immunotherapy in HCC,with a focus on microbiome-based strategies aimed at optimizing clinical outcomes.
文摘Genetic disruption of the RAS binding domain(RBD)of Phosphoinositide 3-kinase alpha(PI3Kα)impairs the growth of tumors driven by the small guanosine triphosphatase RAS in mice and does not impact PI3Kα's role in insulin mediated control of glucose homeostasis.Selectively blocking the RAS-PI3Kαinteraction may represent a strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3Kαlipid kinase activity.We developed compounds that bind covalently to cysteine 242 in the RBD of PI3K p110αand block RAS activation of PI3Kαactivity.In mice,inhibitors slow the growth of RAS mutant tumors and Human Epidermal Growth Factor Receptor 2(HER2)overexpressing tumors,particularly when combined with other inhibitors of the RAS/Mitogen-activated protein kinase pathway,without causing hyperglycemia.Oncogenic mutations in the small guanosine triphosphatase RAS occur in 20%of human cancers,with RAS proteins activating both the mitogen-activated protein kinase(MAPK)and Phosphoinositide 3-kinase(PI3K)pathways(1-3).As each of these pathways has oncogenic potential,simultaneous activation,as occurs in mutant RAS driven cancers,generates aggressive disease.In RAS-driven cell and animal models,inhibition of both the MAPK and PI3K pathways is more efficacious than targeting the individual pathways(4);however,dose-limiting toxicities in humans prevent clinical success of this strategy.
文摘BACKGROUND Long-term use of proton pump inhibitors(PPIs)has been associated with poten-tial adverse effects,including an increased risk of gastric cancer.Despite wide-spread use awareness of these risks among physicians varies considerably.Under-standing physicians’perceptions and prescribing behaviors is critical to impro-ving patient safety and promoting evidence-based practices.This study aimed to assess the level of awareness and risk perception among gastroenterologists and non-gastroenterologists regarding prolonged PPI use and its association with gastric malignancy.AIM To assess physicians’awareness of gastric cancer risk associated with long-term PPI use and compare perceptions between specialties.METHODS A cross-sectional observational study was conducted among 33 physicians(15 gastroenterologists and 18 non-gastroenterologists)in Israel.Participants com-pleted a structured questionnaire evaluating knowledge,attitudes,and prescri-bing behaviors related to PPI use.Data were analyzed using descriptive statistics and nonparametric tests to assess differences between groups and correlation patterns.Ethical approval and informed consent were obtained.RESULTS Gastroenterologists demonstrated significantly higher awareness of the potential gastric cancer risks linked to prolonged PPI use(mean awareness score:6.9±1.2)compared with non-gastroenterologists(4.1±1.3,P<0.01).Despite their awa-reness 80%of gastroenterologists reported frequent long-term prescribing.Non-parametric correlation analysis revealed associations between specialty,know-ledge level,and prescribing habits.Several misconceptions about cancer risk mechanisms were identified across specialties.CONCLUSION Physician awareness regarding gastric cancer risk of long-term PPI use remains inconsistent,especially among non-specialists,emphasizing the need for targeted educational programs and clearer prescribing guidelines.
基金supported by grants from the National Key Research and Development Program of China(No.2023YFA1800403)The Science and Technology Commission of Shanghai Municipality(No.21S11907800)Key Research and Development Program of Ningxia(No.2023BEG02010).
文摘Signal transducer and activator of transcription 3(STAT3)is a member of the transcription factors involved in regulating many physiological and pathological processes,such as cell proliferation,angiogenesis and immune escape.STAT3 has been identified as a potential therapeutic target for various cancers.Although numerous STAT3 inhibitors have been discovered and optimized to directly inhibit STAT3 activity,they are not yet authorized for clinical use and only a few have entered clinical trials.Furthermore,several proteolysis-targeting chimera(PROTAC)molecules with STAT3 degrading effects have been developed.The event-driven action of PROTAC overcome the drawbacks of STAT3,a traditional undruggable target,and addressed possible resistance to small-molecule inhibitors by degrading the entire STAT3 protein.In this review,we presented a brief introduction to STAT3 and its functions in various cancers,and systematically overviewed the pharmacological effects of inhibitors targeting different domains of STAT3 in the last three years,the structural characterization of the main scaffold,the design strategies,and the pharmacological activities of the substituents.Also,the binding patterns and interactions of some inhibitors with STAT3 were analyzed in detail and the recent advances in STAT3 degraders are also summarized.We anticipate that this perspective will contribute to the design and optimize more novel effective and specific STAT3 inhibitors or degraders for carcinoma treatment.
