Electrochemical Study of the Corrosion Inhibitory Capacity of Calcined Attapulgite in Reinforced Concrete Medium

The durability of reinforced concrete structures is greatly influenced by the corrosion of the reinforcement. In addition to air pollution related to the repair of corroded structures, chloride ions are the main factors of corrosion of reinforced concrete structures. This study aims to valorize a clay inhibitor against reinforcement corrosion in reinforced concrete. This clay (Attapulgite) was incorporated into reinforced concretes at different percentages of substitution of calcined attapulgite (0%, 5% and 10%) to cement in the formulation. The corrosion inhibitory power of attapulgite is evaluated in reinforced concretes subjected to the action of chloride ions at different intervals in the NaCl solution (1 day, 21 days and 45 days) by electrochemical methods (zero current chronopotentiometry, polarization curves and electrochemical impedance spectroscopy). This study showed that in the presence of chloride ions, the composition based on 10% attapulgite has an appreciable inhibitory effect with an average inhibitory efficiency of 82%.

New strategies in the diagnosis and treatment of immune-checkpoint inhibitor-mediated colitis

Immune-checkpoint inhibitor-mediated colitis(IMC)is an increasingly recognized adverse event in cancer immunotherapy,particularly associated with immune checkpoint inhibitors(ICIs)such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies.As this revolutionary immunotherapy gains prominence in cancer treatment,understanding,diagnosing,and effectively managing IMC becomes paramount.IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications.However,a precise picture of IMC pathophysiology is currently unavailable.Therefore,we aimed to summarize the existing data while acknowledging the need for further research.This comprehensive review explores the mechanisms underlying ICIs,gastrointestinal adverse effects,and,in particular,IMC’s incidence,prevalence,and features.Our review also emphasizes the importance of recognizing IMC’s distinct clinical and histopathological features to differentiate it from other forms of colitis.Furthermore,this paper highlights the urgentneed for evolving diagnostic methods,therapeutic strategies,and a multidisciplinary approach to effectively manage IMC.

Erdafitinib and checkpoint inhibitors for first-line and second-line immunotherapy of hepatic,gastrointestinal,and urinary bladder carcinomas:Recent concept

Cancer immunotherapy is administered for first-line,second-line,neoadjuvant,or adjuvant treatment of advanced,metastatic,and recurrent cancer in the liver,gastrointestinal tract,and genitourinary tract,and other solid tumors.Erdafitinib is a fibroblast growth factor receptor(FGFR)inhibitor,and it is an adenosine triphosphate competitive inhibitor of FGFR1,FGFR2,FGFR3,and FGFR4.Immune checkpoint inhibitors are monoclonal antibodies that block programmed cell death protein 1(PD-1)and its ligand that exert intrinsic antitumor mechanisms.The promising results of first-line treatment of advanced and metastatic urothelial carcinoma with PD-1 blockades with single or combined agents,indicate a new concept in the treatment of advanced,metastatic,and recurrent hepatic and gastrointestinal carcinomas.Cancer immunotherapy as first-line treatment will improve overall survival and provide better quality of life.Debate is arising as to whether to apply the cancer immunotherapy as first-line treatment in invasive carcinomas,or as second-line treatment in recurrent or metastatic carcinoma following the standard chemotherapy.The literature in the field is not definite,and so far,there has been no consensus on the best approach in this situation.At present,as it is described in this editorial,the decision is applied on a case-by-case basis.

Overlapping approach Proton Pump Inhibitors/Nux vomica-Heel as new intervention for gastro-esophageal reflux management:Delphi consensus study

BACKGROUND Gastro-esophageal reflux disease(GERD)may affect the upper digestive tract;up to 20%of population in Western nations are affected by GERD.Antacids,histamine H2-receptor antagonists,and Proton Pump Inhibitors(PPIs)are considered the referring medications for GERD.Nevertheless,PPIs must be managed carefully because their use,especially chronic,could be linked with some adverse effects.An effective and safe alternative pharmacological tool for GERD is needed.After the identification of potentially new medications to flank PPIs,it is mandatory to revise and improve good clinical practices even through a consensus process.AIM To optimize diagnosis and treatment guidelines for GERD through a consensus based on Delphi method.METHODS The availability of clinical studies describing the action of the multicomponent/multitarget medication Nux vomica-Heel,subject of the consensus,is the basic prerequisite for the consensus itself.A modified Delphi process was used to reach a consensus among a panel of Italian GERD specialists on the overlapping approach PPIs/Nux vomica-Heel as a new intervention model for the management of GERD.The Voting Consensus group was composed of 49 Italian Medical Doctors with different specializations:Gastroenterology,otolaryngology,geriatrics,and general medicine.A scientific committee analyzed the literature,determined areas that required investigation(in agreement with the multiple-choice questionnaire results),and identified two topics of interest:(1)GERD disease;and(2)GERD treatment.Statements for each of these topics were then formulated and validated.The Delphi process involved two rounds of questioning submitted to the panel experts using an online platform.RESULTS According to their routinary GERD practice and current clinical evidence,the panel members provided feedback to each questionnaire statement.The experts evaluated 15 statements and reached consensus on all 15.The statements regarding the GERD disease showed high levels of agreement,with consensus ranging from 70%to 92%.The statements regarding the GERD treatment also showed very high levels of agreement,with consensus ranging from 90%to 100%.This Delphi process was able to reach consensus among physicians in relevant aspects of GERD management,such as the adoption of a new approach to treat patients with GERD based on the overlapping between PPIs and Nux vomica-Heel.The consensus was unanimous among the physicians with different specializations,underlying the uniqueness of the agreement reached to identify in the overlapping approach between PPIs and Nux vomica-Heel a new intervention model for GERD management.The results support that an effective approach to deprescribe PPIs through a progressive decalage timetable(reducing PPIs administration to as-needed use),should be considered.CONCLUSION Nux vomica-Heel appears to be a valid opportunity for GERD treatment to favor the deprescription of PPIs and to maintain low disease activity together with the symptomatology remission.

Potential Secretory Transporters and Biosynthetic Precursors of Biological Nitrification Inhibitor 1,9-Decanediol in Rice as Revealed by Transcriptome and Metabolome Analyses

Biological nitrification inhibitors(BNIs)are released from plant roots and inhibit the nitrification activity of microorganisms in soils,reducing NO_(3)^(‒)leaching and N2O emissions,and increasing nitrogenuse efficiency(NUE).Several recent studies have focused on the identification of new BNIs,yet little is known about the genetic loci that govern their biosynthesis and secretion.We applied a combined transcriptomic and metabolomic analysis to investigate possible biosynthetic pathways and transporters involved in the biosynthesis and release of BNI 1,9-decanediol(1,9-D),which was previously identified in rice root exudates.Our results linked four fatty acids,icosapentaenoic acid,linoleate,norlinolenic acid,and polyhydroxy-α,ω-divarboxylic acid,with 1,9-D biosynthesis and three transporter families,namely the ATP-binding cassette protein family,the multidrug and toxic compound extrusion family,and the major facilitator superfamily,with 1,9-D release from roots into the soil medium.Our finding provided candidates for further work on the genes implicated in the biosynthesis and secretion of 1,9-D and pinpoint genetic loci for crop breeding to improve NUE by enhancing 1,9-D secretion,with the potential to reduce NO_(3)^(‒)leaching and N2O emissions from agricultural soils.

Role of angiotensin receptor-neprilysin inhibitor in diabetic complications

Diabetes mellitus is a prevalent disorder with multi-system manifestations,causing a significant burden in terms of disability and deaths globally.Angio-tensin receptor-neprilysin inhibitor(ARNI)belongs to a class of medications for treating heart failure,with the benefits of reducing hospitalization rates and mortality.This review mainly focuses on the clinical and basic investigations related to ARNI and diabetic complications,discussing possible physiological and molecular mechanisms,with insights for future applications.

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.

Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio:Markers predicting immune-checkpoint inhibitor efficacy and immune-related adverse events

We conducted a comprehensive review of existing prediction models pertaining to the efficacy of immune-checkpoint inhibitor(ICI)and the occurrence of immune-related adverse events(irAEs).The predictive potential of neutrophil-to-lymphocyte ratio(NLR)and platelet-to-lymphocyte ratio(PLR)in determining ICI effectiveness has been extensively investigated,while limited research has been conducted on predicting irAEs.Furthermore,the combined model incor-porating NLR and PLR,either with each other or in conjunction with additional markers such as carcinoembryonic antigen,exhibits superior predictive capabilities compared to individual markers alone.NLR and PLR are promising markers for clinical applications.Forthcoming models ought to incorporate established efficacious models and newly identified ones,thereby constituting a multifactor composite model.Furthermore,efforts should be made to explore effective clinical application approaches that enhance the predictive accuracy and efficiency.

Exploring a novel class tryptophan hydroxylase 1 inhibitor derived from Sambucus williamsii Hance for the osteoporosis treatment

Objective:Gut-derived serotonin strongly inhibits bone formation by inhibiting osteoblast proliferation.Our previous study demonstrated that the lignan-rich fraction prepared from Sambucus willimasii Hance,a folk herbal medicine used to treat bone fractures and joint diseases in China,exerted bone-protective effects,and its actions were modulated by suppressing the synthesis of gut-derived serotonin via the inhibition of intestinal tryptophan hydroxylase 1(TPH-1).However,there is no direct evidence for the action of lignans on TPH-1.This study aimed to verify the direct action of lignans on the TPH-1 and its influence on serotonin synthesis and bone properties.Methods:Molecular docking and surface plasmon resonance were performed to determine the affinities of lignans to TPH-1.The cell viability and the protein activity and expression of TPH-1 were measured in RBL2H3 cells.The serum serotonin level and bone mineral density upon lignan treatment in ovariectomized mice were determined.Result:The lignans showed high binding scores and binding affinities to TPH-1,inhibited the activity and protein expression of TPH-1,suppressed the serum serotonin levels in ovariectomized mice as well as promoted bone mineral density.Conclusion:This is the first study to report that lignans are novel TPH-1 inhibitors and that these lignans could be potential agents for the management of serotonin-related diseases,including osteoporosis.

Efficacy comparison of fruquintinib,regorafenib monotherapy or plus programmed death-1 inhibitors for microsatellite stable metastatic colorectal cancer

BACKGROUND Regorafenib(R)and fruquintinib(F)are the standard third-line regimens for colorectal cancer(CRC)according to the National Comprehensive Cancer Network guidelines,but both have limited efficacy.Several phase 2 trials have indicated that R or F combined with immune checkpoint inhibitors can reverse immunosuppression and achieve promising efficacy for microsatellite stable or proficient mismatch repair(MSS/pMMR)CRC.Due to the lack of studies comparing the efficacy between F,R,F plus programmed death-1(PD-1)inhibitor,and R plus PD-1 inhibitors(RP),it is still unclear whether the combination therapy is more effective than monotherapy.AIM To provide critical evidence for selecting the appropriate drugs for MSS/pMMR metastatic CRC(mCRC)patients in clinical practice.METHODS A total of 2639 CRC patients were enrolled from January 2018 to September 2022 in our hospital,and 313 MSS/pMMR mCRC patients were finally included.RESULTS A total of 313 eligible patients were divided into F(n=70),R(n=67),F plus PD-1 inhibitor(FP)(n=95)and RP(n=81)groups.The key clinical characteristics were well balanced among the groups.The median progression-free survival(PFS)of the F,R,FP,and RP groups was 3.5 months,3.6 months,4.9 months,and 3.0 months,respectively.The median overall survival(OS)was 14.6 months,15.7 months,16.7 months,and 14.1 months.The FP regimen had an improved disease control rate(DCR)(P=0.044)and 6-month PFS(P=0.014)and exhibited a better trend in PFS(P=0.057)compared with F,and it was also significantly better in PFS than RP(P=0.030).RP did not confer a significant survival benefit;instead,the R group had a trend toward greater benefit with OS(P=0.080)compared with RP.No significant differences were observed between the R and F groups in PFS or OS(P>0.05).CONCLUSION FP is superior to F in achieving 6-month PFS and DCR,while RP is not better than R.FP has an improved PFS and 6-month PFS compared with RP,but F and R had similar clinical efficacy.Therefore,FP may be a highly promising strategy in the treatment of MSS/pMMR mCRC.

Application of immune checkpoint inhibitors and microsatellite instability in gastric cancer

In this editorial we comment on the article by Li published in the recent issue of the World Journal of Gastroenterology.We focus specifically on the application of immune checkpoint inhibitors(ICIs)and microsatellite instability(MSI)in gastric cancer(GC).The four pillars of GC management have long been considered,including surgery,chemotherapy,radiotherapy and targeted therapy.However,immunotherapy has recently emerged as a“fifth pillar”,and its use is rapidly expanding.There are four principal strategies for tumor immunotherapy:ICIs,tumor vaccines,adoptive immunotherapy and nonspecific immunomodulators.Of them,ICIs are the most advanced and widespread type of cancer immunotherapy for GC.Recent breakthrough results for ICIs have paved the way to a new era of cancer immunotherapy.In particular,inhibition of the PD-1/PD-L1 axis with ICIs,including nivolumab and pembrolizumab,has emerged as a novel treatment strategy for advanced GC.Unfortunately,these therapies are sometimes associated with often subtle,potentially fatal immune-related adverse events(irAEs),including dermatitis,diarrhea,colitis,endocrinopathy,hepatotoxicity,neuropathy and pneumonitis.We must be aware of these irAEs and improve the detection of these processes to prevent inappropriate discharges,emergency department revisits,and downstream complications.Recent studies have revealed that MSI-high or mismatch-repair-deficient tumors,regardless of their primary site,have a promising response to ICIs.So,it is important to detect MSI before applying ICIs for treatment of GC.

DNA damage response-related immune activation signature predicts the response to immune checkpoint inhibitors: from gastrointestinal cancer analysis to pan-cancer validation

Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor(ICI) therapy in gastrointestinal(GI) cancer.Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts.Results: The DRIA signature includes three genes(CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients(81.8% vs. 8.8%;P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve(AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein–Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer.Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pancancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.

Advancements in enhancing corrosion protection of Mg alloys:A comprehensive review on the synergistic effects of combining inhibitors with PEO coating

Magnesium(Mg)alloys are lightweight materials with excellent mechanical properties,making them attractive for various applications,including aerospace,automotive,and biomedical industries.However,the practical application of Mg alloys is limited due to their high susceptibility to corrosion.Plasma electrolytic oxidation(PEO),or micro-arc oxidation(MAO),is a coating method that boosts Mg alloys'corrosion resistance.However,despite the benefits of PEO coatings,they can still exhibit certain limitations,such as failing to maintain long-term protection as a result of their inherent porosity.To address these challenges,researchers have suggested the use of inhibitors in combination with PEO coatings on Mg alloys.Inhibitors are chemical compounds that can be incorporated into the coating or applied as a post-treatment to further boost the corrosion resistance of the PEO-coated Mg alloys.Corrosion inhibitors,whether organic or inorganic,can act by forming a protective barrier,hindering the corrosion process,or modifying the surface properties to reduce susceptibility to corrosion.Containers can be made of various materials,including polyelectrolyte shells,layered double hydroxides,polymer shells,and mesoporous inorganic materials.Encapsulating corrosion inhibitors in containers fully compatible with the coating matrix and substrate is a promising approach for their incorporation.Laboratory studies of the combination of inhibitors with PEO coatings on Mg alloys have shown promising results,demonstrating significant corrosion mitigation,extending the service life of Mg alloy components in aggressive environments,and providing self-healing properties.In general,this review presents available information on the incorporation of inhibitors with PEO coatings,which can lead to improved performance of Mg alloy components in demanding environments.

Renin-angiotensin system inhibitors prescriptions in Chinese hospitalized chronic kidney disease patients

BACKGROUND Many guidelines have recommended renin-angiotensin system inhibitors(RASI)as the first-line treatment for patients with chronic kidney disease(CKD).We studied RASI prescription trends from 2010 to 2019,and analyzed the characteristics associated with RASI prescription in Chinese hospitalized CKD patients.AIM To study the prescription of renin angiotensin system inhibitors in hospitalized patients with CKD in China.METHODS It was retrospectively,cross-sectional reviewed RASI prescriptions in hospitalized CKD patients in China from 2010 to 2019.RASI prescribing trends were analyzed from 2010 to 2019,and bivariate and multivariate logistic regression analyses were conducted to identify characteristics associated with RASI prescription.RESULTS A total of 35090 CKD patients were included,with 10043(28.6%)RASI prescriptions.Among these patients,18919(53.9%)met the criteria for RASI treatments based on the 2012 kidney disease:Improving global outcomes guidelines.Of these,7246(38.3%)patients received RASI prescriptions.RASI prescriptions showed an initial rapid increase from 2011 to 2012,reached its peak around 2015 and 2016,and then exhibited a subsequent slight decreasing trend.Both bivariate and multivariate analyses showed that several characteristics,including the male gender,age less than 60-year-old,nephrology department admission,lower CKD stage,history of hypertension or diabetes,proteinuria,glomerulonephritis as the CKD etiology,and non-acute kidney injury were associated with RASI prescriptions.CONCLUSION The frequency of RASI prescriptions showed an initial increase but a slight decreasing trend in more recent years.CKD patients with certain characteristics such as elderly age,advanced disease stage,surgery department admission,or acute kidney injury were less likely to receive RASI prescriptions.In the application of RASI in hospitalized CKD patients is insufficient.The actual clinical practice needs to be improved.The development of related research is helpful to guide the correct choice of clinical treatment strategy.

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.

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.

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.

High-throughput computational screening and in vitro evaluation identifies 5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-1H-isoindole-1,3(2H)-dione(C3),as a novel EGFR—HER2 dual inhibitor in gastric tumors

Gastric cancers are caused primarily due to the activation and amplification of the EGFR or HER2 kinases resulting in cell proliferation,adhesion,angiogenesis,and metastasis.Conventional therapies are ineffective due to the intra-tumoral heterogeneity and concomitant genetic mutations.Hence,dual inhibition strategies are recommended to increase potency and reduce cytotoxicity.In this study,we have conducted computational high-throughput screening of the ChemBridge library followed by in vitro assays and identified novel selective inhibitors that have a dual impediment of EGFR/HER2 kinase activities.Diversity-based High-throughput Virtual Screening(D-HTVS)was used to screen the whole ChemBridge small molecular library against EGFR and HER2.The atomistic molecular dynamic simulation was conducted to understand the dynamics and stability of the protein-ligand complexes.EGFR/HER2 kinase enzymes,KATOIII,and Snu-5 cells were used for in vitro validations.The atomistic Molecular Dynamics simulations followed by solvent-based Gibbs binding free energy calculation of top molecules,identified compound C3(5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-1H-isoindole-1,3(2H)-dione)to have a good affinity for both EGFR and HER2.The predicted compound,C3,was promising with better binding energy,good binding pose,and optimum interactions with the EGFR and HER2 residues.C3 inhibited EGFR and HER2 kinases with IC50 values of 37.24 and 45.83 nM,respectively.The GI50 values of C3 to inhibit KATOIII and Snu-5 cells were 84.76 and 48.26 nM,respectively.Based on these findings,we conclude that the identified compound C3 showed a conceivable dual inhibitory activity on EGFR/HER2 kinase,and therefore can be considered as a plausible lead-like molecule for treating gastric cancers with minimal side effects,though testing in higher models with pharmacokinetic approach is required.

Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia

Objective:In B-cell acute lymphoblastic leukemia(B-ALL),current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50%of cases,underscoring the urgent need for new therapeutic regimens for this patient population.The present study aimed to determine whether HZX-02-059,a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase(PIKfyve)and tubulin,is lethal to B-ALL cells and is a potential therapeutic for B-ALL patients.Methods:Cell proliferation,vacuolization,apoptosis,cell cycle,and in-vivo tumor growth were evaluated.In addition,Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in B-ALL.Results:HZX-02-059 was found to inhibit cell proliferation,induce vacuolization,promote apoptosis,block the cell cycle,and reduce in-vivo tumor growth.Downregulation of the p53 pathway and suppression of the phosphoinositide 3-kinase(PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these observations.Conclusion:Overall,these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.