Na^(+)/K^(+)-ATPase:ion pump,signal transducer,or cytoprotective protein,and novel biological functions

Na^(+)/K^(+)-ATPase is a transmembrane protein that has important roles in the maintenance of electrochemical gradients across cell membranes by transporting three Na^(+)out of and two K^(+)into cells.Additionally,Na^(+)/K^(+)-ATPase participates in Ca^(2+)-signaling transduction and neurotransmitter release by coordinating the ion concentration gradient across the cell membrane.Na^(+)/K^(+)-ATPase works synergistically with multiple ion channels in the cell membrane to form a dynamic network of ion homeostatic regulation and affects cellular communication by regulating chemical signals and the ion balance among different types of cells.Therefo re,it is not surprising that Na^(+)/K^(+)-ATPase dysfunction has emerged as a risk factor for a variety of neurological diseases.However,published studies have so far only elucidated the important roles of Na^(+)/K^(+)-ATPase dysfunction in disease development,and we are lacking detailed mechanisms to clarify how Na^(+)/K^(+)-ATPase affects cell function.Our recent studies revealed that membrane loss of Na^(+)/K^(+)-ATPase is a key mechanism in many neurological disorders,particularly stroke and Parkinson's disease.Stabilization of plasma membrane Na^(+)/K^(+)-ATPase with an antibody is a novel strategy to treat these diseases.For this reason,Na^(+)/K^(+)-ATPase acts not only as a simple ion pump but also as a sensor/regulator or cytoprotective protein,participating in signal transduction such as neuronal autophagy and apoptosis,and glial cell migration.Thus,the present review attempts to summarize the novel biological functions of Na^(+)/K^(+)-ATPase and Na^(+)/K^(+)-ATPase-related pathogenesis.The potential for novel strategies to treat Na^(+)/K^(+)-ATPase-related brain diseases will also be discussed.

Clinical application of COVID-19 vaccine in liver transplant recipients

Background:Solid organ transplant(SOT)activities,such as liver transplant,have been greatly influenced by the pandemic of coronavirus disease 2019(COVID-19),a disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Immunosuppressed individuals of liver transplant recipients(LTRs)tend to have a high risk of COVID-19 infection and related complications.Therefore,COVID-19 vaccination has been recommended to be administered as early as possible in LTRs.Data sources:The keywords“liver transplant”,“SARS-CoV-2”,and“vaccine”were used to retrieve articles published in PubMed.Results:The antibody response following the 1st and 2nd doses of vaccination was disappointingly low,and the immune responses among LTRs remarkably improved after the 3rd or 4th dose of vaccination.Although the 3rd or 4th dose of COVID-19 vaccine increased the antibody titer,a proportion of patients remained unresponsive.Furthermore,recent studies showed that SARS-CoV-2 vaccine could trigger adverse events in LTRs,including allograft rejection and liver injury.Conclusions:This review provides the recently reported data on the antibody response of LTRs following various doses of vaccine,risk factors for poor serological response and adverse events after vaccination.

Electrochemical biosensors for point-of-care testing

Point-of-care testing(POCT)is the practice of diagnosing and monitoring diseases where the patient is located,as opposed to traditional treatment conducted solely in a medical laboratory or other clinical setting.POCT has been less common in the recent past due to a lack of portable medical devices capable of facilitating effective medical testing.However,recent growth has occurred in this field due to advances in diagnostic technologies,device miniaturization,and progress in wearable electronics.Among these developments,electrochemical sensors have attracted interest in the POCT field due to their high sensitivity,compact size,and affordability.They are used in various applications,from disease diagnosis to health status monitoring.In this paper we explore recent advancements in electrochemical sensors,the methods of fabricating them,and the various types of sensing mechanisms that can be used.Furthermore,we delve into methods for immobilizing specific biorecognition elements,including enzymes,antibodies,and aptamers,onto electrode surfaces and how these sensors are used in real-world POCT settings.

A nanobody-based blocking enzyme-linked immunosorbent assay for detecting antibodies against pseudorabies virus glycoprotein E

Pseudorabies(PR)is an acute infectious disease of pigs caused by the PR virus(PRV)and results in great economic losses to the pig industry worldwide.PRV glycoprotein E(gE)-based enzyme-linked immunosorbent assay(ELISA)has been used to distinguish gE-deleted vaccine-immunized pigs from wild-type virus-infected pigs to eradicate PR in some countries.Nanobody has the advantages of small size and easy genetic engineering and has been a promising diagnostic reagent.However,there were few reports about developing nanobody-based ELISA for detecting anti-PRV-gE antibodies.In the present study,the recombinant PRV-gE was expressed with a bacterial system and used to immunize the Bactrian camel.Then,two nanobodies against PRV-gE were screened from the immunized camel by phage display technique.Subsequently,two nanobody-HRP fusion proteins were expressed with HEK293T cells.The PRV-gE-Nb36-HRP fusion protein was selected as the probe for developing the blocking ELISA(bELISA)to detect anti-PRV-gE antibodies.Through optimizing the conditions of bELISA,the amount of coated antigen was 200 ng per well,and dilutions of the fusion protein and tested pig sera were separately 1:320 and 1:5.The cut-off value of bELISA was 24.20%,and the sensitivity and specificity were 96.43 and 92.63%,respectively.By detecting 233 clinical pig sera with the developed bELISA and a commercial kit,the results showed that the coincidence rate of two assays was 93.99%.Additionallly,epitope mapping showed that PRV-gE-Nb36 recognized a conserved conformational epitope in different reference PRV strains.Simple,great stability and low-cost nanobody-based bELISA for detecting anti-PRV-gE antibodies were developed.The bELISA could be used for monitoring and eradicating PR.

Anti-PD1 antibody and not anti-LAG-3 antibody improves the antitumor effect of photodynamic therapy for treating metastatic breast cancer

Photodynamic therapy(PDT)has limited effects in treating metastatic breast cancer.Immune checkpoints can deplete the function of immune cells;however,the expression of immune checkpoints after PDT is unclear.This study investigates whether the limited e±cacy of PDT is due to upregulated immune checkpoints and tries to combine the PDT and immune checkpoint inhibitor to observe the e±cacy.A metastatic breast cancer model was treated by PDT mediated by hematoporphyrin derivatives(HpD-PDT).The anti-tumor effect of HpD-PDT was observed,as well as CD4þT,CD8þT and calreticulin(CRT)by immunohistochemistry and immunofluorescence.Immune checkpoints on T cells were analyzed byflow cytometry after HpD-PDT.When combining PDT with immune checkpoint inhibitors,the antitumor effect and immune effect were assessed.For HpD-PDT at 100 mW/cm2 and 40,60 and 80 J/cm2,primary tumors were suppressed and CD4þT,CD8þT and CRT were elevated;however,distant tumors couldn't be inhibited and survival could not be prolonged.Immune checkpoints on T cells,especially PD1 and LAG-3 after HpD-PDT,were upregulated,which may explain the reason for the limited HpD-PDT effect.After PDT combined with anti-PD1 antibody,but not with anti-LAG-3 antibody,both the primary and distant tumors were signi-cantly inhibited and the survival time was prolonged,additionally,CD4þT,CD8þT,IFN-þCD4þT and TNF-þCD4þT cells were signi-cantly increased compared with HpD-PDT.HpD-PDT could not combat metastatic breast cancer.PD1 and LAG-3 were upregulated after HpD-PDT.Anti-PD1 antibody,but not anti-LAG-3 antibody,could augment the antitumor effect of HpD-PDT for treating metastatic breast cancer.

Impact of exercise on markers of B cell-related immunity:A systematic review

Background:B cells represent a crucial component of adaptive immunity that ensures long-term protection from infection by generating pathogen-specific immunoglobulins.Exercise alters B cell counts and immunoglobulin levels,but evidence-based conclusions on potential benefits for adaptive immunity are lacking.This systematic review assessed current literatures on the impact of acute exercise and exercise training on B cells,immunoglobulins,and markers of secretory immunity in human biofluids.Methods:According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)guidelines,MEDLINE,Web of Science,and Embase were searched on March 8,2023.Non-randomized controlled trials and crossover trials investigating the impact of acute exercise or exercise training on B cell counts and proportions,immunoglobulin levels,salivary flow rate,or secretory immunoglobulin A secretion rate were included.Quality and reporting of exercise training studies were assessed using the Tool for the Assessment of Study Quality and reporting in Exercise.Study characteristics,outcome measures,and statistically significant changes were summarized tabularly.Results:Of the 67 eligible studies,22 applied acute exercise and 45 applied exercise training.All included outcomes revealed significant alterations over time in acute exercise and exercise training context,but only a few investigations showed significant differences compared to control conditions.Secretory and plasma immunoglobulin A levels were most consistently increased in response to exercise training.Conclusion:B cell-related outcomes are altered by acute exercise and exercise training,but evidence-based conclusions cannot be drawn with high confidence due to the large heterogeneity in populations and exercise modalities.Well-designed trials with large sample sizes are needed to clarify how exercise shapes B cell-related immunity.

Establishment of an indirect immunofluorescence assay for the detection of African swine fever virus antibodies

African swine fever(ASF)continues to cause enormous economic loss to the global pig industry.Since there is no safe and effective vaccine,accurate and timely diagnosis of ASF is essential to implement control measures.Indirect immunofluorescence assay(IFA)is a gold standard serological method recommended by the World Organization for Animal Health(WOAH).In this study,we used primary fetal kidney cells to establish a wild boar cell line(BK2258)that supported the efficient replication of ASF virus(ASFV)SD/DY-I/21 and showed visible cytopathic effect(CPE).Moreover,using BK2258,we established a sensitive and specific IFA for ASFV antibody detection.To standardize and evaluate the performance of this assay,we used serum samples from pigs infected with the low virulent genotype I SD/DY-I/21 and genotype II HLJ/HRB1/20,and immunized with the vaccine candidate HLJ/18-7GD,field samples,and negative serum samples.The IFA reacted with the ASFV-positive sera and displayed bright fluorescence foci.There was no non-specific green fluorescence due to cellular senescence or other cell damage-causing factors.Compared to a commercial indirect enzyme-linked immunosorbent assay(iELISA),ASFV antibodies were detected 1–4 days earlier using our IFA.The detection limits of the IFA and iELISA for the same ASFV-antibody positive serum samples were 1:25,600 and 1:6,400,respectively,indicating that the IFA is more sensitive than iELISA.The newly established IFA was highly specific and did not cross-react with sera positive for six other important porcine pathogens(i.e.,Classical swine fever virus(CSFV),Porcine reproductive and respiratory syndrome virus(PRRSV),Porcme circovirus type 2(PCV2),Pseudorabies virus(PRV),Foot-and-Mouth disease virus type O(FMDV/O),and Porcine epidemic diarrhea virus(PEDV)).This study thus provides a sensitive,specific,and reliable detection method that is suitable for the serological diagnosis of ASF.

Antibodies Targeting a Conserved Surface Polysaccharide Are Protective Against a Wide Range of Microbial Pathogens Producing β-1-6-Linked Poly-N-Acetylglucosamine(PNAG)

The b-1-6-linked poly-N-acetylglucosamine(PNAG)polymer is a conserved surface polysaccharide produced by many bacteria,fungi,and protozoan(and even filarial)parasites.This wide-ranging expression makes PNAG an attractive target for vaccine development,as it potentially encompasses a broad range of microorganisms.Significant progress has been made in discovering important properties of the biology of PNAG expression in recent years.The molecular characterization and regulation of operons for the production of PNAG biosynthetic proteins and enzymes have been studied in many bacteria.In addition,the physiological function of PNAG has been further elucidated.PNAG-based vaccines and PNAG-targeting antibodies have shown great efficacy in preclinical research.Furthermore,clinical tests for both vaccines and antibodies have been carried out in humans and economically important animals,and the results are promising.Although it is not destined to be a smooth road,we are optimistic about new vaccines and immunotherapeutics targeting PNAG becoming validated and eventually licensed for clinical use against multiple infectious agents.

Antibody Levels and Infection Status of Pertussis in the Population under Pertussis Resurgence in Guangxi in 2018:A Cross-Sectional Survey

Objective Pertussis cases have increased markedly since 2018 in Guangxi.The aim of this study was to evaluate antibody levels and the infection status of pertussis in the resident population.Method A total of 10,215 serum samples from residents were collected from August-November 2018 and tested for anti-pertussis IgG and toxin IgG using the enzyme-linked immunosorbent assay(ELISA).Results Of the collected samples,1,833(17.94%)tested positive for anti-pertussis IgG,with the median concentration of 16.06 IU/mL.Antibody level<10 IU/mL accounted for more than 60%in children under 4 years of age,but declined with age,whereas the percentages of the other three levels(10-40,40-50,and≥50 IU/mL)increased almost with age(P<0.001).Moreover,7,924 samples were selected for anti-pertussis toxin IgG,of which 653(8.24%)tested positive(≥40 IU/mL)with the median concentration of 5.89 IU/mL,and 204 participants(2.56%)had recent pertussis infection(≥100 IU/mL).Among the different age groups,the highest rates of positivity and recent infection were observed at 11-20 years of age,the lowest positivity rate at 5 years of age,and the lowest recent infection rate at 4 years of age(P<0.001,P=0.005,respectively).Conclusion The survey results showed that all age groups in Guangxi lacked immunity against pertussis,which was one of the main factors contributing to the resurgence of pertussis in 2018.In addition,the prevalence of pertussis is relatively high in Guangxi,and its incidence is seriously underestimated,especially in adolescents and adults.

Antibodies elicited by Newcastle disease virus-vectored H7N9 avian influenza vaccine are functional in activating the complement system

H7N9 subtype avian influenza virus poses a great challenge for poultry industry.Newcastle disease virus(NDV)-vectored H7N9 avian influenza vaccines(NDV_(vec)H7N9)are effective in disease control because they are protective and allow mass administration.Of note,these vaccines elicit undetectable H7N9-specific hemagglutination-inhibition(HI)but high IgG antibodies in chickens.However,the molecular basis and protective mechanism underlying this particular antibody immunity remain unclear.Herein,immunization with an NDV_(vec)H7N9 induced low anti-H7N9 HI and virus neutralization titers but high levels of hemagglutinin(HA)-binding IgG antibodies in chickens.Three residues(S150,G151 and S152)in HA of H7N9 virus were identified as the dominant epitopes recognized by the NDV_(vec)H7N9 immune serum.Passively transferred NDV_(vec)H7N9 immune serum conferred complete protection against H7N9 virus infection in chickens.The NDV_(vec)H7N9 immune serum can mediate a potent lysis of HA-expressing and H7N9 virus-infected cells and significantly suppress H7N9 virus infectivity.These activities of the serum were significantly impaired after heat-inactivation or treatment with complement inhibitor,suggesting the engagement of the complement system.Moreover,mutations in the 150-SGS-152 sites in HA resulted in significant reductions in cell lysis and virus neutralization mediated by the NDV_(vec)H7N9 immune serum,indicating the requirement of antibody-antigen binding for complement activity.Therefore,antibodies induced by the NDV_(vec)H7N9 can activate antibody-dependent complement-mediated lysis of H7N9 virus-infected cells and complement-mediated neutralization of H7N9 virus.Our findings unveiled a novel role of the complement in protection conferred by the NDV_(vec)H7N9,highlighting a potential benefit of engaging the complement system in H7N9 vaccine design.

Atypical Guillain-Barrésyndrome with positive anti-sulfatide,anti-GT1b,and anti-GT1a antibodies:A case report

BACKGROUND The role of diverse antibodies in mediating peripheral nerve injury in Guillain-Barrésyndrome(GBS)is becoming clearer,but positivity for multiple antibodies in one case is uncommon.To our knowledge,this is the first case involving GBS with positive anti-sulfatide,anti-GT1a,and anti-GT1b antibodies.CASE SUMMARY A 20-year-old female patient was admitted to the hospital due to weakness of limbs for 5 d,and deterioration of the weakness and muscle aches for 1 d.The patient's limbs were weak,but the tendon reflexes in the part of the limbs were normal.There was no comorbid peripheral nociception or deep sensory dysfunction.She was diagnosed with GBS and was discharged after receiving intravenous human immunoglobulin pulse therapy.CONCLUSION In this article,the clinical manifestations,neurophysiological examination,and auxiliary examination findings of a GBS patient positive for multiple antibodies were analyzed to improve the identification of the disease by clinical physicians at an early stage.

Anti-OX40 Antibody Combined with HBc VLPs Delays Tumor Growth in a Mouse Colon Cancer Model

Objective Combination immunotherapy strategies targeting OX40,a co-stimulatory molecule that can enhance antitumor immunity by modulating the proliferation,differentiation,and effector function of tumor-infiltrating T cells,have attracted much attention for their excellent therapeutic effects.In this study,we aimed to evaluate the antitumor efficacy of combined anti-OX40 and hepatitis B core viruslike particles(HBc VLPs)therapy using a mouse colon cancer model.Methods Humanized B-h OX40 mice were injected subcutaneously with MC38 colon tumor cells and treated with HBc VLPs+anti-h OX40 antibody.Tumor growth was monitored.Flow cytometric analysis was performed to evaluate the populations of T cell subsets in the tumors.Results The combination of anti-OX40 with HBc VLPs resulted in a significant delay in tumor growth,suggesting that a potent antitumor immunity was induced by the combination therapy.Further studies revealed that HBc VLPs+anti-OX40 treatment induced a significant increase in effector T cells(Teffs)and a significant decrease in regulatory T cells(Tregs)in the tumor microenvironment(TME),which accounted for the synergistic antitumor effect of anti-OX40 in combination with HBc VLPs.Conclusion Combination therapy of anti-h OX40 and HBc VLPs provides synergistic antitumor activity in colon cancer-bearing mice,which may represent a potential design strategy for cancer immunotherapy.

Antibody-platinum(IV)prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.

IMpower210:A phase Ⅲ study of second-line atezolizumab vs. docetaxel in East Asian patients with non-small cell lung cancer

Objective: IMpower210(NCT02813785) explored the efficacy and safety of single-agent atezolizumab vs.docetaxel as second-line treatment for advanced non-small cell lung cancer(NSCLC) in East Asian patients.Methods: Key eligibility criteria for this phase Ⅲ, open-label, randomized study included age ≥18 years;histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system(7th edition);Eastern Cooperative Oncology Group performance status of 0 or 1;and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab(1,200 mg) or docetaxel(75 mg/m^(2)). The primary study endpoint was overall survival(OS) in the intention-to-treat(ITT) population with wild-type epidermal growth factor receptor expression(ITT EGFR-WT) and in the overall ITT population.Results: Median OS in the ITT EGFR-WT population(n=467) was 12.3 [95% confidence interval(95% CI),10.3-13.8] months in the atezolizumab arm(n=312) and 9.9(95% CI, 7.8-13.9) months in the docetaxel arm[n=155;stratified hazard ratio(HR), 0.82;95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5(95% CI, 10.8-13.8) months with atezolizumab treatment and 11.1(95% CI, 8.4-14.2) months(n=377) with docetaxel treatment(n=188;stratified HR, 0.87;95% CI, 0.71-1.08). Grade 3/4 treatment-related adverse events(TRAEs) occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel arm.Conclusions: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade3/4 TRAEs.

Preparation of anti-canine interleukin-31 receptor alpha polyclonal antibody and evaluation of its therapeutic efect in canine atopic dermatitis

Canine atopic dermatitis(CAD)is a prevalent genetically susceptible infammatory and pruritic allergic skin condition afecting not only the health of dogs but also the quality of life of their owners.Interleukin-31(IL-31)and interleukin-31 receptor alpha(IL-31RA)are essential for the development of pruritus in primates and mice.Hence,it is expected that inhibiting IL-31RA will be an efective approach to alleviate pruritus.The purpose of the study was to produce anti-canine IL-31RA polyclonal antibodies(anti-IL-31RA pAbs)and evaluate their efcacy in inhibiting house dust mite(HDM)-evoked pruritic responses.Dogs were immunized with antigens formed by IL-31RA recombinant short peptides coupled to BSA to produce anti-IL-31RA pAbs.The CAD model was developed by using HDM allergen stimulation,and the efects of IL-31RA pAbs on the reduction of pruritus in CAD model dogs were examined.The Canine Atopic Dermatitis Extent and Severity Index(CADESI)-4 and pruritus Visual Analog Scale(pVAS)were utilized to evaluate pruritic responses,and skin tissue samples were collected from the inguinal area for pathological assessment of skin infammatory cell infltration.The results showed that anti-IL-31RA pAbs with high titers(1:128,000)and specifcity were efectively produced.In the CAD model group,the severity of skin damage,pruritus score,infammatory cell infltration and level of infammatory factors were considerably elevated.Anti-IL-31RA pAbs relieved pruritic behavior and dermatitis in dogs compared to placebo-treated dogs.In conclusion,anti-IL-31RA pAbs efectively suppressed CAD in vivo and are anticipated to be an efective novel treatment for pruritic skin disorders such as CAD.

Therapeutic targeting of cellular prion protein: toward the development of dual mechanism anti-prion compounds

PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.

Miller fisher syndrome with positive anti-GQ1b/GT1a antibodies associated with COVID-19 infection:A case report

BACKGROUND Miller fisher syndrome(MFS)is a variant of Guillain-Barrésyndrome,an acute immune-mediated peripheral neuropathy that is often secondary to viral infections.Anti-ganglioside antibodies play crucial roles in the development of MFS.The positive rate of ganglioside antibodies is exceptionally high in MFS patients,particularly for anti-GQ1b antibodies.However,the presence of other ganglioside antibodies does not exclude MFS.CASE SUMMARY We present a 56-year-old female patient who suddenly developed right blepharoptosis and progressively worsening vision in both eyes.There were flu symptoms prior to onset,and a coronavirus disease 2019 test was positive.On physical examination,the patient exhibited bilateral extraocular muscle paralysis,weakened reflexes in both limbs,and impaired coordination.The cerebrospinal fluid examination results showed no obvious abnormalities.Bilateral peroneal nerve F-waves were not extracted.Serum anti-GD1b IgG and anti-GT1a IgG antibodies were positive.The patient received intravenous methylprednisolone(1000 mg/day),with the dosage gradually decreased.Additionally,intravenous high-dose immunoglobulin treatment was administered for 5 days(0.4 g/kg/day)from day 2 to day 6 of hospitalization.The patient’s symptoms improved after treatment with immunoglobulins and hormones.CONCLUSION Positive ganglioside antibodies may be used as supporting evidence for the diagnosis;however,the diagnosis of MFS is more reliant on clinical symptoms.

Untoward immune effects of modern medication

Immune-related adverse events(irAEs)represent an increasingly concerning challenge in the assessment of biopharmaceutical products.In contrast to historically rare allergic reactions associated with small chemical drugs,contemporary biotherapeutics exhibit a significantly higher morbidity of irAEs,because of their complex structure and comprehensive mechanisms of action.While the immunogenicity of protein-based compounds is associated with the induction of anti-drug antibodies,the pathogenesis of irAEs in advanced biologics,such as cell and gene therapy,remains to be further delineated.In the current study,I present an updated profile regarding the untoward immune effects of medications,covering various material categories systematically,with the underlying mechanisms to inspire risk mitigation in biopharmaceutical development and application.

Anticancer therapeutic strategies for targeting mutant p53-Y220C

The tumor suppressor p53 is a transcription factor with a powerful antitumor activity that is controlled by its negative regulator murine double minute 2(MDM2,also termed HDM2 in humans)through a feedback mechanism.At the same time,TP53 is the most frequently mutated gene in human cancers.Mutant p53 proteins lose wild-type p53 tumor suppression functions but acquire new oncogenic properties,among which are deregulating cell proliferation,increasing chemoresistance,disrupting tissue architecture,and promoting migration,invasion and metastasis as well as several other pro-oncogenic activities.The oncogenic p53 mutation Y220C creates an extended surface crevice in the DNA-binding domain destabilizing p53 and causing its denaturation and aggregation.This cavity accommodates stabilizing small molecules that have therapeutic values.The development of suitable small-molecule stabilizers is one of the therapeutic strategies for reactivating the Y220C mutant protein.In this review,we summarize approaches that target p53-Y220C,including reactivating this mutation with small molecules that bind Y220C to the hydrophobic pocket and developing immunotherapies as the goal for the near future,which target tumor cells that express the p53-Y220C neoantigen.

Safety of teplizumab in patients with high-risk for diabetes mellitus type 1:A systematic review

BACKGROUND The incidence of diabetes mellitus type 1(DM1)has been rising worldwide because of improvements in diagnostic techniques and improved access to care in countries with lower socioeconomic status.A new anti-CD4 antibody,Teplizumab,has been shown to delay the progression of DM1 and is the only medication approved for this indication.However,more information is needed about the safety profile of this drug.AIM To identify the odds ratios(OR)of systems-based adverse effects for Teplizumab when compared to Placebo.METHODS An extensive systematic review was conducted from the inception of the medication until December 31,2023.All clinical trials and studies that evaluated Teplizumab vs placebo were included in the initial review.The study protocol was designed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines guidelines and was registered in PROSPERO(ID:CRD42024496169).Crude OR were generated using RevMan Software version 5.4.RESULTS After screening and review,5 studies were selected to determine the risk of adverse effects of teplizumab compared to placebo.A total of 561 patients were included in the study population.Total adverse effects and system-based adverse effects were studied and reported.We determined that patients receiving Teplizumab had a higher risk of developing gastrointestinal(GI)(OR=1.60,95%CI:1.01-2.52,P=0.04),dermatological(OR=6.33,95%CI:4.05-9.88,P<0.00001)and hematological adverse effects(OR=19.03,95%CI:11.09-32.66,P<0.00001).These patients were also significantly likely to have active Epstein-Barr Virus infection(OR=3.16,95%CI:1.51-6.64,P<0.002).While our data showed that patients receiving Teplizumab did have a higher incidence of total adverse effects vs placebo,this finding did not reach statistical significance(OR=2.25,95%CI:0.80-6.29,P=0.12).CONCLUSION Our systematic review suggests that Teplizumab patients are at risk for significant adverse effects,primarily related to GI,dermatological,and hematological systems.The total adverse effect data is limited as study populations are small.More studies should be conducted on this medication to better inform the target population of potential adverse effects.