Effects of immunosuppressants after penetrating keratoplasty:meta-analysis of randomized controlled trials

AIM:To assess the effectiveness of immunosuppressants in the prophylaxis of corneal allograft rejection after high-risk keratoplasty and normal-risk keratoplasty.METHODS:We searched the Cochrane Central Register of Controlled Trials(CENTRAL),MEDLINE,EMBASE,CNKI,VIP and reference lists of articles.Date of most recent search:18 June,2011.All randomised controlled trials(RCTs) assessing the use of immunosupressants in the prevention of graft rejection,irrespective of publication language.Two authors assessed trial quality and extracted data independently.Only dichotomous outcomes(clear graft survival,ratio of immune reactions and side effects) were available and were expressed as relative risk(RR) and 95% confidence intervals(CI).RESULTS:Seven studies were included in this review.In the comparing of mycophenolate mofetil(MMF) with placebo,the results showed MMF could significantly reduce immune reactions compared with placebo(RR 1.08 95% Cl 0.95 to 1.21),but no effect on clear graft survival(RR 1.11 95% Cl 0.90 to 1.35).In clear graft survival and immune reactions,MMF and cyclosporine A(CsA) showed similar effect(RR 1.11 95% Cl 0.90 to 1.35,and RR 1.48,95% Cl 0.56 to 3.93,respectively).Tacrolimus(FK506) and steroid showed similar effects on clear graft survival and immune reactions(RR 0.32,95% CI 0.02 to 6.21,and RR 1.00,95%CI 0.88 to 1.14,respectively).No drug relative side effect has been found.CONCLUSION:MMF may reduce immune reactions in both normal-risk and high-risk rejection of penetrating keratoplasty.CsA and FK506 showed similar effects as MMF.However,due to the lack of large clinical trials,the evidence remain weak,the quality of evidences were rated as very low to moderate.Large,properly randomised,placebo-controlled,double masked trials are needed to evaluate the effect of immunosuppressants.

Hepatitis B reactivation in patients with hepatitis B core antibody positive and surface antigen negative on immunosuppressants

Hepatitis B viral(HBV)reactivation in the immunosuppressed is a significant problem even in patients who have achieved serological clearance due to the persistence of HBV as cccDNA.HBV reactivation will continue to pose a significant healthcare burden given the high prevalence of HBV and increasing use of immunosuppressants.Screening of hepatitis B surface antigen,antibody to Hepatitis B core antigen antibody and HBV DNA levels should be done routinely in all patients planned for significant immunosuppressant use.We aimed to examine the factors affecting reactivation risk.This depended on HBV disease status,the underlying disease requiring immunosuppression,and the specific immunosuppressive regime.While antiviral prophylaxis can prevent reactivation,it increases cost and still has risk of delayed reactivation after stopping antivirals and close follow-up and on-demand treatment is a good alternative for patients at risk of reactivation.

Interaction of immunosuppressants with HCV antivirals daclatasvir and asunaprevir: combined effects with mycophenolic acid

AIM To investigate the specific effects of immunosuppressants on the antiviral action of daclatasvir and asunaprevir.METHODS The antiviral activity of daclatasvir(DCV) and asunaprevir(ASV) combined with immunosuppressants was tested using two in vitro models for hepatitis C virus(HCV) infection.RESULTS Tacrolimus, rapamycin and cyclosporine did not negatively affect the antiviral action of DCV or ASV. Mycophenolic acid(MPA) showed additive antiviral effects combined with these direct acting antivirals(DAAs). MPA induces interferon-stimulated genes(ISGs) and is a potent GTP synthesis inhibitor. DCV or ASV did not induce ISGs expression nor affected ISG induction by MPA. Rather, the combined antiviral effect of MPA with DCV and ASV was partly mediated via inhibition of GTP synthesis.CONCLUSION Immunosuppressants do not negatively affect the antiviral activity of DAAs. MPA has additive effect on the antiviral action of DCV and ASV. This combined benefit needs to be confirmed in prospective clinical trials.

A compact liquid chromatography-mass spectrometry instrument for the quantitation of immunosuppressants

Liquid chromatography tandem mass spectrometry(LC-MS/MS) plays an important role in clinical diagnostics. Although LC-MS/MS is superior in terms of accurately quantifying molecules in complex matrices,instrument footprint, operation and maintenance complexity also hinder its expansion as the analytical technique of choice. In this study, a compact LC-MS instrument was developed, in which an assembled liquid chromatograph was coupled with a miniature ion trap mass spectrometer. The overall instrument has a footprint of 69 cm × 31 cm × 31 cm, and it requires no gas supply as well as minimum maintenance. Furthermore, the use of LC-MS is in accord with conventional clinical diagnostic protocols, and the choice of ion trap offers tandem MS performance. The results showed that the use of LC could improve both mixture analysis capability and detection sensitivity of the miniature mass spectrometer. After optimization, feasibility of this instrument in clinical practice was demonstrated by the quantitation of four widely used immunosuppressants in blood samples. Relatively good linearities were obtained, which spanned the reference ranges of effective therapeutic concentrations of each immunosuppressant. Intraday and inter-day accuracy and precision of analytical method were also assessed. This work showed that a compact LC-MS instrument could be used in clinical diagnosis, either to replace conventional lab-scale instruments or to be used in POCT applications.

Effects of Rosa roxburghii&edible fungus fermentation broth on immune response and gut microbiota in immunosuppressed mice

With the rise of probiotics fermentation in food industry,fermented foods have attracted worldwide attention.In this study,protective effects of Rosa roxburghii&edible fungus fermentation broth(REFB)on immune function and gut health in Cyclophosphamide induced immunosuppressed mice were investigated.Results showed that REFB could improve the immune organ index,and promote the proliferation and differentiation of splenic T lymphocytes.In addition,it attenuated intestinal mucosal damage and improved intestinal cellular immunity.REFB administration also up-regulated the expression of IL-4,INF-γ,TNF-α,T-bet and GATA-3 mRNA in small intestine.Furthermore,administration of REFB modulated gut microbiota composition and increased the relative abundance of beneficial genus,such as Bacteroides.It also increased the production of fecal short-chain fatty acids.These indicate that REFB has the potential to improve immunity,alleviate intestinal injury and regulate gut microbiota in immunosuppressed mice.

Pleural empyema with endobronchial mass due to Rhodococcus equi infection after renal transplantation: A case report and review of literature

BACKGROUND Kidney transplantation is the best option for patients with end-stage renal disease.However,the need for lifelong immunosuppression results in renal transplant recipients being susceptible to various infections.Rhodococcus equi(R.equi)is a rare opportunistic pathogen in humans,and there are limited reports of infection with R.equi in post-renal transplant recipients and no uniform standard of treat-ment.This article reports on the diagnosis and treatment of a renal transplant recipient infected with R.equi 21 mo postoperatively and summarizes the charac-teristics of infection with R.equi after renal transplantation,along with a detailed review of the literature.Here,we present the case of a 25-year-old man who was infected with R.equi 21 mo after renal transplantation.Although the clinical features at the time of presentation were not specific,chest computed tomography(CT)showed a large volume of pus in the right thoracic cavity and right middle lung atelectasis,and fiberoptic bronchoscopy showed an endobronchial mass in the right middle and lower lobe orifices.Bacterial culture and metagenomic next-generation sequen-cing sequencing of the pus were suggestive of R.equi infection.The immunosup-pressive drugs were immediately suspended and intravenous vancomycin and azithromycin were administered,along with adequate drainage of the abscess.The endobronchial mass was then resected.After the patient’s clinical symptoms and chest CT presentation resolved,he was switched to intravenous ciprofloxacin and azithromycin,followed by oral ciprofloxacin and azithromycin.The patient was re-hospitalized 2 wk after discharge for recurrence of R.equi infection.He recovered after another round of adequate abscess drainage and intravenous ciprofloxacin and azithromycin.CONCLUSION Infection with R.equi in renal transplant recipients is rare and complex,and the clinical presentation lacks specificity.Elaborate antibiotic therapy is required,and adequate abscess drainage and surgical excision are necessary.Given the recurrent nature of R.equi,patients need to be followed-up closely.

Acute pancreatitis as a complication of acute COVID-19 in kidney transplant recipients

BACKGROUND Acute pancreatitis is a rare extrapulmonary manifestation of coronavirus disease 2019(COVID-19)but its full correlation with COVID-19 infection remains unknown.AIM To identify acute pancreatitis’occurrence,clinical presentation and outcomes in a cohort of kidney transplant recipients with acute COVID-19.METHODS A retrospective observational single-centre cohort study from a transplant centre in Croatia for all adult renal transplant recipients with a functioning kidney allograft between March 2020 and August 2022 to record cases of acute pancreatitis during acute COVID-19.Data were obtained from hospital electronic medical records.Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection was proven by a positive SARS-CoV-2 real-time reverse transcriptase-polymerase chain reaction on the nasopharyngeal swab.RESULTS Four hundred and eight out of 1432(28.49%)patients who received a renal allograft developed COVID-19 disease.The analyzed cohort included 321 patients(57%males).One hundred and fifty patients(46.7%)received at least one dose of the anti-SARS-CoV-2 vaccine before the infection.One hundred twenty-five(39.1%)patients required hospitalization,141(44.1%)developed pneumonia and four patients(1.3%)required mechanical ventilation.Treatment included immunosuppression modification in 233 patients(77.1%)and remdesivir in 53 patients(16.6%),besides the other supportive measures.In the study cohort,only one transplant recipient(0.3%)developed acute pancreatitis during acute COVID-19,presenting with abdominal pain and significantly elevated pancreatic enzymes.She survived without complications with a stable kidney allograft function.CONCLUSION Although rare,acute pancreatitis may complicate the course of acute COVID-19 in kidney transplant recipients.The mechanism of injury to the pancreas and its correlation with the severity of the COVID-19 infection in kidney transplant recipients warrants further research.

Advancements in autoimmune hepatitis management:Perspectives for future guidelines

The first-line treatment for autoimmune hepatitis involves the use of prednisone or prednisolone either as monotherapy or in combination with azathioprine(AZA).Budesonide has shown promise in inducing a complete biochemical response(CBR)with fewer adverse effects and is considered an optional first-line treatment,particularly for patients without cirrhosis;however,it is worth noting that the design of that study favored budesonide.A recent real-life study revealed higher CBR rates with prednisone when equivalent initial doses were administered.Current guidelines recommend mycophenolate mofetil(MMF)for patients who are intolerant to AZA.It is important to mention that the evidence supporting this recommendation is weak,primarily consisting of case series.Nevertheless,MMF has demonstrated superiority to AZA in the context of renal transplant.Recent comparative studies have shown higher CBR rates,lower therapeutic failure rates,and reduced intolerance in the MMF group.These findings may influence future guidelines,potentially leading to a significant modification in the first-line treatment of autoimmune hepatitis.Until recently,the only alternative to corticosteroids was lifelong maintenance treatment with AZA,which comes with notable risks,such as skin cancer and lymphoma.Prospective trials are essential for a more comprehensive assessment of treatment suspension strategies,whether relying on histological criteria,strict biochemical criteria,or a combination of both.Single-center studies using chloroquine diphosphate have shown promising results in significantly reducing relapse rates compared to placebo.However,these interesting findings have yet to be replicated by other research groups.Additionally,second-line drugs,such as tacrolimus,rituximab,and infliximab,should be subjected to controlled trials for further evaluation.

Update on the reciprocal interference between immunosuppressive therapy and gut microbiota after kidney transplantation

Gut microbiota is often modified after kidney transplantation.This principally happens in the first period after transplantation.Antibiotics and,most of all,immunosuppressive drugs are the main responsible.The relationship between immunosuppressive drugs and the gut microbiota is bilateral.From one side immunosuppressive drugs modify the gut microbiota,often generating dysbiosis;from the other side microbiota may interfere with the immunosuppressant pharmacokinetics,producing products more or less active with respect to the original drug.These phenomena have influence over the graft outcomes and clinical consequences as rejections,infections,diarrhea may be caused by the dysbiotic condition.Corticosteroids,calcineurin inhibitors such as tacrolimus and cyclosporine,mycophenolate mofetil and mTOR inhibitors are the immunosuppressive drugs whose effect on the gut microbiota is better known.In contrast is well known how the gut microbiota may interfere with glucocorticoids,which may be transformed into androgens.Tacrolimus may be transformed by microbiota into a product called M1 that is 15-fold less active with respect to tacrolimus.The pro-drug mycophenolate mofetil is normally transformed in mycophenolic acid that according the presence or not of microbes producing the enzyme glucuronidase,may be transformed into the inactive product.

Oesophageal Mycosis: Epidemiological and Clinical Aspects and Risk Factors for Occurrence in the Digestive Endoscopy Unit of the Donka National Hospital, Conakry CHU

Introduction: Oesophageal mycosis (OM) is one of the most common opportunistic infections in patients infected with HIV (Human Immunodeficiency Virus). However, this condition is increasingly observed in immunocompetent subjects. The aim of this study was to determine the endoscopic prevalence, clinical characteristics and risk factors for the occurrence of oesophageal mycosis in our department. Patients and Method: This was a prospective cross-sectional study of all patients who underwent oeso-gastroduodenal fibroscopy during the period from 1st January to 31st December 2022, i.e. one year, at the digestive endoscopy unit of the hepato-gastroenterology department of the Donka CHU national hospital in Conakry. All patients found to have oesophageal mycosis by FOGD were included. The endoscopy was performed using appropriate equipment: A Fujinon 4400 video endoscopy column;Three Fujinon EG 590 video gastroscopes;A hoover;Data were collected using a pre-established survey form and analysed using Epi info software version 6.0.4;Pearson’s Chi2 test as a test of independence and the exact 5% threshold ficher test. Results: Out of 1343 upper gastrointestinal endoscopies performed, 107 cases of oesophageal mycosis were found, representing a prevalence of 7.96%. The mean age was 40 years, with a male predominance of 55.42%. The sex ratio M/F was 1.24. The 45 and over age group was the most affected, with a prevalence of 40.43%, followed by the [35 - 45] age group, with a prevalence of 22.43%. Clinical symptoms were dominated by epigastralgia in 74.76% of cases, followed by odynophagia in 37.38% of cases, nausea and vomiting in 28.03% of cases, and pyrosis in 26.16% of cases. Oesophageal mycosis without oesophagitis was the most common endoscopic finding in 70% of cases. The main associated endoscopic lesions were erythemato-erosive and congestive gastropathy in 28.03% of cases, peptic oesophagitis (9.34%) and gastric ulcer (5.60%). The main risk factors found were positive HIV serology in 39.25% of cases, and diabetes in 24.30% of cases, with a statistically significant relationship of 0.02 and 0.01 respectively. Conclusion: Oesophageal mycosis is the most common opportunistic infection in patients with impaired cellular immunity. The prevalence of oesophageal mycosis in our series was 7.96%. This study enabled us to identify the main risk factors for the occurrence of oesophageal mycosis. Our country needs to step up its programme to combat and prevent immunodeficiency diseases, particularly HIV and diabetes.

Immunology demystified: A guide for transplant hepatologists

Liver transplantation has become standard practice for treating end-stage liver disease.The success of the procedure relies on effective immunosuppressive medications to control the host's immune response.Despite the liver's inherent capacity to foster tolerance,the early post-transplant period is marked by significant immune reactivity.To ensure favorable outcomes,it is imperative to identify and manage various rejection types,encompassing T-cell-mediated,antibody-mediated,and chronic rejection.However,the approach to prescribing immunosuppressants relies heavily on clinical judgment rather than evidencebased criteria.Given that the majority of patients will require lifelong immunosuppression as the mechanisms underlying operational tolerance are still being investigated,healthcare providers must possess an understanding of immune responses,rejection mechanisms,and the pathways targeted by immunosuppressive drugs.This knowledge enables customization of treatments and improved patient care,even though a consensus on an optimal immunosuppressive regimen remains elusive.

Predicting outcomes after kidney transplantation: Can Pareto’s rules help us to do so?

Kidney transplantation is the best option for kidney replacement therapy,even considering that most of the times the grafts do not survive as long as their recipients.In the Khalil et al's experience,published in this issue of the Journal,they analyze their second kidney graft survival and describe those significant predictors of early loss.This editorial comments on the results and put in perspective that most of the times,long-term graft survival could be inadvertently jeopardized if the immunosuppressive therapy is reduced or withdrawn for any reason,and that it could happen frequently if the transplant physician intends to innovate with the clinical care without proper evidence-based data.

Management strategies for common viral infections in pediatric renal transplant recipients

Viral infections have been considered as a major cause of morbidity and mortality after kidney transplantation in pediatric cohort.Children are at high risk of acquiring virus-related complications due to immunological immaturity and the enhanced alloreactivity risk that led to maintenance of high immunosuppressive regimes.Hence,prevention,early detection,and prompt treatment of such infections are of paramount importance.Among all viral infections,herpes viruses(herpes simplex virus,varicella zoster virus,Epstein-Barr virus,cytomegalovirus),hepatitis B and C viruses,BK polyomavirus,and respiratory viruses(respiratory syncytial virus,parainfluenza virus,influenza virus and adenovirus)are common in kidney transplant recipients.These viruses can cause systemic disease or allograft dysfunction affecting the clinical outcome.Recent advances in technology and antiviral therapy have improved management strategies in screening,monitoring,adoption of prophylactic or preemptive therapy and precise treatment in the immunocompromised host,with significant impact on the outcome.This review discusses the etiology,screening and monitoring,diagnosis,prevention,and treatment of common viral infections in pediatric renal transplant recipients.

Kaposi Sarcoma after Kidney Transplant: A Clinical Case Report

Kaposi sarcoma is a neoplasm caused by human herpesvirus 8 (HHV8) that most commonly affects immunosuppressed patients. The skin is the most affected area, but other sites can be involved such as the lung, digestive tract and lymph nodes. The classical presentation involves a violaceous skin lesion that can be small or hidden, leading to a delay in diagnosis. We report a clinical case of a kidney transplant patient, who presented, 14 months after kidney transplant, with unilateral edema of the inferior member and cutaneous rash misdiagnosed and taken initially for erysipelas. The diagnosis of Kaposi’s sarcoma was retained, on a lymph node biopsy of an inguinal adenopathy. The evolution was marked by a local and general improvement after systemic chemotherapy, reducing Tacrolimus and discontinuation of Mycophenolate mofetil. Graft function remained stable during the follow-up.

Effects of Immunosuppressants on Immune Response to Vaccine in Inflammatory Bowel Disease

Objective： To evaluate the response rate to vaccination in different treatment groups （nonimmunosuppressants and immunosuppressants）. Data Sources： We completed an online systematic search using PubMed to identify all articles published in English between January 1990 and December 2013 assessing the effect of the response rate to vaccination in different treatment groups （with and without immunomodulators）. The following terms were used： ＂inflammatory bowel disease （IBD）＂ OR ＂Crohn＇s disease＂ OR ＂ulcerative colitis＂ AND （＂vaccination＂ OR ＂vaccine＂） AND （＂corticosteroids＂ OR ＂mercaptopurine＂ OR ＂azathioprine＂ OR ＂methotrexate [MTX]＂） AND ＂immunomodulators.＂ Study Selection： The inclusion criteria of articles were that the studies： （1） Randomized controlled trials which included patients with a diagnosis of IBD （established by standard clinical, radiographic, endoscopic, and histologic criteria）; （2） exposed patients received immunomodulators for maintenance （weight-appropriate doses of6-mercaptopurine/azathioprine or within 3 months of stopping, 15 mg or more MTX per week or within 3 months of stopping; （3） exposed patients received nonimmunomodulators （no therapy, antibiotics only, mesalazine only, biological agent only such as infliximab, adalimumab, certolizumab or natalizumab or within 3 months of stopping one of these agents）. The exclusion criteria of articles were that the studies： （1） History of hepatitis B virus （HBV）, influenza or streptococcus pneumoniae infection; （2） patients who had previously been vaccinated against HBV, influenza or streptococcus pneumoniae; （3） any medical condition known to cause immunosuppression （e.g. chronic renal failure and human immunodeficiency virus infection）; （4） individuals with positive hepatitis markers or liver cirrhosis; （5） patients with a known allergy to eggs or other components of the vaccines and （6） pregnancy. Results： Patients treated with immunomodulators were associated with lower response rates to vaccination. Conclusions： lmmunomodulators may impair the immune response to vaccination in patients with IBD. Vaccination should be made at the time of diagnosis or before starting immunosuppressed therapy.

Single-cell transcriptome profiling of sepsis identifies HLA-DR^(low)S100A^(high)monocytes with immunosuppressive function

Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.Methods We adopted cross-species,single-cell RNA sequencing(scRNA-seq)analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis.Flow cytometry,laser scanning confocal microscopy(LSCM)imaging and Western blotting were applied to identify the presence of S100A9^(+)monocytes at protein level.To interrogate the immunosuppressive function of this subset,splenic monocytes isolated from septic wild-type or S100a9^(–/–)mice were co-cultured with naive CD4^(+)T cells,followed by proliferative assay.Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.Results scRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis,for which distinct monocyte subsets were enriched in disparate subclusters of septic patients.We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR(HLA-DR),which were prominently enriched in septic patients and might exert immunosuppressive function.By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments,we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice,corresponding to HLA-DR^(low)S100A^(high)monocytes in human sepsis.Moreover,we found that S100A9^(+)monocytes exhibited profound immunosuppressive function on CD4^(+)T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.Conclusions This study identifies HLA-DR^(low)S100A^(high)monocytes correlated with immunosuppressive state upon septic challenge,inhibition of which can markedly mitigate sepsis-induced immune depression,thereby providing a novel therapeutic strategy for the management of sepsis.

Sepsis-induced immunosuppression:mechanisms,diagnosis and current treatment options

Sepsis is a common complication of combat injuries and trauma,and is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection.It is also one of the significant causes of death and increased health care costs in modern intensive care units.The use of antibiotics,fluid resuscitation,and organ support therapy have limited prognostic impact in patients with sepsis.Although its pathophysiology remains elusive,immunosuppression is now recognized as one of the major causes of septic death.Sepsis-induced immunosuppression is resulted from disruption of immune homeostasis.It is characterized by the release of antiinflammatory cytokines,abnormal death of immune effector cells,hyperproliferation of immune suppressor cells,and expression of immune checkpoints.By targeting immunosuppression,especially with immune checkpoint inhibitors,preclinical studies have demonstrated the reversal of immunocyte dysfunctions and established host resistance.Here,we comprehensively discuss recent findings on the mechanisms,regulation and biomarkers of sepsis-induced immunosuppression and highlight their implications for developing effective strategies to treat patients with septic shock.

Smart drug delivery systems to overcome drug resistance in cancer immunotherapy

Cancer immunotherapy,a therapeutic approach that inhibits tumors by activating or strengthening anti-tumor immunity,is currently an important clinical strategy for cancer treatment;however,tumors can develop drug resistance to immune surveillance,resulting in poor response rates and low therapeutic efficacy.In addition,changes in genes and signaling pathways in tumor cells prevent susceptibility to immunotherapeutic agents.Furthermore,tumors create an immunosuppressive microenvironment via immunosuppressive cells and secrete molecules that hinder immune cell and immune modulator infiltration or induce immune cell malfunction.To address these challenges,smart drug delivery systems(SDDSs)have been developed to overcome tumor cell resistance to immunomodulators,restore or boost immune cell activity,and magnify immune responses.To combat resistance to small molecules and monoclonal antibodies,SDDSs are used to co-deliver numerous therapeutic agents to tumor cells or immunosuppressive cells,thus increasing the drug concentration at the target site and improving efficacy.Herein,we discuss how SDDSs overcome drug resistance during cancer immunotherapy,with a focus on recent SDDS advances in thwarting drug resistance in immunotherapy by combining immunogenic cell death with immunotherapy and reversing the tumor immunosuppressive microenvironment.SDDSs that modulate the interferon signaling pathway and improve the efficacy of cell therapies are also presented.Finally,we discuss potential future SDDS perspectives in overcoming drug resistance in cancer immunotherapy.We believe that this review will contribute to the rational design of SDDSs and development of novel techniques to overcome immunotherapy resistance.

Cellular and molecular characteristics of the premetastatic niches

The premetastatic niches(PMN)formed by primary tumor-derived molecules regulate distant organs and tissues to further favor tumor colonization.Targeted PMN therapy may prevent tumor metastasis in the early stages,which is becoming increasingly important.At present,there is a lack of in-depth understanding of the cellular and molecular characteristics of the PMN.Here,we summarize current research advances on the cellular and molecular characteristics of the PMN.We emphasize that PMN intervention is a potential therapeutic strategy for early prevention of tumor metastasis,which provides a promising basis for future research and clinical application.

Advancing our understanding of monocyte HLA-DR,S100A9,and the potential for individualized therapies in sepsis

By def inition, sepsis refers to a life threatening organ dysfunction due to a dysregulated host response to an infection[1]. More precisely, sepsis triggers a multifaceted response characterized by a simultaneous manifestation of proinflammatory and anti-inflammatory elements that disrupt mechanisms intended to maintain homeostasis. Initially, an overwhelming hyperinflammatory reaction ensues, resulting in tissue damage and organ dysfunction.