Analysis of the impact of immunotherapy efficacy and safety in patients with gastric cancer and liver metastasis

BACKGROUND Gastric cancer(GC)is the fifth most common type of cancer and has the fourth highest death rate among all cancers.There is a lack of studies examining the impact of liver metastases on the effectiveness of immunotherapy in individuals diagnosed with GC.AIM To investigate the influence of liver metastases on the effectiveness and safety of immunotherapy in patients with advanced GC.METHODS This retrospective investigation collected clinical data of patients with advanced stomach cancer who had immunotherapy at our hospital from February 2021 to January 2023.The baseline attributes were compared using either the Chi-square test or the Fisher exact probability method.The chi-square test and Kaplan-Meier survival analysis were employed to assess the therapeutic efficacy and survival duration in GC patients with and without liver metastases.RESULTS The analysis comprised 48 patients diagnosed with advanced GC,who were categorized into two groups:A liver metastasis cohort(n=20)and a non-liver metastatic cohort(n=28).Patients with liver metastasis exhibited a more deteriorated physical condition compared to those without liver metastasis.The objective response rates in the cohort with metastasis and the cohort without metastasis were 15.0%and 35.7%(P>0.05),respectively.Similarly,the disease control rates in these two cohorts were 65.0%and 82.1%(P>0.05),respectively.The median progression-free survival was 5.0 months in one group and 11.2 months in the other group,with a hazard ratio of 0.40 and a significance level(P)less than 0.05.The median overall survival was 12.0 months in one group and 19.0 months in the other group,with a significance level(P)greater than 0.05.CONCLUSION Immunotherapy is less effective in GC patients with liver metastases compared to those without liver metastasis.

Activation-induced pyroptosis contributes to the loss of MAIT cells in chronic HIV-1 infected patients

Background: Mucosal-associated invariant T(MAIT) cells are systemically depleted in human immunodeficiency virus type 1(HIV-1) infected patients and are not replenished even after successful combined antiretroviral therapy(cART).This study aimed to identify the mechanism underlying MAIT cell depletion.Methods: In the present study, we applied flow cytometry, single-cell RNA sequencing and immunohistochemical staining to evaluate the characteristics of pyroptotic MAIT cells in a total of 127 HIV-1 infected individuals, including 69 treatment-naive patients, 28 complete responders, 15 immunological non-responders, and 15 elite controllers, at the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.Results: Single-cell transcriptomic profiles revealed that circulating MAIT cells from HIV-1 infected subjects were highly activated, with upregulation of pyroptosis-related genes. Further analysis revealed that increased frequencies of pyroptotic MAIT cells correlated with markers of systemic T-cell activation, microbial translocation, and intestinal damage in cART-naive patients and poor CD4+ T-cell recovery in long-term cART patients. Immunohistochemical staining revealed that MAIT cells in the gut mucosa of HIV-1 infected patients exhibited a strong active gasdermin-D(GSDMD, marker of pyroptosis) signal near the cavity side, suggesting that these MAIT cells underwent active pyroptosis in the colorectal mucosa. Increased levels of the proinflammatory cytokines interleukin-12(IL-12) and IL-18 were observed in HIV-1 infected patients. In addition, activated MAIT cells exhibited an increased pyroptotic phenotype after being triggered by HIV-1 virions, T-cell receptor signals, IL-12 plus IL-18, and combinations of these factors, in vitro.Conclusions: Activation-induced MAIT cell pyroptosis contributes to the loss of MAIT cells in HIV-1 infected patients,which could potentiate disease progression and poor immune reconstitution.

Monkeypox outbreak: a novel threat after COVID-19?

Dear Editor,Monkeypox is a zoonosis caused by monkeypox virus (MPXV)infection first reported in Central and West Africa[1]. The first outbreak of monkeypox outside of Africa was reported in2003[2].Afterthat,Israel,theUnitedKingdom(UK),Singapore, and other countries have reported monkeypox cases among travelers back from Nigeria since 2018[3].

Sofosbuvir and ABT-450: Terminator of hepatitis C virus?

Combination therapy with peginterferon (pegIFN)-α and ribavirin (RBV) has been the standard of care (SOC) for chronic hepatitis C. Unfortunately, not all patients can achieve a sustained virologic response (SVR) with this regimen. SVR rates are approximately 80% in patients with hepatitis C virus (HCV) genotype 2, 3, 5 and 6 and 40%-50% in patients with genotype 1 and 4. Therefore, strategies to improve SVR rates have been an important issue for clinical physicians. Several direct acting antiviral agents (DAAs) have significantly higher SVR rates when combined with pegIFN-α and RBV than pegIFN-α and RBV alone. Treatments containing DAAs have several advantages over the previous SOC, including higher specificity and efficacy, shorter treatment durations, fewer side effects, and oral administration. Based on these advantages, treatment with pegIFN-α and RBV plus telaprevir or boceprevir has become the current SOC for patients with genotype 1 HCV infection. However, many patients are either not eligible for therapy or decline treatment due to coexisting relative or absolute contraindications as well as an inability to tolerate the hematological side effects and adverse events caused by the new SOC. These factors have contributed to the advent of pegIFN-α-free regimens. The newest therapeutic regimens containing sofosbuvir and ABT-450 have shown promising results. In this review, we summarize the development of anti-HCV agents and the clinical efficacy of sofosbuvir and ABT-450-based therapies as well as the potential for future HCV studies.

Risk factors for liver-related mortality in chronic hepatitis C patients:A deceased case-living control study

AIM:To investigate the risk factors for liver-related mortality in chronic hepatitis C(CHC)patients.METHODS:All deceased CHC inpatient data were collected from the Beijing 302 Hospital clinical database,which includes more than 8250 CHC inpatients during the period from 2002 to 2012.The controls were matched to cases by age(±2 years),sex and date of hospital admission(within the same year).Potential risk factors were included for the evaluation,and odds ratios(OR)and 95%CI were estimated using univariate(unadjusted)and multivariate(adjusted OR,AOR)conditional logistic regression.All statistical tests were two-sided.P values<0.05 were considered statistically significant.RESULTS:Based on examinations of 144 CHC-related deceased cases and 576 controls,we found that antiviral therapy with interferon-αwas associated with a 47%decrease in the risk of hepatic mortality(AOR=0.53,95%CI:0.28-0.99,P=0.048).Additionally,the initial diagnostic stage of the disease(AOR=2.89,95%CI:1.83-4.56 and P<0.001 for liver cirrhosis/AOR=8.82,95%CI:3.99-19.53 and P<0.001for HCC compared with CHC),diabetes(AOR=2.35,95%CI:1.40-3.95,P=0.001),hypertension(AOR=1.76,95%CI:1.09-2.82,P=0.020),alcohol consumption(AOR=1.73,95%CI:1.03-2.81,P=0.037)and HBsAg positivity(AOR=22.28,95%CI:5.58-89.07,P<0.001)were associated with a significant increase in the risk of liver-related mortality in CHC patients.CONCLUSION:This study indicates that interferon-αtreatment,the stage at the initial diagnosis of the disease and comorbidities are all independent risk factors for liver-related mortality in CHC patients.

Hepatitis C: Milestones from discovery to clinical cure

On October 5th, 2020, Drs. Harvey J. Alter, Michael Houghton and Charles M. Rice were rewarded with Nobel Prize in Physiology or Medicine for "the discovery of hepatitis C virus(HCV)". During the past 50 years, remarkable achievements have been made in treatment of HCV infection: it has changed from being a life-threatening chronic disease to being curable. In this commentary, we briefly summarized the milestone events in the "scientific journey" from the first report of non-A, non-B hepatitis and discovery of the pathogen(HCV) to final identification of efficacious direct-acting antivirals. Further, we address the challenges and unmet issues in this field.

Advances and Challenges of Epidemic Outbreaks in the Post-COVID-19 Era in China

The coronavirus disease 2019(COVID-19)outbreak,caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2),[1]has spread globally,having profound impacts on peoples'lives,social and economic activities,and national security.Throughout the pandemic,China has adopted a policy of putting“the people and their lives first”and provided comprehensive free medical care for all infected patients.[2]The first wave of Wuhan outbreak was successfully controlled within 3 months in early 2020.Since then,China has effectively curbed more than 100 clusters of SARS-CoV-2 infections and subsequent outbreaks,and 5 waves of global epidemics from 2020 to 2021.Overall,the proportion of confirmed cases in China is 0.27%of the global average,and the case fatal rate is 0.43%of the global average.[3]These achievements emphasize the important role that professional medical care and holistic nonpharmaceutical intervention played from 2020 to the end of 2021,in protecting the population from SARS-CoV-2 infection and death associated with COVID-19 in China[Figure 1].

Improved survival ratios correlate with myeloid dendritic cell restoration in acute-on-chronic liver failure patients receiving methylprednisolone therapy

Acute-on-chronic liver failure （ACLF） is a severe life-threatening complication. Liver transplantation is the only available therapeutic option; however, several limitations have restricted its use in patients. The use of corticosteroids as an optional therapy for ACLF has received a great deal of interest. The rationale behind its use is the possible role of the immune system in initiating and perpetuating hepatic damage. In order to assess the relationship between myeloid dendritic cells （mDCs） and the efficacy of methylprednisolone （MP） treatment for hepatitis B virus （H BV）-associated ACLF patients, we recruited 30 HBV-associated ACLF patients who had received MP treatment at lO-day intervals; 26 patients received conservative medical （CM） management as a control. The functionality of DC subsets was lower in these ACLF patients compared with healthy subjects. In addition, compared with survivors, dead/transplanted patients had lower functional mDC in both groups. Furthermore, a decreased numbers of mDC at baseline was associated with high mortality of ACLF patients. Importantly, MP treatment resulted in a significant decrease in 28-day mortality, and all MP patients exhibited an initial rapid decrease in circulating mDC numbers within 10 days of MP treatment. Subsequently, MP survivors displayed a continuous increase in mDC numbers accompanied by a decrease in total bilirubin levels by more than 30%. However, MP dead/ transplanted patients lacked these sequential responses compared with survivors. This evidence suggests strongly that the higher mDC numbers at baseline and the recovery of mDC number at the end of treatment may represent a prognostic marker for favorable response to corticosteroid treatment in ACLF patients.

Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19:a phase 1 clinical trial

No effective drug treatments are available for coronavirus disease 2019(COVID-19).Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage,death,or long-term functional disability in survivors require clinical evaluation.We performed a parallel assigned controlled,non-randomized,phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells(UC-MSCs)infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease.The study enrolled 18 hospitalized patients with COVID-19(n=9 for each group).The treatment group received three cycles of intravenous infusion of UC-MSCs(3×107 cells per infusion)on days 0,3,and 6.Both groups received standard COVID-treatment regimens.Adverse events,duration of clinical symptoms,laboratory parameters,length of hospitalization,serial chest computed tomography(CT)images,the PaO2/FiO2 ratio,dynamics of cytokines,and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed.No serious UC-MSCs infusion-associated adverse events were observed.Two patients receiving UC-MSCs developed transient facial flushing and fever,and one patient developed transient hypoxia at 12 h post UC-MSCs transfusion.Mechanical ventilation was required in one patient in the treatment group compared with four in the control group.All patients recovered and were discharged.Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated.Phase 2/3 randomized,controlled,double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19.

Emerging Role of Interleukin 22 in Hepatitis B Virus Infection: a Double-edged Sword

Hepatitis B virus (HBV) infection remains a worldwide health problem,and is the major cause of hepatitis,liver cirrhosis,and hepatocellular carcinoma.The innate and adaptive immune responses of the HBV-infected host contribute greatly to the development and pathogenesis of chronic HBV infection,and often affect the efficacy of anti-HBV drugs.Interleukin (IL)-22 is a newly identified cytokine that is involved in the pathogenesis of liver disease,but its role in liver inflammation in patients with HBV infection remains controversial.In this report,we summarize the production and function of IL-22 in inflammatory environments,and review the current research into IL-22 biology in HBV infection.A better understanding of the intrahepatic micro-environments that directly influence the activity of IL-22 will be important for the development of new immunotherapeutic approaches that target IL-22-producing cells or IL-22 itself.

HLA-mismatched allogeneic adoptive immune therapy in severely immunosuppressed AIDS patients

Severely immunosuppressed AIDS patients with recurrent opportunistic infections(Ols)represent an unmet medical need even in the era of antiretroviral therapy(ART).Here we report the development of a human leukocyte antigen(HLA)-mismatched allogeneic adaptive immune therapy(AAIT)for severely immunosuppressed AIDS patients.Twelve severely immunosuppressed AIDS patients with severe Ols were enrolled in this single-arm study.Qualified donors received subcutaneous recombinant granulocyte-colony-stimulating factor twice daily for 4-5 days to stimulate hematopoiesis.Peripheral blood mononuclear cells were collected from these donors via leukapheresis and transfused into the coupled patients.Clinical,immunological,and virological parameters were monitored during a 12-month follow-up period.We found AAIT combined with ART was safe and well-tolerated at the examined doses and transfusion regimen in all 12 patients.Improvements in clinical symptoms were evident throughout the study period.All patients exhibited a steady increase of peripheral CD4^(+)T cells from a median 10.5 to 207.5 cells/μl.Rapid increase in peripheral CD8^(+)T-cell count from a median 416.5 to 1206.5 cells/μl was found in the first 90 days since initiation of AAIT.In addition,their inflammatory cytokine levels and HIV RNA viral load decreased.A short-term microchimerism with donor cells was found.There were no adverse events associated with graft-versus-host disease throughout the study period.Overall,AAIT treatment was safe,and might help severely immunosuppressed AIDS patients to achieve a better immune restoration.A further clinical trial with control is necessary to confirm the efficacy of AAIT medication.

异常的CD39/CD73/腺苷通路导致慢性乙型肝炎患者B细胞超活化和疾病进展

背景:乙肝病毒(HBV)感染患者B细胞超活化的机制尚不明确。本研究旨在评估CD39/CD37/腺苷通路在慢性乙型肝炎(CHB)患者中的临床特点。方法:我们检测了202例HBV感染患者B细胞CD39和CD73表达及腺苷产生情况。CpG+CD40配体刺激B细胞后,阻断或激活CD39/CD73/腺苷通路,然后通过流式细胞术检测B细胞活化表型结果:在具有高HBV DNA载量,HBeAg阳性,高HBsAg水平以及肝脏炎症活跃的CHB患者中,外周血B细胞的CD39和CD73表达降低,并且在HBeAg血清转化或HBsAg降低的完全应答者中逐步恢复。尽管进行了有效的抗病毒治疗,但完全应答者中活化记忆B细胞亚群和组织样记忆B细胞亚群的CD39和CD73表达并未增加。此外,在炎性肝脏中,肝内B细胞的CD39和CD73表达降低。在体外,CHB患者的B细胞显示产生CD39/CD73依赖性细胞外腺苷的能力明显降低。阻断腺苷生成后B细胞活化标志物表达增加。相反,二甲双胍通过调节腺苷酸活化蛋白激酶,激活CD39/CD73/腺苷通路,从而使B细胞活化标志物表达显著降低。结论:B细胞中CD39和CD73表达下调可导致CHB患者的高病毒负荷,加重肝脏炎性反应,并影响抗病毒疗效。异常的CD39/CD73/腺苷通路导致B细胞超活化。使用二甲双胍调节CD39/CD73/腺苷通路可能作为一种能够逆转HBV诱导的免疫发病机制的治疗选择。

Reversal of B-cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients

B cells play an important role in the clearance of hepatitis B virus （HBV） and protection against reinfection. However, the functional characteristics of these cells that are associated with the outcome of chronic HBV infection remain unknown. We comprehensively investigated the frequency, phenotype, and function of peripheral B-cell subsets from CHB patients in different phases： immune tolerance （IT）, immune activation （IA）, immune clearance （IC）, responders with HBsAg seroconversion （resolved patients, RP）, and healthy controls （HC）. IA patients displayed lower percentages of peripheral blood memory B cells compared with the other groups. Overall polyclonal activation of B cells, indicated by higher levels of activation markers and secretion of IgG and IgM, was observed in IA patients. This B-cell hyperactivation could be induced by increased IFN-a and soluble CD40 ligands in IA patients. Notably, the expression of the co-stimulator molecule CD80 and serum HBsAb and the frequency of HBsAg-specific B cells were significantly decreased in IT, IA, and IC patients compared with HC subjects. More importantly, the B-cell hyperactivation, co-stimulatory molecule downregulation and HBsAg-specific B-cell impairment were reversed in RP patients. The reversal of B-cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients.

Pediatric Acute Severe Hepatitis of Unknown Origin: What is New?

Globally,there are emerging cases of acute severe hepatitis of unknown origin in children.These cases have gathered increasing attention,owing to the development of acute liver failure in some cases that resulted in liver transplantation.This review briefly summarizes the outbreak and diagnostic criteria of the disease.We further discuss the possible causes and related mechanisms underlying its occurrence and progression,and analyze the challenges in management.Finally,this review emphasizes patient management in clinical settings and a combination of efforts to unmask the disease.

Changes of Damage Associated Molecular Patterns in COVID-19 Patients

Background:The development of severe coronavirus disease 2019(COVID-19)is associated with systemic hyperinflammation,which drives multi-organ failure and death.Disease deterioration tends to occur when the virus is receding;however,whether other factors besides viral products are involved in the inflammatory cascade remains unclear.Methods:Twenty-eight COVID-19 patients with laboratory-confirmed SARS-CoV-2 infection hospitalized at the Fifth Medical Center of Chinese PLA General Hospital from January 23 to February 20,2020 and nine healthy donors during the same period were recruited in the study.COVID-19 patients were grouped as mild,moderate,severe based on disease severity.Plasma damage-associated molecular patterns(DAMPs),including high mobility group box 1(HMGB1),calprotectin(S100A8/A9),surfactant protein A(SP-A),cold-inducible RNA-binding protein(CIRBP),and Histone H4 were detected by ELISA assay,and analyzed in combination with clinical data.Plasma cytokines,chemokines and lymphocytes were determined by flow cytometry.Results:Plasma levels of HMGB1(38292.3±4564.4 vs.32686.3±3678.1,P=0.002),S100A8/A9(1490.8±819.3 vs.742.2±300.8,P=0.015),and SP-A(6713.6±1708.7 vs.5296.3±1240.4,P=0.048)were increased in COVID-19 patients compared to healthy donors,while CIRBP(57.4±30.7 vs.111.9±55.2,P=0.004)levels decreased.Five DAMPs did not vary among mild,moderate,and severe patients.Moreover,SP-A levels correlated positively with inflammatory cytokines and negatively with time elapsed after symptom onset,whereas CIRBP showed an opposite pattern.Conclusions:These findings suggest SP-A may involve in the inflammation of COVID-19,while CIRBP likely plays a protective role.Therefore,DAMPs represent a potential target in the prevention or treatment of COVID-19.

Systematic Discovery and Pathway Analyses of Metabolic Disturbance in COVID-19

Background:The ongoing global coronavirus disease 2019(COVID-19)pandemic is posing a serious public health threat to nations worldwide.Understanding the pathogenesis of the disease and host immune responses will facilitate the discovery of therapeutic targets and better management of infected patients.Metabolomics technology can provide an unbiased tool to explore metabolic perturbation.Methods:Twenty-six healthy controls and 50 COVID-19 patients with mild,moderate,and severe symptoms in the Fifth Medical Center of PLA General Hospital from January 22 to February 16,2020 were recruited into the study.Fasting blood samples were collected and subject to metabolomics analysis by liquid chromatography–mass spectrometry.Metabolite abundance was measured by peak area and was log-transformed before statistical analysis.The principal component analysis,different expression analysis,and metabolic pathway analysis were performed using R package.Co-regulated metabolites and their associations with clinical indices were identified by the weighted correlation network analysis and Spearman correlation coefficients.The potential metabolite biomarkers were analyzed using a random forest model.Results:We uncovered over 100 metabolites that were associated with COVID-19 disease and many of them correlated with disease severity.Sets of highly correlated metabolites were identified and their correlations with clinical indices were presented.Further analyses linked the differential metabolites with biochemical reactions,metabolic pathways,and biomedical MeSH terms,offering contextual insights into disease pathogenesis and host responses.Finally,a panel of metabolites was discovered to be able to discriminate COVID-19 patients from healthy controls,and also another list for mild against more severe cases.Our findings showed that in COVID-19 patients,citrate cycle,sphingosine 1-phosphate in sphingolipid metabolism,and steroid hormone biosynthesis were downregulated,while purine metabolism and tryptophan metabolism were disturbed.Conclusion:This study discovered key metabolites as well as their related biological and medical concepts pertaining to COVID-19 pathogenesis and host immune response,which will facilitate the selection of potential biomarkers for prognosis and discovery of therapeutic targets.

Human Atypical Monkeypox:Early Warning for Global Outbreak?

Monkeypox is usually considered as a zoonosis caused bymonkeypox viruswith potential threat to public health in the post-smallpox era.The recent outbreak ofmonkeypox began inMay 7,2022,and has been found in many countries out of Africa.TheWorldHealth Organization declared that this endemic is an“atypical”phenomenon with definite human-to-human transmission.To understand the situation more clearly,this review briefly summarizes the epidemiologic and clinical characteristics of the disease and highlights the clinical management and preventive strategies.