New perspective on the treatment of rheumatic arthritis based on“strengthening body resistance(Fú Zhèng)”in the theory of co-inhibitory receptor-regulated T-cell immunity

Co-inhibitory receptors serve as crucial regulators of T-cell function,playing a pivotal role in modulating the delicate balance between immune tolerance and autoimmunity.Initially identified in autoimmune disease models,co-inhibitory receptors,including CTLA-4,PD-1,TIM-3,and TIGIT,were found to be integral to immune regulation.Their blockade or absence in these models resulted in the induction or exacerbation of autoimmune diseases.Additionally,scholars have observed that co-inhibitory receptors on lymphocytes hold the potential to influence the prognosis in the context of chronic inflammation.Consequently,the blocking of co-suppressor receptors has emerged as a novel therapeutic approach for inhibiting refractory inflammatory diseases,particularly rheumatoid arthritis.From the standpoint of traditional Chinese medicine(TCM),the treatment of rheumatoid arthritis based on the“strengthening body resistance(FúZhèng)”theory can be construed as the regulation of co-suppressor receptors to modulate the body’s immune function in combating chronic inflammation.This article provides a succinct overview of the role of co-suppressor receptors in anti-inflammatory processes and explores the research prospects of co-suppressor receptor intervention in the treatment of rheumatoid arthritis.The exploration integrates the“strengthening body resistance(FúZhèng)”theory with relevant Chinese medicine formulations.

Assessing the corrosion protection property of coatings loaded with corrosion inhibitors using the real-time atmospheric corrosion monitoring technique

The atmospheric corrosion monitoring(ACM)technique has been widely employed to track the real-time corrosion behavior of metal materials.However,limited studies have applied ACM to the corrosion protection properties of organic coatings.This study compared a bare epoxy coating with one containing zinc phosphate corrosion inhibitors,both applied on ACM sensors,to observe their corrosion protection properties over time.Coatings with artificial damage via scratches were exposed to immersion and alternating dry and wet environments,which allowed for monitoring galvanic corrosion currents in real-time.Throughout the corrosion tests,the ACM currents of the zinc phosphate/epoxy coating were considerably lower than those of the blank epoxy coating.The trend in ACM current variations closely matched the results obtained from regular electrochemical tests and surface analysis.This alignment highlights the potential of the ACM technique in evaluating the corrosion protection capabilities of organic coatings.Compared with the blank epoxy coating,the zinc phosphate/epoxy coating showed much-decreased ACM current values that confirmed the effective inhibition of zinc phosphate against steel corrosion beneath the damaged coating.

Programmed cell death 1 inhibitor sintilimab plus S-1 and gemcitabine for liver metastatic pancreatic ductal adenocarcinoma

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly aggressive cancer with poor prognosis.When it metastasizes to the liver,treatment options become particularly limited and challenging.Current treatment options for liver metastatic PDAC are limited,and chemotherapy alone often proves insufficient.Immunotherapy,particularly programmed cell death 1(PD-1)inhibitors like sintilimab,shows potential efficacy for various cancers but has limited reports on PDAC.This study compares the efficacy and safety of sintilimab plus S-1 and gemcitabine vs S-1 and gemcitabine alone in liver metastatic PDAC.AIM To explore the feasibility and effectiveness of combined PD-1 inhibitor sintilimab and S-1 and gemcitabine(combination group)vs S-1 and gemcitabine used alone(chemotherapy group)for treating liver metastatic pancreatic adenocarcinoma.METHODS Eligible patients were those with only liver metastatic PDAC,an Eastern Cooperative Oncology Group performance status of 0-1,adequate organ and marrow functions,and no prior anticancer therapy.Participants in the combination group received intravenous sintilimab 200 mg every 3 weeks,oral S-140 mg/m²twice daily on days 1-14 of a 21-day cycle,and intravenous gemcitabine 1000 mg/m²on days 1 and 8 of the same cycle for up to eight cycles or until disease progression,death,or unacceptable toxicity.Participants in the chemotherapy group received oral S-140 mg/m²twice daily on days 1-14 of a 21-day cycle and intravenous gemcitabine 1000 mg/m²on days 1 and 8 of the same cycle for up to eight cycles.Between June 2020 and December 2021,66 participants were enrolled,with 32 receiving the combination treatment and 34 receiving chemotherapy alone.RESULTS The group receiving the combined therapy exhibited a markedly prolonged median overall survival(18.8 months compared to 10.3 months,P<0.05)and progression-free survival(9.6 months vs 5.4 months,P<0.05).compared to the chemotherapy group.The incidence of severe adverse events did not differ significantly between the two groups(P>0.05).CONCLUSION The combination of PD-1 inhibitor sintilimab with S-1 and gemcitabine demonstrated effectiveness and safety for treating liver metastatic PDAC,meriting further investigation.

Proton pump inhibitors and all-cause mortality risk among cancer patients

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.

Risk of hepatitis B virus reactivation in oncological patients treated with tyrosine kinase inhibitors:A case report and literature analysis

Hepatitis B virus(HBV)reactivation(HBVr)represents a severe and potentially life-threatening condition,and preventive measures are available through blood test screening or prophylactic therapy administration.The assessment of HBVr traditionally considers factors such as HBV profile,including hepatitis B surface antigen(HBsAg)and antibody to hepatitis B core antigen,along with type of medication(chemotherapy;immunomodulants).Nevertheless,consideration of possible patient’s underlying tumor and the specific malignancy type(solid or hematologic)plays a crucial role and needs to be assessed for decision-making process.

Sodium-dependent glucose transporter 2 inhibitors effects on myocardial function in patients with type 2 diabetes and asymptomatic heart failure

BACKGROUND Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)have shown efficacy in reducing heart failure(HF)burden in a very heterogeneous groups of patients,raising doubts about some contemporary assumptions of their mechanism of action.We previously published a prospective observational study that evaluated mechanisms of action of SGLT2i in patients with type 2 diabetes who were in HF stages A and B on dual hypoglycemic therapy.Two groups of patients were included in the study:the ones receiving SGLT2i as an add-on agent to metformin and the others on dipeptidyl peptidase-4 inhibitors as an add-on to metformin due to suboptimal glycemic control.AIM To evaluate the outcomes regarding natriuretic peptide,oxidative stress,inflammation,blood pressure,heart rate,cardiac function,and body weight.METHODS The study outcomes were examined by dividing each treatment arm into two subgroups according to baseline parameters of global longitudinal strain(GLS),N-terminal pro-brain natriuretic peptide,myeloperoxidase(MPO),high-sensitivity C-reactive protein(hsCRP),and systolic and diastolic blood pressure.To evaluate the possible predictors of observed changes in the SGLT2i arm during follow-up,a rise in stroke volume index,body mass index(BMI)decrease,and lack of heart rate increase,linear regression analysis was performed.RESULTS There was a greater reduction of MPO,hsCRP,GLS,and blood pressure in the groups with higher baseline values of mentioned parameters irrespective of the therapeutic arm after 6 months of follow-up.Significant independent predictors of heart rate decrease were a reduction in early mitral inflow velocity to early diastolic mitral annular velocity at the interventricular septal annulus ratio and BMI,while the predictor of stroke volume index increase was SGLT2i therapy itself.CONCLUSION SGLT2i affect body composition,reduce cardiac load,improve diastolic/systolic function,and attenuate the sympathetic response.Glycemic control contributes to the improvement of heart function,blood pressure control,oxidative stress,and reduction in inflammation.

Immune checkpoint inhibitor-associated gastritis:Patterns and management

Immune checkpoint inhibitors(ICIs)are widely used due to their effectiveness in treating various tumors.Immune-related adverse events(irAEs)are defined as adverse effects resulting from ICI treatment.Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects,such as diarrhea and colitis,which may lead to the cessation of ICIs.Although irAE gastritis is rarely reported,it may lead to serious complications such as gastrorrhagia.Furthermore,irAE gastritis is often difficult to identify early due to its diverse symptoms.Although steroid hormones and immunosuppressants are commonly used to reverse irAEs,the best regimen and dosage for irAE gastritis remains uncertain.In addition,the risk of recurrence of irAE gastritis after the reuse of ICIs should be considered.In this editorial,strategies such as early identification,pathological diagnosis,mana-gement interventions,and immunotherapy rechallenge are discussed to enable clinicians to better manage irAE gastritis and improve the prognosis of these patients.

Present and prospect of transarterial chemoembolization combined with tyrosine kinase inhibitor and PD-1 inhibitor for unresectable hepatocellular carcinoma

In this editorial,we comment on the article(World J Gastrointest Oncol 2024;16:1236-1247),which is a retrospective study of transarterial chemoembolization(TACE)combined with multi-targeted tyrosine kinase inhibitor(TKI)and programmed cell death protein-1(PD-1)inhibitor for the treatment of unresectable hepatocellular carcinoma(HCC).Herein,we focus specifically on the mechanisms of this triple therapy,administration sequence and selection of each medication,and implications for future clinical trials.Based on the interaction mechanisms between medications,the triple therapy of TACE+TKI+PD-1 is proposed to complement the deficiency of each monotherapy,and achieve synergistic antitumor effects.Although this triple therapy has been evaluated by several retrospective trials,it is still controversial whether the triple therapy achieves better clinical benefits,due to the flawed study design and heterogeneity in medications.In addition,the administration sequence,which may greatly affect the clinical benefit,needs to be fully considered at clinical decision-making for obtaining better prognosis.We hope that this editorial could contribute to the design and optimization of future trials.

Hepatic arterial infusion chemotherapy with anti-angiogenesis agents and immune checkpoint inhibitors for unresectable hepatocellular carcinoma and meta-analysis

BACKGROUND Hepatic arterial infusion chemotherapy(HAIC)has been proven to be an ideal choice for treating unresectable hepatocellular carcinoma(uHCC).HAIC-based treatment showed great potential for treating uHCC.However,large-scale studies on HAIC-based treatments and meta-analyses of first-line treatments for uHCC are lacking.AIM To investigate better first-line treatment options for uHCC and to assess the safety and efficacy of HAIC combined with angiogenesis inhibitors,programmed cell death of protein 1(PD-1)and its ligand(PD-L1)blockers(triple therapy)under real-world conditions.METHODS Several electronic databases were searched to identify eligible randomized controlled trials for this meta-analysis.Study-level pooled analyses of hazard ratios(HRs)and odds ratios(ORs)were performed.This was a retrospective single-center study involving 442 patients with uHCC who received triple therapy or angiogenesis inhibitors plus PD-1/PD-L1 blockades(AIPB)at Sun Yat-sen University Cancer Center from January 2018 to April 2023.Propensity score matching(PSM)was performed to balance the bias between the groups.The Kaplan-Meier method and cox regression were used to analyse the survival data,and the log-rank test was used to compare the suvival time between the groups.RESULTS A total of 13 randomized controlled trials were included.HAIC alone and in combination with sorafenib were found to be effective treatments(P values for ORs:HAIC,0.95;for HRs:HAIC+sorafenib,0.04).After PSM,176 HCC patients were included in the analysis.The triple therapy group(n=88)had a longer median overall survival than the AIPB group(n=88)(31.6 months vs 14.6 months,P<0.001)and a greater incidence of adverse events(94.3%vs 75.4%,P<0.001).CONCLUSION This meta-analysis suggests that HAIC-based treatments are likely to be the best choice for uHCC.Our findings confirm that triple therapy is more effective for uHCC patients than AIPB.

Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer:Unravelling challenges and future directions

Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

Effects of proton pump inhibitors on inflammatory bowel disease:An updated review

Inflammatory bowel disease(IBD)is believed to be caused by various factors,including abnormalities in disease susceptibility genes,environmental factors,immune factors,and intestinal bacteria.Proton pump inhibitors(PPIs)are the primary drugs used to treat acid-related diseases.They are also commonly prescribed to patients with IBD.Recent studies have suggested a potential association between the use of certain medications,such as PPIs,and the occurrence and progression of IBD.In this review,we summarize the potential impact of PPIs on IBD and analyze the underlying mechanisms.Our findings may provide insights for conducting further investigations into the effects of PPIs on IBD and serve as an important reminder for physicians to exercise caution when prescribing PPIs to patients with IBD.

Hepatocellular carcinoma immune microenvironment and check point inhibitors-current status

Hepatocellular carcinoma(HCC)is the most common primary tumor of the liver and has a high mortality rate.The Barcelona Clinic Liver Cancer staging system in addition to tumor staging also links the modality of treatment available to a particular stage.The recent description of the tumor microenvironment(TME)in HCC has provided a new concept of immunogenicity within the HCC.Virusrelated HCC has been shown to be more immunogenic with higher expression of cytotoxic T lymphocytes and decreased elements for immunosuppression such as regulatory T cells.This immunogenic milieu provides a better response to immunotherapy especially immune checkpoint inhibitors(ICIs).In addition,the recent data on combining locoregional therapies and other strategies may convert the less immunogenic state of the TME towards higher immunogenicity.Therefore,data are emerging on the use of combinations of locoregional therapy and ICIs in unresectable or advanced HCC and has shown better survival outcomes in this difficult population.

Transcatheter arterial chemoembolization combined with PD-1 inhibitors and Lenvatinib for hepatocellular carcinoma with portal vein tumor thrombus

BACKGROUND Hepatocellular carcinoma(HCC)patients complicated with portal vein tumor thrombus(PVTT)exhibit poor prognoses and treatment responses.AIM To investigate efficacies and safety of the combination of PD-1 inhibitor,transcatheter arterial chemoembolization(TACE)and Lenvatinib in HCC subjects comorbid with PVTT.METHODS From January 2019 to December 2020,HCC patients with PVTT types Ⅰ-Ⅳ were retrospectively enrolled at Beijing Ditan Hospital.They were distributed to either the PTL or TACE/Lenvatinib(TL)group.The median progression-free survival(mPFS)was set as the primary endpoint,while parameters like median overall survival,objective response rate,disease control rate(DCR),and toxicity level served as secondary endpoints.RESULTS Forty-one eligible patients were finally recruited for this study and divided into the PTL(n=18)and TL(n=23)groups.For a median follow-up of 21.8 months,the DCRs were 88.9%and 60.9%in the PTL and TL groups(P=0.046),res-pectively.Moreover,mPFS indicated significant improvement(HR=0.25;P<0.001)in PTL-treated patients(5.4 months)compared to TL-treated(2.7 months)patients.There were no treatment-related deaths or differences in adverse events in either group.CONCLUSION A triplet regimen of PTL was safe and well-tolerated as well as exhibited favorable efficacy over the TL regimen for advanced-stage HCC patients with PVTT types Ⅰ-Ⅳ.

Evaluating the influence of sarcopenia and myosteatosis on clinical outcomes in gastric cancer patients undergoing immune checkpoint inhibitor

BACKGROUND The development and progression of gastric cancer(GC)are closely linked to the nutritional status of patients.Although immunotherapy has been demonstrated to be clinically effective,the relationships of sarcopenia and myosteatosis with the use of immune checkpoint inhibitors(ICIs)in patients with gastric cancer remain to be characterized.METHODS We performed a retrospective study of patients who were undergoing immuno-therapy for GC.For the evaluation of sarcopenia,the optimal cut-off value for the skeletal muscle index was established using receiver operating characteristic analysis of data obtained from pre-treatment computed tomography images at the L3 vertebral level.Myosteatosis was defined using the mean skeletal muscle density(SMD),with a threshold value of<41 Hounsfield units(HU)for patients with a body mass index(BMI)<25 kg/m^(2)and<33 HU for those with a BMI≥25 kg/m^(2).The log-rank test was used to compare progression-free survival(PFS)and overall survival(OS),and a Cox proportional hazard model was used to identify prognostic factors.Nomograms were developed to predict the PFS and OS of patients on the basis of the results of multivariate analyses.RESULTS We studied 115 patients who were undergoing ICI therapy for GC,of whom 27.4%had sarcopenia and 29.8%had myosteatosis.Patients with sarcopenia or myosteatosis had significantly shorter PFS and OS than those without these conditions.Furthermore,both sarcopenia and myosteatosis were found to be independent predictors of PFS and OS in patients with GC administering an ICI.The prediction models created for PFS and OS were associated with C-indexes of 0.758 and 0.781,respectively.CONCLUSION The presence of sarcopenia or myosteatosis is a reliable predictor of the clinical outcomes of patients with GC who are undergoing treatment with an ICI.

Metastatic stomach lymphoepithelioma-like carcinoma and immune checkpoint inhibitor therapy:A case report

BACKGROUND Pulmonary lymphoepithelioma-like carcinoma(PLELC)is a rare type of nonsmall-cell lung cancer.Stomach lymphoepithelioma-like carcinoma(LELC)metastasis secondary to PLELC has not been reported recently.CASE SUMMARY A 64-year-old female was admitted to our hospital for a regular gastroscopy examination with a 6-year history of surgical resection for left PLELC.Positron emission tomography/computed tomography suggested high accumulation of 18F-fludeoxyglucose in the gastric cardia region.Upper gastrointestinal endoscopy confirmed a large mass at the stomach fundus.Immunohistochemistry(IHC)of the biopsy suggested metastatic stomach LELC.Proximal gastrectomy showed that this 6.5 cm×5.0 cm mass was located in the stomach fundus near the cardia.Histopathological examination showed a poorly differentiated carcinoma with prominent lymphoplasmacytic infiltration.IHC demonstrated that the tumor was positive for CK(AE1/AE3),p63,p40,p53,Ki-67(70%),and EGFR(3+)and negative for CK7,CK20,Her2,and CD10.In situ hybridization analysis showed positive staining Epstein-Barr virus-encoded RNA.Tumor programmed cell death ligand 1(PD-L1)expression score was 98%,and the combined positive score was 100,with no evidence of microsatellite instability.Thus,the patient was unequivocally diagnosed with metastatic stomach LELC secondary to pulmonary LELC.After discharge,this patient underwent PD-1 inhibitor treatment(toripalimab,240 mg)every 3 wk for ten cycles,and she has had no tumor recurrence.CONCLUSION For gastric LELC metastasis,PD-1 inhibitor therapy could become a new therapeutic approach,though there is still no evidence from large data sets to support this.

HIV-1 fusion inhibitor VIR576 interferes with T-cell activation by targeting TCR

Aim To determine the effect of VIR576, a dimeric 20-mer peptide potently inhibits HIV-1 entry, on antigen-specific T cell and non-antigen-specific T cell activation. Methods In vitro T-cell proliferation assays were estalished to investigate the potential effect of FP16, VIR576 on the proliferation of A2b cells in response to MOG35-55. A fluorescence-based binding assay using Rhodamine （Rho）-conjugated VIR576 was estalished to e- valuate the potential interaction between VIR576 and TCR-TMD. Fluorescence confocal microscopy was used to to study whether VIR576 could colocalize with CD4 molecule in the CD4 ＋ T cell membrane to interact with TCR. Re- suits The effects of VIR576 on the proliferation of MOG-specific A2b T cells in response to the stimulation of MOG 35 -55 peptide wasevaluated. VIR576 itself could directly inhibit antigen-specific T-cell activation. Further studies confirmed that VIR576 also inhibited the proliferation of splenocytes and primary CD4 ＋ CD25- T cells iso- lated from the spleens of DOll. 10 OVA Tg mice in response to OVA stimulation in vitro. However, VIR576 had no effect on the proliferation of normal mouse splenocytes and T lymphocytes stimulated with Con A or anti-CD3 anti- body. The FRET assay confirmed that VIR576 effectively binds to the core peptide （CP） , corresponding to the N- terminal 9-residue region of TCR-TMD. Confocal microscopy revealed that VIR576 colocalizes with CD4 on the ac- tivated CD4 ＋ T-cell membrane, particularly within the activation cluster including re-assembled CD4 and TCR mol- ecules. Conclusion These results suggest that VIR576 is effective in suppressing antigen-specific T-cell activa- tion, but it has no effect on non-specific T-cell proliferation, and VIR576 has the ability to down-regulate antigen- specific T-cell activation by interaction with TCR transmembrane domain.

Type-B monoamine oxidase inhibitors in neurological diseases:clinical applications based on preclinical findings

Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.

Comparative efficacy of sodium glucose cotransporter-2 inhibitors in the management of type 2 diabetes mellitus:A real-world experience

BACKGROUND Sodium glucose cotransporter-2 inhibitors(SGLT-2i)are a class of drugs with modest antidiabetic efficacy,weight loss effect,and cardiovascular benefits as proven by multiple randomised controlled trials(RCTs).However,real-world data on the comparative efficacy and safety of individual SGLT-2i medications is sparse.AIM To study the comparative efficacy and safety of SGLT-2i using real-world clinical data.METHODS We evaluated the comparative efficacy data of 3 SGLT-2i drugs(dapagliflozin,canagliflozin,and empagliflozin)used for treating patients with type 2 diabetes mellitus.Data on the reduction of glycated hemoglobin(HbA1c),body weight,blood pressure(BP),urine albumin creatinine ratio(ACR),and adverse effects were recorded retrospectively.RESULTS Data from 467 patients with a median age of 64(14.8)years,294(62.96%)males and 375(80.5%)Caucasians were analysed.Median diabetes duration was 16.0(9.0)years,and the duration of SGLT-2i use was 3.6(2.1)years.SGLT-2i molecules used were dapagliflozin 10 mg(n=227;48.6%),canagliflozin 300 mg(n=160;34.3%),and empagliflozin 25 mg(n=80;17.1).Baseline median(interquartile range)HbA1c in mmol/mol were:dapagliflozin-78.0(25.3),canagliflozin-80.0(25.5),and empagliflozin-75.0(23.5)respectively.The respective median HbA1c reduction at 12 months and the latest review(just prior to the study)were:66.5(22.8)&69.0(24.0),67.0(16.3)&66.0(28.0),and 67.0(22.5)&66.5(25.8)respectively(P<0.001 for all comparisons from baseline).Significant improvements in body weight(in kilograms)from baseline to study end were noticed with dapagliflozin-101(29.5)to 92.2(25.6),and canagliflozin 100(28.3)to 95.3(27.5)only.Significant reductions in median systolic and diastolic BP,from 144(21)mmHg to 139(23)mmHg;(P=0.015),and from 82(16)mmHg to 78(19)mmHg;(P<0.001)respectively were also observed.A significant reduction of microalbuminuria was observed with canagliflozin only[ACR 14.6(42.6)at baseline to 8.9(23.7)at the study end;P=0.043].Adverse effects of SGLT-2i were as follows:genital thrush and urinary infection-20(8.8%)&17(7.5%)with dapagliflozin;9(5.6%)&5(3.13%)with canagliflozin;and 4(5%)&4(5%)with empagliflozin.Diabetic ketoacidosis was observed in 4(1.8%)with dapagliflozin and 1(0.63%)with canagliflozin.CONCLUSION Treatment of patients with SGLT-2i is associated with statistically significant reductions in HbA1c,body weight,and better than those reported in RCTs,with low side effect profiles.A review of large-scale real-world data is needed to inform better clinical practice decision making.

Advanced Lung Adenocarcinoma with EGFR 19-del Mutation Transformed into SCC after EGFR-tyrosine Kinase inhibitors Treatment:A Case report

BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)significantly improve the survival of patients with Epidermal growth factor receptor(EGFR)sensitive mutations in non-small cell lung cancer(NSCLC).CASE SUMMARY A 67-year-old female patient in advanced lung adenocarcinoma suffered from drug resistance after EGFR-TKIs treatment.Secondary pathological tissue biopsy confirmed squamous cell carcinoma(SCC)transformation.Patients inevitably encountered drug resistance issues after receiving EGFR-TKIs treatment for a certain period of time,while EGFR-TKIs can significantly improve the survival of patients with EGFR-sensitive mutations in NSCLC.Notably,EGFR-TKIs resistance includes primary and acquired.Pathological transformation is one of the mechanisms of acquired resistance in EGFR-TKIs,with SCC transformation being relatively rare.Our results provide more detailed results of the patient’s diagnosis and treatment process on SCC transformation after EGFR-TKIs treatment for lung adenocarcinoma.CONCLUSION Squamous cell carcinoma transformation is one of the acquired resistance mechanisms of EGFR-TKIs in advanced lung adenocarcinoma with EGFR mutations.

COVID-19 vaccination produces exercise-responsive SARS-CoV-2 specific T-cells regardless of infection history

Background:The mobilization and redistribution of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)specific T-cells and neutralizing antibodies(nAbs)during exercise is purported to increase immune surveillance and protect against severe coronavirus disease 2019(COVID-19).We sought to determine if COVID-19 vaccination would elicit exercise-responsive SARS-CoV-2 T-cells and transiently alter nAb titers.Methods:Eighteen healthy participants completed a 20-min bout of graded cycling exercise before and/or after receiving a COVID-19 vaccine.All major leukocyte subtypes were enumerated before,during,and after exercise by flow cytometry,and immune responses to SARS-CoV-2 were determined using whole blood peptide stimulation assays,T-cell receptor(TCR)-βsequencing,and SARS-CoV-2 nAb serology.Results:COVID-19 vaccination had no effect on the mobilization or egress of major leukocyte subsets in response to intensity-controlled graded exercise.However,non-infected participants had a significantly reduced mobilization of CD4+and CD8+naive T-cells,as well as CD4+central memory T-cells,after vaccination(synthetic immunity group);this was not seen after vaccination in those with prior SARS-CoV-2 infection(hybrid immunity group).Acute exercise after vaccination robustly mobilized SARS-CoV-2 specific T-cells to blood in an intensity-dependent manner.Both groups mobilized T-cells that reacted to spike protein;however,only the hybrid immunity group mobilized T-cells that reacted to membrane and nucleocapsid antigens.nAbs increased significantly during exercise only in the hybrid immunity group.Conclusion:These data indicate that acute exercise mobilizes SARS-CoV-2 specific T-cells that recognize spike protein and increases the redistribution of nAbs in individuals with hybrid immunity.