Novel disulfidptosis-derived gene blueprint stratifying patients with breast cancer.

INTRODUCTION: Breast cancer remains the predominant cancer among females, accounting for about 24.2% of all cancer cases. Alarmingly, it is the primary cause of cancer-related mortality in women under 45. METHODS: This research analyzed RNA sequencing data from 1082 TCGA-BRCA and 107 GSE58812 breast cancer patients. Single-cell RNA data from five patients in the GSE118389 data set were also studied. Using Random forest and COX regression, we developed a prognostic model. Pathway analysis employed GSVA and GO, while immune profiles were assessed via ssGSEA and MCPcounter. Mutation patterns utilized maftools, and drug sensitivity scores were derived from the GDSC database with oncoPredict. RESULTS: Analysis of the GSE118389 data set identified three distinct cell types: immune, epithelial, and stromal. P53 and VEGF were notably enriched. Five key genes (TMEM251, ADAMTSL2, CDC123, PSMD1, TLE1) were pinpointed for their prognostic significance. We introduced a disulfidptosis-associated score as a novel risk factor for breast cancer prognosis. Survival outcomes varied significantly between training and validation sets. Comprehensive immune profiling revealed no difference in activated CD8-positive T cells between risk groups, but a positive correlation of NK cells, neutrophils, cytotoxic lymphocytes, and monocytic cells with the riskscore was noted. Importantly, a negative association between the drug Nelarabine and riskscore was identified. CONCLUSION: This research underscores the significance of a disulfidptosis-associated gene signature in breast cancer prognosis.

Recent advances in treatment Crimean-Congo hemorrhagic fever virus: A concise overview.

The Crimean Congo Hemorrhagic Fever Virus (CCHFV) is widespread in Africa, Asia, and Europe, among other places. The disease was initially discovered in the Crimean cities of the Soviet Union and the Congo, and it was given the name Crimean Congo because it induces hemorrhagic fever. According to studies, when the virus enters the body, it settles in immune cells such as macrophages and dendritic cells, causing them to malfunction and secrete inflammatory cytokines such as TNF-alpha, IL1, and IL6, resulting in cytokine storms that induces shock via endothelial activation and vascular leakage, while on the other hand, clots and disseminated intravascular coagulation (DIC) formation causes massive defects in various organs such as the liver and kidneys, as well as fatal bleeding. Disease prevention and treatment are crucial since no other effective vaccination against the disease has yet been developed. Immunotherapy is utilized as a consequence. One of the most effective treatments, when combined with compensatory therapies such as blood and platelet replacement, water, electrolytes, Fresh Frozen Plasma (FFP) replacement, and other compensatory therapies, is one of the most effective treatments. Studies; show that immunotherapy using IVIG and neutralizing and non-neutralizing monoclonal antibodies; cytokine therapy, and anti-inflammatory therapy using corticosteroids are effective ways to treat the disease.

A mathematical model of immunomodulatory treatment in myocardial infarction.

A heart attack, or acute myocardial infarction (MI) is caused by the acute occlusion of a coronary artery. MI is associated with 30% mortality; approximately half of the deaths occur prior to arrival at the hospital. Reperfusion therapy in the hospital is a medical treatment to restore blood flow through the blocked artery; treatment includes drugs and surgery. However, the damage to the heart muscles through the infarct area is permanent and there is additional damage around the infarct area due to inflammation or insufficient oxygen supply. Approximately half of the patients who survive MI are hospitalized again within one year after reperfusion treatment. In this paper we develop a mathematical model of MI and use it to assess the efficacy of drugs used, post reperfusion, to reduce the damage caused by inflammation in a region of the left ventricular wall surrounding the infarct area. The mathematical model, represented by a system of partial differential equations. The model variables include myocytes, endothelial cells, neutrophils, macrophages, fibroblasts and cytokines that play a role in the interactions among these cells. The drugs used to in the model include IL-1, TNF-α and TGF-ß inhibitors, and the delivery of VEGF. The model is based on mice data. In particular, we find that immunomodulatory treatment with TNF-α and IL-1 inhibitors can significantly increase the low density of myocytes bordering the infarct area by 50-60% and decrease the abnormally high density of ECM in a region surrounding the infarct area.

[Retrospectively analysis of characteristics and risk factors of immune treatment-related hepatic adverse events in malignant tumor].

Objective: To explore the clinical features and risk factors of hepatic injury due to immune checkpoint inhibitors (CPI) therapy in malignant tumor. Methods: Data of 112 patients (64 men and 48 women) who received CPI between January 2016 and March 2019 in Chinese Academy of Medical Sciences and Peking Union Medical College Shenzhen Hospital, and Huazhong University of Science and Techology Union Shenzhen Hospital were retrospectively collected. The median age of these patients was 60 years. Results: Hepatic adverse events were observed in 30 patients out of 112 patients (26.8%). Among them, the incidence of grade 3-5 hepatic adverse events were 7.14% (8/112). The median time of hepatic adverse event occurrence was 3 weeks (2-30) after undergoing therapy. The results of univariate and multivariate analyses showed that liver cancer was attributed to the CPI induced hepatitis (P<0.05). Patients with severe hepatic injury got almost complete resolution after receiving methlprednisolone for 4 to 6 weeks. Conclusion: Live cancer is the risk factor of CPI-related hepatic adverse events.

Regulatory T cells protected against abdominal aortic aneurysm by suppression of the COX-2 expression.

CD4+ CD25+ regulatory T cells (Tregs) have been shown to protect against the development of abdominal aortic aneurysm (AAA). Cyclooxygenase-2 (COX-2), a pro-inflammatory protein, can convert arachidonic acid into prostaglandins (PGs). The present study was aimed to investigate the effect of Tregs on COX-2 expression in angiotension II (Ang II)-induced AAA in ApoE-/- mice. Tregs were injected via tail vein in every 2 weeks. Ang II was continuously infused by a micropump for 28 days to induce AAA. In vivo, compared with the control group, adoptive transfer of Tregs significantly reduced the incidence of AAA, maximal diameter, and the mRNA and protein expression of COX-2 in mice. Immunofluorescence showed that Tregs treatment reduced COX-2 expression both in smooth muscle cells (SMCs) and macrophages in AAA. In vitro, the Western blot analysis showed that Tregs reduced Ang II-induced COX-2 expression in macrophages and SMCs. Meanwhile, ELISA showed that Tregs reduced Ang II-induced prostaglandin E2 (PGE2 ) secretion. Moreover, Tregs increased SMC viability and induced transition of macrophages phenotype from M1 to M2. In conclusion, Tregs treatment dramatically decreased the expression of COX-2 in vivo and in vitro, suggesting that Tregs could protect against AAA through inhibition of COX-2. The study may shed light on the immune treatment of AAA.

APOBEC3C is a novel target for the immune treatment of lower-grade gliomas.

BACKGROUND: Apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) type 3C (A3C) has been identified as a cancer molecular biomarker in the past decade. However, the practical role of A3C in lower-grade gliomas (LGGs) in improving the clinical outcome remains unclear. This study aims to discuss the function of A3C in immunotherapy in LGGs. METHODS: The RNA-Sequencing (RNA-seq) and corresponding clinical data were extracted from UCSC Xena and the results were verified in the Chinese Glioma Genome Atlas (CGGA). Weighted gene co-expression network analysis (WGCNA) was used for screening A3C-related genes. Comprehensive bioinformation analyses were performed and multiple levels of expression, survival rate, and biological functions were assessed to explore the functions of A3C. RESULTS: A3C expression was significantly higher in LGGs than in normal tissues but lower than in glioblastoma (GBM), indicating its role as an independent prognosis predictor for LGGs. Twenty-eight A3C-related genes were found with WGCNA for unsupervised clustering analysis and three modification patterns with different outcomes and immune cell infiltration were identified. A3C and the A3C score were also correlated with immune cell infiltration and the expression of immune checkpoints. In addition, the A3C score was correlated with increased sensitivity to chemotherapy. Single-cell RNA (scRNA) analysis indicated that A3C most probably expresses on immune cells, such as T cells, B cells and macrophage. CONCLUSIONS: A3C is an immune-related prognostic biomarker in LGGs. Developing drugs to block A3C could enhance the efficiency of immunotherapy and improve disease survival.Abbreviation: A3C: Apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) type 3C; LGGs: lower-grade gliomas; CGGA: Chinese Glioma Genome Atlas; WGCNA: Weighted gene co-expression network analysis; scRNA: Single-cell RNA; HGG: higher-grade glioma; OS: overall survival; TME: tumor microenvironment; KM: Kaplan-Meier; PFI: progression-free interval; IDH: isocitrate dehydrogenase; ROC: receiver operating characteristic; GS: gene significance; MM: module membership; TIMER: Tumor IMmune Estimation Resource; GSVA: gene set variation analysis; ssGSEA: single-sample gene-set enrichment analysis; PCA: principal component analysis; AUC: area under ROC curve; HAVCR2: hepatitis A virus cellular receptor 2; PDCD1: programmed cell death 1; PDCD1LG2: PDCD1 ligand 2; PTPRC: protein tyrosine phosphatase receptor type C; ACC: Adrenocortical carcinoma; BLCA: Bladder Urothelial Carcinoma;BRCA: Breast invasive carcinoma; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOLCholangiocarcinoma; COADColon adenocarcinoma; DLBC: Lymphoid Neoplasm Diffuse Large B-cell Lymphoma; ESCA: Esophageal carcinoma; GBM: Glioblastoma multiforme; HNSC: Head and Neck squamous cell carcinoma; KICH: Kidney Chromophobe; KIRC: Kidney renal clear cell carcinoma; KIRP: Kidney renal papillary cell carcinoma; LAML: Acute Myeloid Leukemia; LGG: Brain Lower Grade Glioma; LIHC: Liver hepatocellular carcinoma; LUAD: Lung adenocarcinoma; LUSC: Lung squamous cell carcinoma; MESO: Mesothelioma; OV: Ovarian serous cystadenocarcinoma; PAAD: Pancreatic adenocarcinoma; PCPG: Pheochromocytoma and Paraganglioma; PRAD: Prostate adenocarcinoma; READ: Rectum adenocarcinoma; SARC: Sarcoma; SKCM: Skin Cutaneous Melanoma; STAD: Stomach adenocarcinoma; TGCT: Testicular Germ Cell Tumors; THCA: Thyroid carcinoma; THYM: Thymoma; UCEC: Uterine Corpus Endometrial Carcinoma; UCS: Uterine Carcinosarcoma; UVM: Uveal Melanoma.

The use of immunomodulation therapy in women with recurrent implantation failure undergoing assisted conception: A multicentre cohort study.

PROBLEM: Recurrent implantation failure (RIF) after multiple embryo transfers remains a vexing problem and immunomodulators have been used with conflicting results. This study aims to assess the effect of immunomodulation therapy on live birth rate (LBR) in women with RIF undergoing assisted reproduction treatment (ART). METHOD OF STUDY DESIGN: This is a retrospective cohort study in multicentre network of private assisted conception units in the UK. The study included women who had at least two failed attempts of embryo transfers at CARE fertility network in the period from 1997 to 2018. Women in the treatment group had immunomodulator drugs in the form of corticosteroids, low molecular weight heparin (LMWH), and intravenous intralipid (IVIL) infusions, either separately or in combination, after immunological testing, in addition to standard ART whilst women in the control group had only ART without immunomodulators. The primary outcome was LBR per cycle. Secondary outcomes included the rates of clinical pregnancy (CPR), cumulative live birth (CLBR), and miscarriage. RESULTS: A total of 27 163 ART cycles fulfilled the inclusion criteria, of which 5083 had immunomodulation treatment in addition to standard ART treatment, and 22 080 had standard ART treatment alone. Women in the treatment group were significantly older (mean age 38.5 vs. 37.1 years, p < .001), and had a higher number of previous failed ART cycles (mean 4.3 vs. 3.8, p < .01). There was a higher LBR in women who received immunomodulation therapy when compared with the control group (20.9% vs. 15.8%, odds ratio [OR] 1.4, 95% confidence interval [CI] 1.29-1.53, p < .001). Multivariate regression analysis showed that immunomodulation treatment was a significant independent predictor of live birth after adjusting for other confounders (adjusted OR [aOR] 1.33, 95% CI 1.15-1.54, p < .001). Survival analysis showed a higher CLBR in the treatment group (adjusted hazard ratio [aHR] 1.78, 95% CI 1.62-1.94, p < .001). CONCLUSION(S): This study provides evidence of a potential beneficial effect of immunomodulation therapy in women with RIF after immunological testing. There remains a need for high quality, adequately powered multicentre RCTs to robustly address the role of immunomodulation in women with RIF. There is also an urgent need for standardised screening tests for immune disorders that could preclude implantation.

Comprehensive analysis of the prognosis, tumor microenvironment, and immunotherapy response of SDHs in colon adenocarcinoma.

Background: Succinate dehydrogenase (SDH), one of the key enzymes in the tricarboxylic acid cycle, is mainly found in the mitochondria. SDH consists of four subunits encoding SDHA, SDHB, SDHC, and SDHD. The biological function of SDH is significantly related to cancer progression. Colorectal cancer (CRC) is one of the most common malignant tumors globally, whose most common histological subtype is colon adenocarcinoma (COAD). However, the correlation between SDH factors and COAD remains unclear. Methods: The data on pan-cancer was obtained from The Cancer Genome Atlas (TCGA) database. Kaplan-Meier survival analysis showed the prognostic ability of SDHs. The cBioPortal database reflected genetic variations of SDHs. The correlation analysis was conducted between SDHs and mitochondrial energy metabolism genes (MMGs) and the protein-protein interaction (PPI) network was built. Consequently, Univariate and Multivariate Cox Regression Analysis on SDHs and other clinical characteristics were conducted. A nomogram was established. The ssGSEA analysis visualized the association between SDHs and immune infiltration. Immunophenoscore (IPS) explored the correlation between SDHs and immunotherapy, and the correlation between SDHs and targeted therapy was investigated through Genomics of Drug Sensitivity in Cancer. Finally, qPCR and immunohistochemistry detected SDHs' expression. Results: After assessing SDHs differential expression in pan-cancer, we found that SDHB, SDHC, and SDHD benefit COAD patients. The cBioPortal database demonstrated that SDHA was the top gene in mutation frequency rank. Correlation analysis mirrored a strong link between SDHs and MMGs. We formulated a nomogram and found that SDHB, SDHC, SDHD, and clinical characteristics correlated with COAD patients' survival. For T helper cells, Th2 cells, and Tem, SDHA, SDHB, SDHC, and SDHD were significantly enriched in the high expression group. Moreover, COAD patients with high SDHA expression were more suitable for immunotherapy. And COAD patients with different SDHs' expression have different sensitivity to targeted drugs. Further verifying the gene and protein expression levels of SDHs, we found that the tissues were consistent with the bioinformatics analysis. Conclusions: Our study analyzed the expression and prognostic value of SDHs in COAD, explored the pathway mechanisms involved, and the immune cell correlations, indicating that SDHs might be biomarkers for COAD patients.

Blood alkaline phosphatase predicts prognosis of patients with advanced HER2-negative gastric cancer receiving immunotherapy.

BACKGROUND: Immune checkpoint blockade is effective against many cancer types, but few patients achieve a complete response (OR). Therefore, effective prognostic biomarkers are needed for metastatic gastric cancer (GC) patients after immune treatment. The present study assessed the value of hematological parameters as markers of the effectiveness of immune checkpoint blockade among metastatic GC patients. METHODS: This retrospective study included patients with metastatic GC who underwent multiline chemotherapy including at least two courses of immunotherapy between September 2018 and December 2020. Patient and tumor characteristics were tested for prognostic significance by analysis of variance or chi-square test. Kaplan-Meier and Cox analyses were performed to identify factors associated with progression-free survival (PFS). RESULTS: Sixty-one GC patients (mean age 55.61±11.97 years, range 23-80 years, 24 females, and 37 males) were included, and 27, 9 and 25 cases had organ only, peritoneum only, and simultaneous organ and peritoneum metastasis, respectively. Gastrectomy was performed in 24 cases, and there was no operative treatment in the other 37 cases, while all patients received two or more lines of chemotherapy. After immune treatment, 13 patients achieved a partial response (PR), 16 stable disease (SD), and 32 progressive disease (PD). The median PFS was 4.93±3.47 months. An alkaline phosphatase (ALP) level >225 U/L, a lactate dehydrogenase level (LDH) >299 U/L, and a body mass index (BMI) >24 kg/m2 were associated with a short PFS (P=0.01, P=0.008, and P=0.039, respectively). A Cox multivariate proportional hazard model indicated that higher ALP level was a significant prognostic indicator for adverse PFS. CONCLUSIONS: Our data show an ALP cutoff of 225 U/L offered good prognostic sensitivity for HER2-negative metastatic GC. ALP measurement represents a convenient, cost-effective, and relatively sensitive screening tool, and prospective studies involving its evaluation in addition to other biomarkers in metastatic GC patients are indicated.

TLR3 regulates PD-L1 expression in human cytomegalovirus infected glioblastoma.

Glioblastoma, the most common primary brain tumor of adults, is characterized by poor survival rates. Programmed death ligand 1 (PD-L1, CD274) has been implicated in the immune escape of glioblastoma. The presence of human cytomegalovirus (HCMV) in glioblastoma multiforme (GBM) has sparked considerable interest and controversy. The exposure of toll-like receptor 3 (TLR3) to pathogens induces an antiviral state in cells or in animals. In the current study, the expression of PD-L1 and TLR3 in HCMV-infected glioma specimens was observed to be higher compared to the control. We therefore investigated if PD-L1 expression in glioblastoma is mediated by TLR3 triggering in HCMV infected glioblastoma. TLR3 siRNA transfections were utilized to identify the induction of PD-L1 via TLR3 triggering in HCMV infected cell lines. Also, IL-8 and TGF-ß were detected by ELISA for the antitumor role of TLR3. Thus, we propose a novel immune treatment using a combination of PD-L1 blockade with TLR3 triggering against HCMV infected glioblastoma.

Retrospectively analysis of characteristics and risk factors of immune treatment-related hepatic adverse events in malignant tumor / 中华肿瘤杂志

Objective@#To explore the clinical features and risk factors of hepatic injury due to immune checkpoint inhibitors (CPI) therapy in malignant tumor.@*Methods@#Data of 112 patients (64 men and 48 women) who received CPI between January 2016 and March 2019 in Chinese Academy of Medical Sciences and Peking Union Medical College Shenzhen Hospital, and Huazhong University of Science and Techology Union Shenzhen Hospital were retrospectively collected. The median age of these patients was 60 years.@*Results@#Hepatic adverse events were observed in 30 patients out of 112 patients (26.8%). Among them, the incidence of grade 3-5 hepatic adverse events were 7.14% (8/112). The median time of hepatic adverse event occurrence was 3 weeks (2-30) after undergoing therapy. The results of univariate and multivariate analyses showed that liver cancer was attributed to the CPI induced hepatitis (P<0.05). Patients with severe hepatic injury got almost complete resolution after receiving methlprednisolone for 4 to 6 weeks.@*Conclusion@#Live cancer is the risk factor of CPI-related hepatic adverse events.

Host genomic HIV restriction factors modulate the response to dendritic cell-based treatment against HIV-1.

Host genome is still poorly investigated in the context of vaccine or immunotherapy, however recently findings emphasized that it may affect the response to those treatments. In our retrospective study we evaluated the effect of HIV-1 genetic restriction factors on the response to dendritic cell (DC)-based immunotherapy in a Brazilian cohort of HIV positive (HIV+) patients that underwent a phase I clinical trial in 2004. Genomic DNA from 18 HIV+ individuals that underwent DC-based immunotherapy was analyzed for selected polymorphisms known to be associated with susceptibility to HIV-1 infection and/or AIDS progression. Allelic and genotypic distribution of the 22 polymorphisms was evaluated considering the response to the treatment. The rs11884476 SNP in PARD3B resulted associated with good response to immune treatment according to an over-dominant model. Even if functional effect of this variation is still unknown, our data suggested that it could play a role in the control of viral replication. Our findings, being aware of the limitation represented by the small number of subjects analyzed, suggest that genetic factors involved in AIDS progression could affect the response to immunotherapy, reinforcing the idea that deeper investigation on host genetic variations will be fundamental for a rational vaccine development.

Progress on the treatment of mycoplasma pneumoniae pneumonia / 中国小儿急救医学

Mycoplasma pneumoniae is the common pathogen of community-acquired pneumonia in children. In recent years,the incidence of mycoplasma pneumoniae pneumonia(MPP) has increased year by year. And it is found that case reports about intractable MPP at home and abroad have also significantly increased. The treatments of MPP become the focus in clinical physicians. This paper summarized about progress of MPP in antibiotic therapy,immune therapy and other ancillary treatment.

A clinical study on immune treatment of oral lichen planus by integrated traditional Chinese and western medicine / 实用口腔医学杂志

Objective: To observe the clinical efficacy of integrated traditional China and western medicine in the immune treatment of oral lichen planus(OLP)and the effectiveness of this method on improving immune state of patients with OLP.Methods: Forty patients with OLP were randomly divided into two groups,integrated traditional China and western medicine group(ITAWMG)and western medicine group(WMG).20 patients were treated by integrated traditional China and western medicine and 20 patients treated by western medicine and observed and compared.TNF-?,IL-1,IL-8 were examined before and after the treatment to observe the changes of immune state.Results: 1.Short-term effect: The markedly effective rate and total effective rate of ITAWMG were 90.00% and 95.00%.While those of WMG were 10% and 50%,the difference between the two groups was significant(P