BACKGROUND The gluten-free diet(GFD)has limitations,and there is intense research in the development of adjuvant therapies.AIM To examine the effects of orally administered Aspergillus niger prolyl endopeptidase prote...BACKGROUND The gluten-free diet(GFD)has limitations,and there is intense research in the development of adjuvant therapies.AIM To examine the effects of orally administered Aspergillus niger prolyl endopeptidase protease(AN-PEP)on inadvertent gluten exposure and symptom prevention in adult celiac disease(CeD)patients following their usual GFD.METHODS This was an exploratory,double-blind,randomized,placebo-controlled trial that enrolled CeD patients on a long-term GFD.After a 4-wk run-in period,patients were randomized to 4 wk of two AN-PEP capsules(GliadinX;AVI Research,LLC,United States)at each of three meals per day or placebo.Outcome endpoints were:(1)Average weekly stool gluten immunogenic peptides(GIP)between the run-in and end of treatments and between AN-PEP and placebo;(2)celiac symptom index(CSI);(3)CeD-specific serology;and(4)quality of life.Stool samples were collected for GIP testing by ELISA every Tuesday and Friday during run-ins and treatments.RESULTS Forty patients were randomized for the intention-to-treat analysis,and three were excluded from the per-protocol assessment.Overall,628/640(98.1%)stool samples were collected.GIP was undetectable(<0.08μg/g)in 65.6%of samples,and no differences between treatment arms were detected.Only 0.5%of samples had GIP concentrations sufficiently high(>0.32μg/g)to potentially cause mucosal damage.Median GIP concentration in the AN-PEP arm was 44.7%lower than in the run-in period.One-third of patients exhibiting GIP>0.08μg/g during run-in had lower or undetectable GIP after AN-PEP treatment.Compared with the run-in period,the proportion of symptomatic patients(CSI>38)in the AN-PEP arm was significantly lower(P<0.03).AN-PEP did not result in changes in specific serologies.CONCLUSION This exploratory study conducted in a real-life setting revealed high adherence to the GFD.The AN-PEP treatment did not significantly reduce the overall GIP stool concentration.However,given the observation of a significantly lower prevalence of patients with severe symptoms in the AN-PEP arm,further clinical research is warranted.展开更多
Monomethyl auristatin E(MMAE)is a derivative of the marine peptide Dolastatin 10,which has therapeutic effects against various cancers according to its antimitotic activity in multiple clinical trials.The antibody dru...Monomethyl auristatin E(MMAE)is a derivative of the marine peptide Dolastatin 10,which has therapeutic effects against various cancers according to its antimitotic activity in multiple clinical trials.The antibody drug conjugate(ADC)of MMAE is currently used in clinical practice.However,the safety issues of MMAE-based ADC,such as high drug toxicity and poor bioavailability,still exist when using it for anticancer therapy.A sustained release of drug delivery approach should be used to reduce toxicity and achieve sufficient anticancer effects.Herein,PLGA-b-PEG 2000 with excellent biocompatibility and slow degradation ability was adopted to construct MMAE-loaded nanoparticles for safe and effective chemotherapy.The sustained release effect and the immunogenic cell death(ICD)effect of PLGA-MMAE nanoparticles were assessed by in vitro experiments.The PLGA-MMAE nanoparticles effectively accumulated in the tumor through the enhanced permeability and retention(EPR)effect,inducing cell apoptosis and causing a certain degree of immune response.The sustained drug release of PLGA-MMAE improved the bioavailability and effectively reduced the toxicity and development of the tumor compared to the effect of free MMAE or ADC.Overall,this study provides a safe and effective chemotherapeutic approach,as well as a simple and effective synthetic process for MMAE-based nanoparticles,improving their therapeutic efficacy and safety.展开更多
Food allergens are mainly naturally-occurring proteins with immunoglobulin E(IgE)-binding epitopes.Understanding the structural and immunogenic characteristics of allergenic proteins is essential in assessing whether ...Food allergens are mainly naturally-occurring proteins with immunoglobulin E(IgE)-binding epitopes.Understanding the structural and immunogenic characteristics of allergenic proteins is essential in assessing whether and how food processing techniques reduce allergenicity.We here discuss the impacts of food processing technologies on the modification of physicochemical,structural,and immunogenic properties of allergenic proteins.Detection techniques for characterizing changes in these properties of food allergens are summarized.Food processing helps to reduce allergenicity by aggregating or denaturing proteins,which masks,modifies,or destroys antigenic epitopes,whereas,it cannot eliminate allergenicity completely,and sometimes even improves allergenicity by exposing new epitopes.Moreover,most food processing techniques have been tested on purified food allergens rather than food products due to potential interference of other food components.We provide guidance for further development of processing operations that can decrease the allergenicity of allergenic food proteins without negatively impacting the nutritional profile.展开更多
The modulated electro-hyperthermia (mEHT) method is a unique approach that utilizes all the essential apoptotic pathways through an external radiofrequency (RF) signal. The high-frequency RF is amplitude-modulated and...The modulated electro-hyperthermia (mEHT) method is a unique approach that utilizes all the essential apoptotic pathways through an external radiofrequency (RF) signal. The high-frequency RF is amplitude-modulated and coupled capacitively to the target. The provided energy triggers the death receptors and FAS-FADD complexes in the malignant cells. Multi-pathway apoptosis produces immunogenic cell death (ICD). This ICD provides intracellular information about cancer cells by releasing damage-associated molecular patterns (DAMP), including membrane expression of calreticulin (CRT) and extracellular ATP, HMGB1, and HSP70, executing tumor-specific antigen presentation. The antigen-presenting cells (APCs) play a crucial role in reestablishing immune surveillance and hampering the tumor cells’ ability to hide, thereby evading immune attacks. The matured DCs (generally APCs) produce tumor-specific killer and helper T-cells, which have the potential to be active in distant metastases from the treated location. This unique mechanism of action underscores its potential in cancer treatment and extends the local mEHT treatment to the whole body anticancer therapy with an abscopal effect.展开更多
Objective:This study aimed to describe,optimize and evaluate a method for preparing multivalent conjugate vaccines by simultaneous conjugation of two different bacterial capsular polysaccharides(CPs)with tetanus toxoi...Objective:This study aimed to describe,optimize and evaluate a method for preparing multivalent conjugate vaccines by simultaneous conjugation of two different bacterial capsular polysaccharides(CPs)with tetanus toxoid(TT)as bivalent conjugates.Methods:Different molecular weights(MWs)of polysaccharides,activating agents and capsular polysaccharide/protein(CP/Pro)ratio that may influence conjugation and immunogenicity were investigated and optimized to prepare the bivalent conjugate bulk.Using the described method and optimized parameters,a 20-valent pneumococcal conjugate vaccine and a bivalent meningococcal vaccine were developed and their effectiveness was compared to that of corresponding licensed vaccines in rabbit or mouse models.Results:The immunogenicity test revealed that polysaccharides with lower MWs were better for Pn1-TT-Pn3 and MenA-TT-MenC,while higher MWs were superior for Pn4-TT-Pn14,Pn6A-TT-Pn6B,Pn7F-TT-Pn23F and Pn8-TT-Pn11A.For activating polysaccharides,1-cyano-4-dimethylaminopyridinium tetrafluoroborate(CDAP)was superior to cyanogen bromide(CNBr),but for Pn1,Pn3 and MenC,N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride(EDAC)was the most suitable option.For Pn6A-TT-Pn6B and Pn8-TT-Pn11A,rabbits immunized with bivalent conjugates with lower CP/Pro ratios showed significantly stronger CP-specific antibody responses,while for Pn4-TT-Pn14,higher CP/Pro ratio was better.Instead of interfering with the respective immunological activity,our bivalent conjugates usually induced higher IgG titers than their monovalent counterparts.Conclusion:The result indicated that the described conjugation technique was feasible and efficacious to prepare glycoconjugate vaccines,laying a solid foundation for developing extended-valent multivalent or combined conjugate vaccines without potentially decreased immune function.展开更多
Growing evidence suggests that the presence of cancer stem cells(CSCs)is a major challenge in current tumor treatments,especially the transition from non-CSCs to differentiation of CSCs for evading conventional therap...Growing evidence suggests that the presence of cancer stem cells(CSCs)is a major challenge in current tumor treatments,especially the transition from non-CSCs to differentiation of CSCs for evading conventional therapies and driving metastasis.Here we propose a therapeutic strategy of synergistic differentiation therapy and phototherapy to induce differentiation of CSCs into mature tumor cells by differentiation inducers and synergistic elimination of them and normal cancer cells through phototherapy.In this work,we synthesized a biomimetic nanoplatform loaded with IR-780 and all-trans retinoic acid(ATRA)via biomineralization.This method can integrate aluminum ions into small-sized protein carriers to form nanoclusters,which undergo responsive degradation under acidic conditions and facilitate deep tumor penetration.With the help of CSC differentiation induced by ATRA,IR-780 inhibited the self-renewal of CSCs and cancer progression by generating hyperthermia and reactive oxygen species in a synergistic manner.Furthermore,ATRA can boost immunogenic cell death induced by phototherapy,thereby strongly causing a systemic anti-tumor immune response and efficiently eliminating CSCs and tumor cells.Taken together,this dual strategy represents a new paradigm of targeted eradication of CSCs and tumors by inducing CSC differentiation,improving photothermal therapy/photodynamic therapy and enhancing antitumor immunity.展开更多
To overcome immune tolerance to cancer,the immune system needs to be exposed to a multi-target action intervention.Here,we investigated the activating effect of CpG oligodeoxynucleotides(ODNs),mesyl phosphoramidate Cp...To overcome immune tolerance to cancer,the immune system needs to be exposed to a multi-target action intervention.Here,we investigated the activating effect of CpG oligodeoxynucleotides(ODNs),mesyl phosphoramidate CpG ODNs,anti-OX40 antibodies,and OX40 RNA aptamers on major populations of immunocompetent cells ex vivo.Comparative analysis of the antitumor effects of in situ vaccination with CpG ODNs and anti-OX40 antibodies,as well as several other combinations,such as mesyl phosphoramidate CpG ODNs and OX40 RNA aptamers,was conducted.Antibodies against programmed death 1(PD1)checkpoint inhibitors or their corresponding PD1 DNA aptamers were also added to vaccination regimens for analytical purposes.Four scenarios were considered:a weakly immunogenic Krebs-2 carcinoma grafted in CBA mice;a moderately immunogenic Lewis carcinoma grafted in C57Black/6 mice;and an immunogenic A20 B cell lymphoma or an Ehrlich carcinoma grafted in BALB/c mice.Adding anti-PD1 antibodies(CpG+αOX40+αPD1)to in situ vaccinations boosts the antitumor effect.When to be used instead of antibodies,aptamers also possess antitumor activity,although this effect was less pronounced.The strongest effect across all the tumors was observed in highly immunogenic A20 B cell lymphoma and Ehrlich carcinoma.展开更多
The tumor microenvironment(TME)promotes pro-tumor and anti-infammatory metabolismsand suppresses the host immune system.It prevents immune cells from fighting against cancereffectively,resulting in limited efficacy of...The tumor microenvironment(TME)promotes pro-tumor and anti-infammatory metabolismsand suppresses the host immune system.It prevents immune cells from fighting against cancereffectively,resulting in limited efficacy of many current cancer treatment modalities.Differenttherapies aim to overcome the immunosuppressive TME by combining various approaches tosynergize their effects for enhanced antitumor activity and augmented stimulation of the im-mune system.Immunotherapy has become a major therapeutic strategy because it unleashes thepower of the immune system by activating,enhancing,and directing immune responses to pre-vent,control,and eliminate cancer.Phototherapy uses light iradiation to induce tumor celldeath through photothermal,photochemical,and photo-immunological interactions.Photo-therapy induces tumor immunogenic cell death,which is a precursor and enhancer for anti-tumorimmunity.However,phototherapy alone has limited effects on long-term and systemic anti-tumor immune responses.Phototherapy can be combined with immunotherapy to improve thetumoricidal effect by killing target tumor cells,enhancing immune cell infiltration in tumors,andrewiring pathways in the TME from antinfammatory to pro-inflammatory.Phototherapy-enhanced immunotherapy triggers effective cooperation bet ween innate and adaptive immunities,specifically targeting the tumor cells,whether they are localized or distant.Herein,the successes and limitations of phototherapy combined with other cancer treatmentmodalities will be discussed.Specifically,we will review the symergistic effects of phototherapy combined with different cancer therapies on tumor elimination and remodeling of the immuno-suppressive TME.Overll,phototherapy,in combination with other therapeutic modalities,canestablish anti-tumor pro-infammatory phenotypes in activated tumor-infiltrating T cells andB cells and activate systemic anti-tumor immune responses.展开更多
Lung adenocarcinoma(LUAD)is the leading cause of cancer-related deaths,accounting for over a million deaths worldwide annually.Immunogenic cell death(ICD)elicits an adaptive immune response.However,the role of ICD-rel...Lung adenocarcinoma(LUAD)is the leading cause of cancer-related deaths,accounting for over a million deaths worldwide annually.Immunogenic cell death(ICD)elicits an adaptive immune response.However,the role of ICD-related long noncoding RNAs(lncRNAs)in LUAD is unknown.In this study,we investigated the characteristics of the tumor microenvironment in LUAD,the prognostic significance of ICD-related lncRNAs,and the half-maximal inhibitory concentration(IC50)of possible chemotherapeutic drugs.We sorted prognostic lncRNAs using univariate Cox regression and constructed a risk signature based on them.We then confirmed the model’s accuracy and generated a nomogram.Additionally,we performed immune microenvironment analysis,somatic mutation calculation,Tumor Immune Dysfunction and Exclusion(TIDE)analysis,and anticancer pharmaceutical IC50 prediction.Least absolute shrinkage and selection operator Cox regression identified 27 prognostic lncRNAs related to ICD,and a unique risk signature using 10 ICD-related lncRNAs was constructed.The risk score was confirmed to be a reliable predictor of survival,with the highest c-index score.The signature had a remarkable predictive performance with clinical applicability and could accurately predict the overall survival in LUAD.Furthermore,the lncRNA signature was closely associated with immunocyte invasion.We also analyzed the correlation between the risk score,tumor-infiltrating immune cells,and prognosis and identified high immune and ESTIMATE scores in low-risk patients.Moreover,we observed elevated checkpoint gene expression and low TIDE scores in high-risk patients,indicating a good immunotherapy response.Finally,high-risk patients were shown to be susceptible to anticancer medications.Therefore,our unique risk signature comprising 10 ICD-related lncRNAs was demonstrated to indicate the characteristics of the tumor-immune microenvironment in LUAD,predict patients’overall survival,and guide individualized treatment.展开更多
As a non-apoptotic cell death form,ferroptosis offers an alternative approach to overcome cancer chemotherapy resistance.However,accumulating evidence indicates cancer cells can develop ferroptosis resistance by evolv...As a non-apoptotic cell death form,ferroptosis offers an alternative approach to overcome cancer chemotherapy resistance.However,accumulating evidence indicates cancer cells can develop ferroptosis resistance by evolving antioxidative defense mechanisms.To address this issue,we prepared a Buthionine-(S,R)-sulfoximine(BSO)loaded metal organic framework(MOF)of BSO-MOF-HA(BMH)with the combination effect of boosting oxidative damage and inhibiting antioxidative defense.MOF nanoparticle was constructed by the photosensitizer of[4,4,4,4-(porphine-5,10,15,20-tetrayl)tetrakis(benzoic acid)](TCPP)and the metal ion of Zr6,which was further decorated with hyaluronic acid(HA)in order to impart active targeting to CD44 receptors overexpressed cancer cells.BMH exhibited a negative charge and spherical shape with average particle size about 162.5nm.BMH was found to restore the susceptibility of 4T1 cells to ferroptosis under irradiation.This was attributed to the combination of photodynamic therapy(PDT)andγ-glutamylcysteine synthetase inhibitor of BSO,shifting the redox balance to oxidative stress.Enhanced ferroptosis also induced the release of damage associated molecular patterns(DAMPs)to maturate dendritic cells and activated T lymphocytes,leading to superior anti-tumor performance in vivo.Taken together,our findings demonstrated that boosting oxidative damage with photosensitizer serves as an effective strategy to reverse ferroptosis resistance.展开更多
To investigate the immunogenic Cell Death gene’s potential mechanism and prognostic value in glioblastoma. Information on GBM samples from The Cancer Genome Atlas database was downloaded, ICD genes were obtained, gen...To investigate the immunogenic Cell Death gene’s potential mechanism and prognostic value in glioblastoma. Information on GBM samples from The Cancer Genome Atlas database was downloaded, ICD genes were obtained, genotyping, integrated bioinformatics to verify the prognostic value of genotyping, and finally, prognostic model construction. Two subtypes associated with the ICD gene were obtained by consensus clustering, and the high ICD subtype (risk) group was associated with poor prognosis, high mutations in the PTEN gene, high stromal score, and high immune score. We also constructed a new classification system for GBM based on ICD characteristics. This study is the first to use immunogenic cell death genes for genotyping and successfully build a prognostic model.展开更多
Although the coronavirus disease 2019(COVID-19)pandemic was declared to be no longer“a public health emergency of international concern”with its wide range of clinical manifestations and late complications,severe ac...Although the coronavirus disease 2019(COVID-19)pandemic was declared to be no longer“a public health emergency of international concern”with its wide range of clinical manifestations and late complications,severe acute respiratory syndrome coronavirus 2 infection proved to be a serious threat,especially to the elderly and patients with comorbidities.Patients with oncologic diseases are vulnerable to severe infection and death.Indeed,patients with oncohematological diseases have a higher risk of severe COVID-19 and impaired post-vaccination immunity.Unfortunately,cancer patients are usually excluded from vaccine trials and investigations of post-vaccinal immune responses and the effectiveness of the vaccines.We aimed to elucidate to what extent patients with cancer are at increased risk of developing severe COVID-19 and what is their overall case fatality rate.We also present the current concept and evidence on the effectiveness and safety of COVID-19 vaccines,including boosters,in oncology patients.In conclusion,despite the considerably higher mortality in the cancer patient group than the general population,countries with high vaccination rates have demonstrated trends toward improved survival of cancer patients early and late in the pandemic.展开更多
Objective: To analyze the relationship between TIGIT and clinical features of Esophageal Squamous Cell Carcinoma, we use transcriptomic data from the TCGA database, and to investigate the relationship between TIGIT an...Objective: To analyze the relationship between TIGIT and clinical features of Esophageal Squamous Cell Carcinoma, we use transcriptomic data from the TCGA database, and to investigate the relationship between TIGIT and the immune microenvironment of Esophageal Squamous Cell Carcinoma, to provide a basis for improving the treatment strategy and prognosis of patients with Esophageal Squamous Cell Carcinoma. Methods: RNA sequencing data and clinical data corresponding to cancer tissues were obtained from the TCGA database for Esophageal carcinoma, Esophageal Squamous Cell Carcinoma tissues, and paraneoplastic tissues;then we analyzed the differences in TIGIT expression in Esophageal carcinoma, Esophageal Squamous Cell Carcinoma, and normal esophageal tissues;then we analyzed the relationship between TIGIT expression levels and overall survival in Esophageal Squamous Cell Carcinoma;finally, we explored the relationship between TIGIT expression levels and overall survival in Esophageal Squamous Cell Carcinoma. We investigated the relationship between TIGIT and the tumor immune microenvironment of Esophageal Squamous Cell Carcinoma by tumor immune infiltration and functional enrichment analysis. Results: Our study revealed that TIGIT was highly expressed in Esophageal Squamous Cell Carcinoma, and patients with high TIGIT expression had worse overall survival. We also found a close relationship between TIGIT expression levels and the immune microenvironment of Esophageal Squamous Cell Carcinoma, with high TIGIT expression positively correlated with multiple immune cells. Conclusion: Our study demonstrates that TIGIT is associated with Esophageal Squamous Cell Carcinoma malignancy and is closely linked to the immune microenvironment. Furthermore, high expression of TIGIT often predicts poorer clinical features.展开更多
BACKGROUND Several studies report the useful therapeutic results of regional hyperthermia in association with chemotherapy(CHT) and radiotherapy for the treatment of pancreatic cancer. Modulated electrohyperthermia(mE...BACKGROUND Several studies report the useful therapeutic results of regional hyperthermia in association with chemotherapy(CHT) and radiotherapy for the treatment of pancreatic cancer. Modulated electrohyperthermia(mEHT) is a new hyperthermia technique that induces immunogenic death or apoptosis of pancreatic cancer cells in laboratory experiments and increases tumor response rate and survival in pancreatic cancer patients, offering beneficial therapeutic effects against this severe type of cancer.AIM To assess survival, tumor response and toxicity of mEHT alone or combined with CHT compared with CHT for the treatment of locally advanced or metastatic pancreatic cancer.METHODS This was a retrospective data collection on patients affected by locally advanced or metastatic pancreatic cancer(stage Ⅲ and IV) performed in 9 Italian centers, members of International Clinical Hyperthermia Society-Italian Network. This study included 217 patients, 128(59%) of them were treated with CHT(no-mEHT) and 89(41%) patients received mEHT alone or in association with CHT. mEHT treatments were performed applying a power of 60-150 watts for 40-90 min, simultaneously or within 72 h of administration of CHT.RESULTS Median patients’ age was 67 years(range 31-92 years). mEHT group had a median overall survival greater than non-mEHT group(20 mo, range 1.6-24, vs 9 mo, range 0.4-56.25, P < 0.001). mEHT group showed a higher number of partial responses(45% vs 24%, P = 0.0018) and a lower number of progressions(4% vs 31%, P < 0.001) than the no-mEHT group, at the three months follow-up. Adverse events were observed as mild skin burns in 2.6% of mEHT sessions.CONCLUSION mEHT seems safe and has beneficial effects on survival and tumor response of stage Ⅲ-IV pancreatic tumor treatment. Further randomized studies are warranted to confirm or not these results.展开更多
Objective:To review the current literature on the practice of intramuscular injections(IMIs),focusing on immunizations.Methods:The present study comprises 2 reviews,characterized by high-quality evidence,per taining t...Objective:To review the current literature on the practice of intramuscular injections(IMIs),focusing on immunizations.Methods:The present study comprises 2 reviews,characterized by high-quality evidence,per taining to the deployment of the slow injection technique without aspiration(referred to in this paper as the without-aspiration slow injection technique[WASi T])and combined with the Zeta-track technique(ZTT).The literature review is oriented toward the analysis of 2 features associated with IMIs techniques:safety and pain,integrating new evidence on vaccinee positioning for each muscle site and general relaxation techniques in the multi-parametric analysis.Results:The rigorous and in-depth reviews in the current study reveal the usefulness of including,among the international guidelines for via intramuscular immunizations,the adoption of WASi T only for compliant vaccinees,and in combination with all validated techniques for IMIs,and the use of ZTT limitedly if specific well-developed muscles are indicated.All the technique's limitations are exposed.Conclusions:Future research directions are presented by including the author's study designs to provide indirect evidence for the validity of the rationale of the slow injection technique using scientific methods,and for the conduction of future randomized controlled trials(RCTs)focused on revisiting the adoption of ZTT in a dynamic and integrated immunizations protocol in anterolateral thigh(ALT),ventrogluteal(VG),and also in the deltoid muscle,in the specific cases analyzed.展开更多
Objective Graft rejection, with the possibility of a violent immune response, may be severe and life threatening. Our aim was to thoroughly investigate the biocompatibility and immunotoxicology of collagen-based derma...Objective Graft rejection, with the possibility of a violent immune response, may be severe and life threatening. Our aim was to thoroughly investigate the biocompatibility and immunotoxicology of collagen-based dermal matrix(DM) before assessment in clinical trials. Methods DM was subcutaneously implanted in BALB/c mice in two doses to induce a potential immune response. The spleen and lymph nodes were assessed for shape, cell number, cell phenotype via flow cytometry, cell activation via CCK8 kit, Annexin V kit, and Ki67 immunostaining. Serum samples were used to measure antibody concentration by enzyme-linked immunosorbent assay. Local inflammation was analyzed by histology and immunohistochemistry staining. Data analysis was performed by one-way ANOVA and non-parametric tests. Results Our data illustrate that the spleen and lymph node sizes were similar between the negative control mice and mice implanted with DM. However, in the high-dose DM(DM-H) group, the total cell populations in the spleen and lymph nodes, T cells and B cells in the spleen had slight increases in prophase, and the low-dose DM(DM-L) group did not display gross abnormities. Moreover, DM-H initiated moderate cell activation and proliferation in the early phase post-immunization, whereas DM-L did not. Neither DM-H nor DM-L implantation noticeably increased IgM and IgG serum concentrations. Examination of the local cellular response revealed only benign cell infiltration and TNF-α expression in slides of DM in the early phase. Conclusion Overall, DM-H may have induced a benign temporary acute immune response post-implantation, whereas DM-L had quite low immunogenicity. Thus, this DM can be regarded as a safe product.展开更多
AIM:To investigate whether tumor debris created by high-intensity focused ultrasound(HIFU)could trigger antitumor immunity in a mouse hepatocellular carcinoma model. METHODS:Twenty C57BL/6J mice bearing H22 hepatocell...AIM:To investigate whether tumor debris created by high-intensity focused ultrasound(HIFU)could trigger antitumor immunity in a mouse hepatocellular carcinoma model. METHODS:Twenty C57BL/6J mice bearing H22 hepatocellular carcinoma were used to generate antitumor vaccines.Ten mice underwent HIFU ablation,and the remaining 10 mice received a sham-HIFU procedure with no ultrasound irradiation.Sixty normal mice were randomly divided into HIFU vaccine,tumor vaccine and control groups.These mice were immunized with HIFU-generated vaccine,tumor-generated vaccine,and saline,respectively.In addition,20 mice bearing H22 tumors were successfully treated with HIFU ablation. The protective immunity of the vaccinated mice was investigated before and after a subsequent H22 tumor challenge.Using the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide assay,the cytotoxicity of splenic lymphocytes co-cultured with H22 cells wasdetermined in vitro before the tumor challenge,and tumor volume and survival were measured in vivo after the challenge in each group.The mechanism was also explored by loading the vaccines with bone marrowderived dendritic cells(DCs). RESULTS:Compared to the control,HIFU therapy, tumor-generated and HIFU-generated vaccines significantly increased cytolytic activity against H22 cells in the splenocytes of the vaccinated mice(P<0.001). The tumor volume was significantly smaller in the HIFU vaccine group than in the tumor vaccine group(P <0.05)and control group(P<0.01).However,there was no tumor growth after H22 rechallenge in the HIFU therapy group.Forty-eight-day survival rate was 100%in mice in the HIFU therapy group,30%in both the HIFU vaccine and tumor vaccine groups,and 20% in the control group,indicating that the HIFU-treated mice displayed significantly longer survival than the vaccinated mice in the remaining three groups(P< 0.001).After bone marrow-derived DCs were incubated with HIFU-generated and tumor-generated vaccines, the number of mature DCs expressing MHC-Ⅱ + ,CD80 + and CD86 + molecules was significantly increased,and interleukin-12 and interferon-γlevels were significantly higher in the supernatants when compared with immature DCs incubated with mouse serum(P<0.001). However,no differences of the number of mature DCs and cytokine levels were observed between the HIFU- generated and tumor-generated vaccines(P>0.05). CONCLUSION:Tumor debris remaining after HIFU can improve tumor immunogenicity.This debris releases tumor antigens as an effective vaccine to develop host antitumor immune response after HIFU ablation.展开更多
Chemotherapy-induced diarrhea(CID)is a common and often severe side effect experienced by colorectal cancer(CRC)patients during their treatment.As chemotherapy regimens evolve to include more efficacious agents,CID is...Chemotherapy-induced diarrhea(CID)is a common and often severe side effect experienced by colorectal cancer(CRC)patients during their treatment.As chemotherapy regimens evolve to include more efficacious agents,CID is increasingly becoming a major cause of dose limiting toxicity and merits further investigation.Inflammation is a key factor behind gastrointestinal(GI)toxicity of chemotherapy.Different chemotherapeutic agents activate a diverse range of pro-inflammatory pathways culminating in distinct histopathological changes in the small intestine and colonic mucosa.Here we review the current understanding of the mechanisms behind GI toxicity and the mucositis associated with systemic treatment of CRC.Insights into the inflammatory response activated during this process gained from various models of GI toxicity are discussed.The inflammatory processes contributing to the GI toxicity of chemotherapeutic agents are increasingly being recognised as having an important role in the development of anti-tumor immunity,thus conferring added benefit against tumor recurrence and improving patient survival.We review the basic mechanisms involved in the promotion of immunogenic cell death and its relevance in the treatment of colorectal cancer.Finally,the impact of CID on patient outcomes and therapeutic strategies to prevent or minimise the effect of GI toxicity and mucositis are discussed.展开更多
基金Supported by the Asociación de Celíacos y Sensibles al Gluten de Madrid,No.ACM2020)and Research Committee Argentine Society of Gastroenterology,No.2020.
文摘BACKGROUND The gluten-free diet(GFD)has limitations,and there is intense research in the development of adjuvant therapies.AIM To examine the effects of orally administered Aspergillus niger prolyl endopeptidase protease(AN-PEP)on inadvertent gluten exposure and symptom prevention in adult celiac disease(CeD)patients following their usual GFD.METHODS This was an exploratory,double-blind,randomized,placebo-controlled trial that enrolled CeD patients on a long-term GFD.After a 4-wk run-in period,patients were randomized to 4 wk of two AN-PEP capsules(GliadinX;AVI Research,LLC,United States)at each of three meals per day or placebo.Outcome endpoints were:(1)Average weekly stool gluten immunogenic peptides(GIP)between the run-in and end of treatments and between AN-PEP and placebo;(2)celiac symptom index(CSI);(3)CeD-specific serology;and(4)quality of life.Stool samples were collected for GIP testing by ELISA every Tuesday and Friday during run-ins and treatments.RESULTS Forty patients were randomized for the intention-to-treat analysis,and three were excluded from the per-protocol assessment.Overall,628/640(98.1%)stool samples were collected.GIP was undetectable(<0.08μg/g)in 65.6%of samples,and no differences between treatment arms were detected.Only 0.5%of samples had GIP concentrations sufficiently high(>0.32μg/g)to potentially cause mucosal damage.Median GIP concentration in the AN-PEP arm was 44.7%lower than in the run-in period.One-third of patients exhibiting GIP>0.08μg/g during run-in had lower or undetectable GIP after AN-PEP treatment.Compared with the run-in period,the proportion of symptomatic patients(CSI>38)in the AN-PEP arm was significantly lower(P<0.03).AN-PEP did not result in changes in specific serologies.CONCLUSION This exploratory study conducted in a real-life setting revealed high adherence to the GFD.The AN-PEP treatment did not significantly reduce the overall GIP stool concentration.However,given the observation of a significantly lower prevalence of patients with severe symptoms in the AN-PEP arm,further clinical research is warranted.
基金funded by the Hainan Provincial Joint Project of Sanya Yazhou Bay Science and Technology City(No.820LH027)the Hainan Provincial Natural Science Foundation of China(No.823RC472)+1 种基金the Open Project Program of Wuhan National Laboratory for Optoelectronics(No.2021WNLOKF008)the Hainan University Scientific Research Foundation(KYQD(ZR)19107).
文摘Monomethyl auristatin E(MMAE)is a derivative of the marine peptide Dolastatin 10,which has therapeutic effects against various cancers according to its antimitotic activity in multiple clinical trials.The antibody drug conjugate(ADC)of MMAE is currently used in clinical practice.However,the safety issues of MMAE-based ADC,such as high drug toxicity and poor bioavailability,still exist when using it for anticancer therapy.A sustained release of drug delivery approach should be used to reduce toxicity and achieve sufficient anticancer effects.Herein,PLGA-b-PEG 2000 with excellent biocompatibility and slow degradation ability was adopted to construct MMAE-loaded nanoparticles for safe and effective chemotherapy.The sustained release effect and the immunogenic cell death(ICD)effect of PLGA-MMAE nanoparticles were assessed by in vitro experiments.The PLGA-MMAE nanoparticles effectively accumulated in the tumor through the enhanced permeability and retention(EPR)effect,inducing cell apoptosis and causing a certain degree of immune response.The sustained drug release of PLGA-MMAE improved the bioavailability and effectively reduced the toxicity and development of the tumor compared to the effect of free MMAE or ADC.Overall,this study provides a safe and effective chemotherapeutic approach,as well as a simple and effective synthetic process for MMAE-based nanoparticles,improving their therapeutic efficacy and safety.
基金supported by the National Natural Science Foundation of China (32102605)the Agricultural Science and Technology Innovation Program under Grant (CAAS-ASTIP-2020IAR)the Earmarked Fund for CARS (CARS-44)。
文摘Food allergens are mainly naturally-occurring proteins with immunoglobulin E(IgE)-binding epitopes.Understanding the structural and immunogenic characteristics of allergenic proteins is essential in assessing whether and how food processing techniques reduce allergenicity.We here discuss the impacts of food processing technologies on the modification of physicochemical,structural,and immunogenic properties of allergenic proteins.Detection techniques for characterizing changes in these properties of food allergens are summarized.Food processing helps to reduce allergenicity by aggregating or denaturing proteins,which masks,modifies,or destroys antigenic epitopes,whereas,it cannot eliminate allergenicity completely,and sometimes even improves allergenicity by exposing new epitopes.Moreover,most food processing techniques have been tested on purified food allergens rather than food products due to potential interference of other food components.We provide guidance for further development of processing operations that can decrease the allergenicity of allergenic food proteins without negatively impacting the nutritional profile.
文摘The modulated electro-hyperthermia (mEHT) method is a unique approach that utilizes all the essential apoptotic pathways through an external radiofrequency (RF) signal. The high-frequency RF is amplitude-modulated and coupled capacitively to the target. The provided energy triggers the death receptors and FAS-FADD complexes in the malignant cells. Multi-pathway apoptosis produces immunogenic cell death (ICD). This ICD provides intracellular information about cancer cells by releasing damage-associated molecular patterns (DAMP), including membrane expression of calreticulin (CRT) and extracellular ATP, HMGB1, and HSP70, executing tumor-specific antigen presentation. The antigen-presenting cells (APCs) play a crucial role in reestablishing immune surveillance and hampering the tumor cells’ ability to hide, thereby evading immune attacks. The matured DCs (generally APCs) produce tumor-specific killer and helper T-cells, which have the potential to be active in distant metastases from the treated location. This unique mechanism of action underscores its potential in cancer treatment and extends the local mEHT treatment to the whole body anticancer therapy with an abscopal effect.
文摘Objective:This study aimed to describe,optimize and evaluate a method for preparing multivalent conjugate vaccines by simultaneous conjugation of two different bacterial capsular polysaccharides(CPs)with tetanus toxoid(TT)as bivalent conjugates.Methods:Different molecular weights(MWs)of polysaccharides,activating agents and capsular polysaccharide/protein(CP/Pro)ratio that may influence conjugation and immunogenicity were investigated and optimized to prepare the bivalent conjugate bulk.Using the described method and optimized parameters,a 20-valent pneumococcal conjugate vaccine and a bivalent meningococcal vaccine were developed and their effectiveness was compared to that of corresponding licensed vaccines in rabbit or mouse models.Results:The immunogenicity test revealed that polysaccharides with lower MWs were better for Pn1-TT-Pn3 and MenA-TT-MenC,while higher MWs were superior for Pn4-TT-Pn14,Pn6A-TT-Pn6B,Pn7F-TT-Pn23F and Pn8-TT-Pn11A.For activating polysaccharides,1-cyano-4-dimethylaminopyridinium tetrafluoroborate(CDAP)was superior to cyanogen bromide(CNBr),but for Pn1,Pn3 and MenC,N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride(EDAC)was the most suitable option.For Pn6A-TT-Pn6B and Pn8-TT-Pn11A,rabbits immunized with bivalent conjugates with lower CP/Pro ratios showed significantly stronger CP-specific antibody responses,while for Pn4-TT-Pn14,higher CP/Pro ratio was better.Instead of interfering with the respective immunological activity,our bivalent conjugates usually induced higher IgG titers than their monovalent counterparts.Conclusion:The result indicated that the described conjugation technique was feasible and efficacious to prepare glycoconjugate vaccines,laying a solid foundation for developing extended-valent multivalent or combined conjugate vaccines without potentially decreased immune function.
基金supported by National Science and Technology Major Special Project-Major New Drug Creation(2019ZX09301-112)Shandong Natural Science Foundation(ZR2020QH351)+1 种基金Shandong Provincial Program of Taishan Industrial Experts(2019TSCYCX-31)the Fundamental Research Funds of Shandong University(2020GN091)
文摘Growing evidence suggests that the presence of cancer stem cells(CSCs)is a major challenge in current tumor treatments,especially the transition from non-CSCs to differentiation of CSCs for evading conventional therapies and driving metastasis.Here we propose a therapeutic strategy of synergistic differentiation therapy and phototherapy to induce differentiation of CSCs into mature tumor cells by differentiation inducers and synergistic elimination of them and normal cancer cells through phototherapy.In this work,we synthesized a biomimetic nanoplatform loaded with IR-780 and all-trans retinoic acid(ATRA)via biomineralization.This method can integrate aluminum ions into small-sized protein carriers to form nanoclusters,which undergo responsive degradation under acidic conditions and facilitate deep tumor penetration.With the help of CSC differentiation induced by ATRA,IR-780 inhibited the self-renewal of CSCs and cancer progression by generating hyperthermia and reactive oxygen species in a synergistic manner.Furthermore,ATRA can boost immunogenic cell death induced by phototherapy,thereby strongly causing a systemic anti-tumor immune response and efficiently eliminating CSCs and tumor cells.Taken together,this dual strategy represents a new paradigm of targeted eradication of CSCs and tumors by inducing CSC differentiation,improving photothermal therapy/photodynamic therapy and enhancing antitumor immunity.
基金supported by the Russian Ministry of Science and High Education via the Institute of Cytology and Genetics (State Budget Project No.FWNR-2022-0016)the Russian Foundation for Basic Research (Grant No.18-29-09045).
文摘To overcome immune tolerance to cancer,the immune system needs to be exposed to a multi-target action intervention.Here,we investigated the activating effect of CpG oligodeoxynucleotides(ODNs),mesyl phosphoramidate CpG ODNs,anti-OX40 antibodies,and OX40 RNA aptamers on major populations of immunocompetent cells ex vivo.Comparative analysis of the antitumor effects of in situ vaccination with CpG ODNs and anti-OX40 antibodies,as well as several other combinations,such as mesyl phosphoramidate CpG ODNs and OX40 RNA aptamers,was conducted.Antibodies against programmed death 1(PD1)checkpoint inhibitors or their corresponding PD1 DNA aptamers were also added to vaccination regimens for analytical purposes.Four scenarios were considered:a weakly immunogenic Krebs-2 carcinoma grafted in CBA mice;a moderately immunogenic Lewis carcinoma grafted in C57Black/6 mice;and an immunogenic A20 B cell lymphoma or an Ehrlich carcinoma grafted in BALB/c mice.Adding anti-PD1 antibodies(CpG+αOX40+αPD1)to in situ vaccinations boosts the antitumor effect.When to be used instead of antibodies,aptamers also possess antitumor activity,although this effect was less pronounced.The strongest effect across all the tumors was observed in highly immunogenic A20 B cell lymphoma and Ehrlich carcinoma.
基金supported in part by the National Cancer Institute(R01CA205348 and R01CA269897)the Oklahoma Center for the Advancement of Science and Technology(HR16-085 and HF20-019)+1 种基金supported in part by the Institutional Development Award(IDeA)from the National Institute of General Medical Sciences,National Institutes of Health,under Grant Number P20GM135009Trisha I.Valerio and Coline L.Furrer contributed equally to this work.
文摘The tumor microenvironment(TME)promotes pro-tumor and anti-infammatory metabolismsand suppresses the host immune system.It prevents immune cells from fighting against cancereffectively,resulting in limited efficacy of many current cancer treatment modalities.Differenttherapies aim to overcome the immunosuppressive TME by combining various approaches tosynergize their effects for enhanced antitumor activity and augmented stimulation of the im-mune system.Immunotherapy has become a major therapeutic strategy because it unleashes thepower of the immune system by activating,enhancing,and directing immune responses to pre-vent,control,and eliminate cancer.Phototherapy uses light iradiation to induce tumor celldeath through photothermal,photochemical,and photo-immunological interactions.Photo-therapy induces tumor immunogenic cell death,which is a precursor and enhancer for anti-tumorimmunity.However,phototherapy alone has limited effects on long-term and systemic anti-tumor immune responses.Phototherapy can be combined with immunotherapy to improve thetumoricidal effect by killing target tumor cells,enhancing immune cell infiltration in tumors,andrewiring pathways in the TME from antinfammatory to pro-inflammatory.Phototherapy-enhanced immunotherapy triggers effective cooperation bet ween innate and adaptive immunities,specifically targeting the tumor cells,whether they are localized or distant.Herein,the successes and limitations of phototherapy combined with other cancer treatmentmodalities will be discussed.Specifically,we will review the symergistic effects of phototherapy combined with different cancer therapies on tumor elimination and remodeling of the immuno-suppressive TME.Overll,phototherapy,in combination with other therapeutic modalities,canestablish anti-tumor pro-infammatory phenotypes in activated tumor-infiltrating T cells andB cells and activate systemic anti-tumor immune responses.
文摘Lung adenocarcinoma(LUAD)is the leading cause of cancer-related deaths,accounting for over a million deaths worldwide annually.Immunogenic cell death(ICD)elicits an adaptive immune response.However,the role of ICD-related long noncoding RNAs(lncRNAs)in LUAD is unknown.In this study,we investigated the characteristics of the tumor microenvironment in LUAD,the prognostic significance of ICD-related lncRNAs,and the half-maximal inhibitory concentration(IC50)of possible chemotherapeutic drugs.We sorted prognostic lncRNAs using univariate Cox regression and constructed a risk signature based on them.We then confirmed the model’s accuracy and generated a nomogram.Additionally,we performed immune microenvironment analysis,somatic mutation calculation,Tumor Immune Dysfunction and Exclusion(TIDE)analysis,and anticancer pharmaceutical IC50 prediction.Least absolute shrinkage and selection operator Cox regression identified 27 prognostic lncRNAs related to ICD,and a unique risk signature using 10 ICD-related lncRNAs was constructed.The risk score was confirmed to be a reliable predictor of survival,with the highest c-index score.The signature had a remarkable predictive performance with clinical applicability and could accurately predict the overall survival in LUAD.Furthermore,the lncRNA signature was closely associated with immunocyte invasion.We also analyzed the correlation between the risk score,tumor-infiltrating immune cells,and prognosis and identified high immune and ESTIMATE scores in low-risk patients.Moreover,we observed elevated checkpoint gene expression and low TIDE scores in high-risk patients,indicating a good immunotherapy response.Finally,high-risk patients were shown to be susceptible to anticancer medications.Therefore,our unique risk signature comprising 10 ICD-related lncRNAs was demonstrated to indicate the characteristics of the tumor-immune microenvironment in LUAD,predict patients’overall survival,and guide individualized treatment.
文摘As a non-apoptotic cell death form,ferroptosis offers an alternative approach to overcome cancer chemotherapy resistance.However,accumulating evidence indicates cancer cells can develop ferroptosis resistance by evolving antioxidative defense mechanisms.To address this issue,we prepared a Buthionine-(S,R)-sulfoximine(BSO)loaded metal organic framework(MOF)of BSO-MOF-HA(BMH)with the combination effect of boosting oxidative damage and inhibiting antioxidative defense.MOF nanoparticle was constructed by the photosensitizer of[4,4,4,4-(porphine-5,10,15,20-tetrayl)tetrakis(benzoic acid)](TCPP)and the metal ion of Zr6,which was further decorated with hyaluronic acid(HA)in order to impart active targeting to CD44 receptors overexpressed cancer cells.BMH exhibited a negative charge and spherical shape with average particle size about 162.5nm.BMH was found to restore the susceptibility of 4T1 cells to ferroptosis under irradiation.This was attributed to the combination of photodynamic therapy(PDT)andγ-glutamylcysteine synthetase inhibitor of BSO,shifting the redox balance to oxidative stress.Enhanced ferroptosis also induced the release of damage associated molecular patterns(DAMPs)to maturate dendritic cells and activated T lymphocytes,leading to superior anti-tumor performance in vivo.Taken together,our findings demonstrated that boosting oxidative damage with photosensitizer serves as an effective strategy to reverse ferroptosis resistance.
文摘To investigate the immunogenic Cell Death gene’s potential mechanism and prognostic value in glioblastoma. Information on GBM samples from The Cancer Genome Atlas database was downloaded, ICD genes were obtained, genotyping, integrated bioinformatics to verify the prognostic value of genotyping, and finally, prognostic model construction. Two subtypes associated with the ICD gene were obtained by consensus clustering, and the high ICD subtype (risk) group was associated with poor prognosis, high mutations in the PTEN gene, high stromal score, and high immune score. We also constructed a new classification system for GBM based on ICD characteristics. This study is the first to use immunogenic cell death genes for genotyping and successfully build a prognostic model.
基金Supported by the European Union-Next Generation EU,through the National Recovery and Resilience Plan of the Republic of Bulgaria,No.BG-RRP-2.004-0008.
文摘Although the coronavirus disease 2019(COVID-19)pandemic was declared to be no longer“a public health emergency of international concern”with its wide range of clinical manifestations and late complications,severe acute respiratory syndrome coronavirus 2 infection proved to be a serious threat,especially to the elderly and patients with comorbidities.Patients with oncologic diseases are vulnerable to severe infection and death.Indeed,patients with oncohematological diseases have a higher risk of severe COVID-19 and impaired post-vaccination immunity.Unfortunately,cancer patients are usually excluded from vaccine trials and investigations of post-vaccinal immune responses and the effectiveness of the vaccines.We aimed to elucidate to what extent patients with cancer are at increased risk of developing severe COVID-19 and what is their overall case fatality rate.We also present the current concept and evidence on the effectiveness and safety of COVID-19 vaccines,including boosters,in oncology patients.In conclusion,despite the considerably higher mortality in the cancer patient group than the general population,countries with high vaccination rates have demonstrated trends toward improved survival of cancer patients early and late in the pandemic.
文摘Objective: To analyze the relationship between TIGIT and clinical features of Esophageal Squamous Cell Carcinoma, we use transcriptomic data from the TCGA database, and to investigate the relationship between TIGIT and the immune microenvironment of Esophageal Squamous Cell Carcinoma, to provide a basis for improving the treatment strategy and prognosis of patients with Esophageal Squamous Cell Carcinoma. Methods: RNA sequencing data and clinical data corresponding to cancer tissues were obtained from the TCGA database for Esophageal carcinoma, Esophageal Squamous Cell Carcinoma tissues, and paraneoplastic tissues;then we analyzed the differences in TIGIT expression in Esophageal carcinoma, Esophageal Squamous Cell Carcinoma, and normal esophageal tissues;then we analyzed the relationship between TIGIT expression levels and overall survival in Esophageal Squamous Cell Carcinoma;finally, we explored the relationship between TIGIT expression levels and overall survival in Esophageal Squamous Cell Carcinoma. We investigated the relationship between TIGIT and the tumor immune microenvironment of Esophageal Squamous Cell Carcinoma by tumor immune infiltration and functional enrichment analysis. Results: Our study revealed that TIGIT was highly expressed in Esophageal Squamous Cell Carcinoma, and patients with high TIGIT expression had worse overall survival. We also found a close relationship between TIGIT expression levels and the immune microenvironment of Esophageal Squamous Cell Carcinoma, with high TIGIT expression positively correlated with multiple immune cells. Conclusion: Our study demonstrates that TIGIT is associated with Esophageal Squamous Cell Carcinoma malignancy and is closely linked to the immune microenvironment. Furthermore, high expression of TIGIT often predicts poorer clinical features.
文摘BACKGROUND Several studies report the useful therapeutic results of regional hyperthermia in association with chemotherapy(CHT) and radiotherapy for the treatment of pancreatic cancer. Modulated electrohyperthermia(mEHT) is a new hyperthermia technique that induces immunogenic death or apoptosis of pancreatic cancer cells in laboratory experiments and increases tumor response rate and survival in pancreatic cancer patients, offering beneficial therapeutic effects against this severe type of cancer.AIM To assess survival, tumor response and toxicity of mEHT alone or combined with CHT compared with CHT for the treatment of locally advanced or metastatic pancreatic cancer.METHODS This was a retrospective data collection on patients affected by locally advanced or metastatic pancreatic cancer(stage Ⅲ and IV) performed in 9 Italian centers, members of International Clinical Hyperthermia Society-Italian Network. This study included 217 patients, 128(59%) of them were treated with CHT(no-mEHT) and 89(41%) patients received mEHT alone or in association with CHT. mEHT treatments were performed applying a power of 60-150 watts for 40-90 min, simultaneously or within 72 h of administration of CHT.RESULTS Median patients’ age was 67 years(range 31-92 years). mEHT group had a median overall survival greater than non-mEHT group(20 mo, range 1.6-24, vs 9 mo, range 0.4-56.25, P < 0.001). mEHT group showed a higher number of partial responses(45% vs 24%, P = 0.0018) and a lower number of progressions(4% vs 31%, P < 0.001) than the no-mEHT group, at the three months follow-up. Adverse events were observed as mild skin burns in 2.6% of mEHT sessions.CONCLUSION mEHT seems safe and has beneficial effects on survival and tumor response of stage Ⅲ-IV pancreatic tumor treatment. Further randomized studies are warranted to confirm or not these results.
文摘Objective:To review the current literature on the practice of intramuscular injections(IMIs),focusing on immunizations.Methods:The present study comprises 2 reviews,characterized by high-quality evidence,per taining to the deployment of the slow injection technique without aspiration(referred to in this paper as the without-aspiration slow injection technique[WASi T])and combined with the Zeta-track technique(ZTT).The literature review is oriented toward the analysis of 2 features associated with IMIs techniques:safety and pain,integrating new evidence on vaccinee positioning for each muscle site and general relaxation techniques in the multi-parametric analysis.Results:The rigorous and in-depth reviews in the current study reveal the usefulness of including,among the international guidelines for via intramuscular immunizations,the adoption of WASi T only for compliant vaccinees,and in combination with all validated techniques for IMIs,and the use of ZTT limitedly if specific well-developed muscles are indicated.All the technique's limitations are exposed.Conclusions:Future research directions are presented by including the author's study designs to provide indirect evidence for the validity of the rationale of the slow injection technique using scientific methods,and for the conduction of future randomized controlled trials(RCTs)focused on revisiting the adoption of ZTT in a dynamic and integrated immunizations protocol in anterolateral thigh(ALT),ventrogluteal(VG),and also in the deltoid muscle,in the specific cases analyzed.
基金supported by the National Natural Science Foundation of China [No.31470915]Shenzhen Science and Technology Project [No.JCYJ20170817140537062]+1 种基金the Fundamental Research Funds for the Central Universities [No.YWF-18-BJ-J-217]the 111 Project [No.B13003]
文摘Objective Graft rejection, with the possibility of a violent immune response, may be severe and life threatening. Our aim was to thoroughly investigate the biocompatibility and immunotoxicology of collagen-based dermal matrix(DM) before assessment in clinical trials. Methods DM was subcutaneously implanted in BALB/c mice in two doses to induce a potential immune response. The spleen and lymph nodes were assessed for shape, cell number, cell phenotype via flow cytometry, cell activation via CCK8 kit, Annexin V kit, and Ki67 immunostaining. Serum samples were used to measure antibody concentration by enzyme-linked immunosorbent assay. Local inflammation was analyzed by histology and immunohistochemistry staining. Data analysis was performed by one-way ANOVA and non-parametric tests. Results Our data illustrate that the spleen and lymph node sizes were similar between the negative control mice and mice implanted with DM. However, in the high-dose DM(DM-H) group, the total cell populations in the spleen and lymph nodes, T cells and B cells in the spleen had slight increases in prophase, and the low-dose DM(DM-L) group did not display gross abnormities. Moreover, DM-H initiated moderate cell activation and proliferation in the early phase post-immunization, whereas DM-L did not. Neither DM-H nor DM-L implantation noticeably increased IgM and IgG serum concentrations. Examination of the local cellular response revealed only benign cell infiltration and TNF-α expression in slides of DM in the early phase. Conclusion Overall, DM-H may have induced a benign temporary acute immune response post-implantation, whereas DM-L had quite low immunogenicity. Thus, this DM can be regarded as a safe product.
基金Supported by The Foundation of Ministry of Education of China,No.IRT0454
文摘AIM:To investigate whether tumor debris created by high-intensity focused ultrasound(HIFU)could trigger antitumor immunity in a mouse hepatocellular carcinoma model. METHODS:Twenty C57BL/6J mice bearing H22 hepatocellular carcinoma were used to generate antitumor vaccines.Ten mice underwent HIFU ablation,and the remaining 10 mice received a sham-HIFU procedure with no ultrasound irradiation.Sixty normal mice were randomly divided into HIFU vaccine,tumor vaccine and control groups.These mice were immunized with HIFU-generated vaccine,tumor-generated vaccine,and saline,respectively.In addition,20 mice bearing H22 tumors were successfully treated with HIFU ablation. The protective immunity of the vaccinated mice was investigated before and after a subsequent H22 tumor challenge.Using the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide assay,the cytotoxicity of splenic lymphocytes co-cultured with H22 cells wasdetermined in vitro before the tumor challenge,and tumor volume and survival were measured in vivo after the challenge in each group.The mechanism was also explored by loading the vaccines with bone marrowderived dendritic cells(DCs). RESULTS:Compared to the control,HIFU therapy, tumor-generated and HIFU-generated vaccines significantly increased cytolytic activity against H22 cells in the splenocytes of the vaccinated mice(P<0.001). The tumor volume was significantly smaller in the HIFU vaccine group than in the tumor vaccine group(P <0.05)and control group(P<0.01).However,there was no tumor growth after H22 rechallenge in the HIFU therapy group.Forty-eight-day survival rate was 100%in mice in the HIFU therapy group,30%in both the HIFU vaccine and tumor vaccine groups,and 20% in the control group,indicating that the HIFU-treated mice displayed significantly longer survival than the vaccinated mice in the remaining three groups(P< 0.001).After bone marrow-derived DCs were incubated with HIFU-generated and tumor-generated vaccines, the number of mature DCs expressing MHC-Ⅱ + ,CD80 + and CD86 + molecules was significantly increased,and interleukin-12 and interferon-γlevels were significantly higher in the supernatants when compared with immature DCs incubated with mouse serum(P<0.001). However,no differences of the number of mature DCs and cytokine levels were observed between the HIFU- generated and tumor-generated vaccines(P>0.05). CONCLUSION:Tumor debris remaining after HIFU can improve tumor immunogenicity.This debris releases tumor antigens as an effective vaccine to develop host antitumor immune response after HIFU ablation.
基金Supported by A Newman Fellowship awarded by the University College Dublin Foundation and sponsored by Helsinn-Birex Pharmaceuticals
文摘Chemotherapy-induced diarrhea(CID)is a common and often severe side effect experienced by colorectal cancer(CRC)patients during their treatment.As chemotherapy regimens evolve to include more efficacious agents,CID is increasingly becoming a major cause of dose limiting toxicity and merits further investigation.Inflammation is a key factor behind gastrointestinal(GI)toxicity of chemotherapy.Different chemotherapeutic agents activate a diverse range of pro-inflammatory pathways culminating in distinct histopathological changes in the small intestine and colonic mucosa.Here we review the current understanding of the mechanisms behind GI toxicity and the mucositis associated with systemic treatment of CRC.Insights into the inflammatory response activated during this process gained from various models of GI toxicity are discussed.The inflammatory processes contributing to the GI toxicity of chemotherapeutic agents are increasingly being recognised as having an important role in the development of anti-tumor immunity,thus conferring added benefit against tumor recurrence and improving patient survival.We review the basic mechanisms involved in the promotion of immunogenic cell death and its relevance in the treatment of colorectal cancer.Finally,the impact of CID on patient outcomes and therapeutic strategies to prevent or minimise the effect of GI toxicity and mucositis are discussed.