Multicenter integration analysis of TRP channels revealed potential mechanisms of immunosuppressive microenvironment activation and identified a machine learning-derived signature for improving outcomes in gliomas.

AIM: This study aimed to explore the mechanisms of transient receptor potential (TRP) channels on the immune microenvironment and develop a TRP-related signature for predicting prognosis, immunotherapy response, and drug sensitivity in gliomas. METHODS: Based on the unsupervised clustering algorithm, we identified novel TRP channel clusters and investigated their biological function, immune microenvironment, and genomic heterogeneity. In vitro and in vivo experiments revealed the association between TRPV2 and macrophages. Subsequently, based on 96 machine learning algorithms and six independent glioma cohorts, we constructed a machine learning-based TRP channel signature (MLTS). The performance of the MLTS in predicting prognosis, immunotherapy response, and drug sensitivity was evaluated. RESULTS: Patients with high expression levels of TRP channel genes had worse prognoses, higher tumor mutation burden, and more activated immunosuppressive microenvironment. Meanwhile, TRPV2 was identified as the most essential regulator in TRP channels. TRPV2 activation could promote macrophages migration toward malignant cells and alleviate glioma prognosis. Furthermore, MLTS could work independently of common clinical features and present stable and superior prediction performance. CONCLUSION: This study investigated the comprehensive effect of TRP channel genes in gliomas and provided a promising tool for designing effective, precise treatment strategies.

Clinical characteristics and prognostic analysis of metachronous bilateral breast carcinoma: a retrospective study based on propensity score matching.

BACKGROUND: To investigate clinical characteristics, treatment, outcomes, and prognostic risk factors of metachronous bilateral breast carcinoma (MBBC) and provide a theoretical basis for clinical management of MBBC. METHODS: This was a retrospective study. From January 1, 2010 to March 31, 2022, a total of 23,010 patients with breast cancer underwent surgical treatment at the Breast Center of the Fourth Hospital of Hebei Medical University, including 386 patients with MBBC. Propensity score matching (PSM) was performed on MBBC patients and unilateral breast cancer (UBC) patients in a 1:1 ratio, and 210 UBC patients and 210 MBBC patients were finally matched. Clinical medical records of all patients were collected, including age of onset, family history of breast cancer, tumor size, lymph node status, TNM stage, mode of surgery, menstruation, pathological type, immunohistochemical (IHC) typing, treatment, disease-free survival (DFS), and overall survival (OS). RESULTS: The result showed that age of onset of the second primary cancer (SPC) was significantly older than that of the first primary cancer (FPC) (P = 0.024). Baseline data from MPPC patients showed that the tumor size of FPC was significantly larger than that of SPC (P = 0.043), and the proportion of PR ( +) in FPC is significantly higher than that in SPC (P = 0.045). Among MBBC patients with FPC for estrogen receptor (ER) or progesterone receptor (PR) ( +) and Her-2 (-), clinical characteristics and treatment results showed that the proportion of PR ( +) in the drug-resistant group was significantly lower than that in the non-drug-resistant group. The 2-year OS rate of SPC in the drug-resistant group was significantly shorter than those of the non-drug-resistant group (78.9% vs 100%, P < 0.05). The result of PSM-based comparison between MBBC patients and UBC patients showed significantly lower proportion of MBBC patients with SPC received chemotherapy compared to UBC patients (P = 0.026), and there was no significant difference in OS and DFS between SPC course of MBBC patients and UBC patients (P > 0.05). The univariate analysis showed that high TNM stage was a risk factor for death and disease progression in MBBC patients, with the risk of death in stage III MBBC patients being about 5 times higher than that in stage I MBBC patients (HR = 4.97, 95%CI = 1.42-17.31, P = 0.012), and the risk of disease recurrence being about 3.5 times higher than that in stage I MBBC patients (HR = 3.55, 95%CI = 1.07-11.81, P = 0.039). CONCLUSION: In summary, this study presented clinical characteristics, treatment options, and outcomes of MBBC patients and patients with MBBC who were resistant to endocrine therapy have a worse SPC survival prognosis. The course of SPC in MBBC patients was similar to that of UBC in terms of prognosis and survival, which suggested that SPC can be treated according to UBC treatment regimen. High TNM stage was a prognostic risk factor for SPC patients.

miR-30d-5p inhibits proliferation, invasion and migration of breast cancer cells by targeting SERPINE1 and promoting fatty acid ß-oxidation.

Breast cancer (BC) is among the top three most prevalent cancers across the world, especially in women, and its pathogenesis is still unknown. Fatty acid ß-oxidation is highly associated with breast cancer. Serpin family E member 1 (SERPINE1)-induced down-regulation of fatty acid ß-oxidation can facilitate BC cell proliferation, invasion, and metastasis. In this paper, the difference of miR-30d-5p expressions in both cancerous tissues and para-carcinoma tissues was first detected. Next, the expressions of SERPINE1, long-chain acyl-CoA dehydrogenase (LCAD) and medium-chain acyl-CoA dehydrogenase (MCAD) in the aforementioned tissues were analyzed. Finally, miR-30d-5p mimics were supplemented to breast cancer cells to observe the miR-30d-5p effect upon breast cancer cells. Via immunofluorescence assay and Western blotting, it was found that cancerous tissues had lower expressions of miR-30d-5p, MCAD and LCAD and a higher expression of SERPINE1 than para-carcinoma tissues. The miR-30d-5p mimic group had a decreased SERPINE1 expression and increased MCAD and LCAD expressions compared with the NC group, thus inhibiting BC cell proliferation, invasion, and metastasis. To sum up, miR-30d-5p blocks the cell proliferation, invasion and metastasis by targeting SERPINE1 and promoting fatty acid ß-oxidation. Preclinical studies are further required to establish a fatty acid ß-oxidation-targeting therapy for breast cancer.

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.

CAR-T treatment for cancer: prospects and challenges.

Chimeric antigen receptor (CAR-T) cell therapy has been widely used in hematological malignancies and has achieved remarkable results, but its long-term efficacy in solid tumors is greatly limited by factors such as the tumor microenvironment (TME). In this paper, we discuss the latest research and future views on CAR-T cell cancer immunotherapy, compare the different characteristics of traditional immunotherapy and CAR-T cell therapy, introduce the latest progress in CAR-T cell immunotherapy, and analyze the obstacles that hinder the efficacy of CAR-T cell therapy, including immunosuppressive factors, metabolic energy deficiency, and physical barriers. We then further discuss the latest therapeutic strategies to overcome these barriers, as well as management decisions regarding the possible safety issues of CAR-T cell therapy, to facilitate solutions to the limited use of CAR-T immunotherapy.

Characterizing polyproline II conformational change of collagen superhelix unit on adsorption on gold surface.

The dynamic process of protein binding onto a metal surface is a frequent occurrence as gold nanoparticles are increasingly being used in biomedical applications, including wound treatment and drug transport. Collagen, as a major component of the extracellular matrix, has potentially advantageous biomedical applications, due to its excellent biocompatibility and elasticity properties. Therefore, a mechanistic comprehension of how and which species in collagen interact with gold nanoparticles is a prerequisite for collagen-gold complexes in clinical application. However, the dynamic behavior of collagen with the polyproline II (PPII) conformation on gold sheets at the molecular level is too complex to capture under current experimental conditions. Here, using molecular dynamics simulations, we investigate the adsorption process and conformational behavior of the tripeptide Gly-Pro-Hyp with the repetitive unit of the collagen superhelix on the gold surface as a function of number of repeating units from 1 to 10. The different numbers of repeating units all prefer to approach the gold surface and adsorb via charged residues at the C-terminal or N-terminal ends, tending to form arch structures on the gold surface. Compared with the various tripeptide units in solution still retaining the native PPII conformation, the presence of the gold surface affects the formation of hydrogen bonds between the protein and water molecules, thus disrupting the PPII conformation of collagen. Specifically, the interaction between the gold surface and HYP limits the rotation of the dihedral angle of collagen, resulting in a tendency for the PPII conformation of the gold surface to transform to the ß-sheet conformation. The results provide an indication of how to improve the interaction between the terminal groups and the gold surface for the design of a bioavailable protein-gold material for medicinal purposes.

Evaluation of the Clinical Efficacy of Heart Valve Surgery in Patients with a Cardiac Disorder and the Factors Contributing to Poor Patient Prognosis.

Objective: We aimed to investigate the clinical efficacy of heart valve surgery in patients with heart disease and the factors contributing to poor patient prognosis. Methods: This was a retrospective analysis of 172 patients with heart disease treated in Peking University International Hospital between January 2019 and December 2021, with surgical treatment in the study group (86 patients) and conservative treatment in the control group (86 patients), by comparing factors such as patient age, preoperative cardiac function status, type and degree of valve lesion, surgical method and time of aortic block and perioperative treatment in both groups with clinical cure rate. The risk factors for early postoperative death were analyzed by single-factor and multi-factor logistic regression methods. Results: Regression analysis showed that age, peripheral artery disease (PAD), diabetes mellitus (DM), hypertension (HTN), dietary habits and medical compliance were prognostic factors in patients after heart valve surgery. The incidence of complications was lower in the study group than in the control group (P < .05). The left anterior descending artery (LAD), left ventricular end-diastolic internal diameter (LVEDD), cardiothoracic ratio (CTR) and left ventricular end-systolic internal diameter (LVDS) was decreased in both groups, whereas the left ventricular ejection fraction (LVEF) and peak early diastolic flow rate/peak late diastolic flow rate (E/A) were increased. The changes were greater in the study group than in the control group (P < .05); life function scores and survival rates were higher in the study group than in the control group (P < .05). Conclusions: The analysis of relevant clinical risk factors identified some independent prognostic factors affecting early death after valve replacement. These can be used for preoperative risk assessment, identification of high-risk surgical patients and guiding daily clinical work. Rationalizing the indications for surgery, choosing the timing of surgery, myocardial protection and appropriate surgical approach can further reduce the rate of surgical morbidity and mortality and complications in this patient population.

Effect of tumor-infiltrating lymphocytes depending on the presence of postmastectomy radiotherapy on the prognosis in pT1-2N1M0 breast cancer.

Background: Currently, it remains unclear regarding the association between tumor-infiltrating lymphocytes (TILs) and the efficacy of postoperative radiotherapy in primary tumors. Here we attempted to investigate the effect of TILs depending on the presence of postmastectomy radiotherapy (PMRT) on the prognosis in pT1-2N1M0 breast cancer. Methods: The clinical data of pT1-2N1M0 breast cancer patients undergoing mastectomy and axillary lymph node dissection were retrospectively analyzed. The effect of TILs on the prognosis was assessed based on the infiltration degree (low: TILs ≤10%, high: TILs >10%), and then the prognosis of patients with low and high infiltration of TILs was analyzed based on presence or absence of PMRT. Results: Totally 213 patients were eligible for the study, including 162 cases of low infiltration and 51 of high infiltration. High-infiltration patients tended to be ER/PR-negative, HER2-positive, and have high histological grade. The infiltration in triple-negative and HER2-positive subtypes was higher compared with Luminal A subtype. Regarding local-regional recurrence-free survival, recurrence-free survival, and overall survival (OS) rates, the differences were all inapparent whether in high- and low-infiltration patients or in high-infiltration patients with/without PMRT. Compared with those without PMRT, low-infiltration patients with PMRT showed a significantly increased OS rate (92.8% vs. 80.0%, p=0.023). Multivariate analysis further confirmed PMRT as an independent predicator of OS in low-infiltration patients (HR: 0.228, 95%CI: 0.081-0.644, p=0.005). Conclusion: High infiltration of TILs in pT1-2N1M0 breast cancer may be associated with clinicopathological factors. Low-infiltration patients, but not high-infiltration patients, may derive survival benefits from PMRT.

A Bibliometric Analysis of Diagnosis Related Groups from 2013 to 2022.

Purpose: As an important management method of the global healthcare system, diagnosis related groups (DRGs) classify patients into different cost groups and pay more attention to the equitable distribution of medical resources and the quality of medical services. At present, most countries have used DRGs to help medical institutions and doctors to treat patients more accurately, avoid the waste of medical resources, and improve treatment efficiency. Methods: The Web of Science database was searched to collect all relevant literature on DRGs from 2013 to 2022. The literature information was imported into CiteSpace, Vosviewer, and Histcite for data analysis and visualization of the results. Analyze the cooperative relationship among the countries, institutions, journals, and authors. The usage trend of keywords; Highlight the content of the cited articles. Results: The number of articles published in this decade was stable, and the number of citations in 2014 was the highest. The United States and Germany, as the first countries to use the DRGs system, are ahead of other countries in terms of the number and quality of articles. We have carried out content research on the articles with high citations, and summarized the application range of DRGs; classification method; advantages and disadvantages of the application. In general, the development trend of DRGs in foreign countries is to continuously optimize the classification method, expand the scope of application, and improve the application effect. These provide support and reference for the improvement of medical services and the perfection of the medical insurance system. Conclusion: The application of DRGs can improve the quality and efficiency of medical services, and reduce the waste of medical expenses. It can also promote the rational allocation of medical resources and the equity of medical services. In the future, DRGs will pay more attention to the personalized diagnosis and treatment and fine management of patients, and the sharing and standardization of medical data, to promote the development of medical informatization.

Gene Targets of CAR-T Cell Therapy for Glioblastoma.

Glioblastoma (GBM) is an aggressive primary brain tumor with a poor prognosis following conventional therapeutic interventions. Moreover, the blood-brain barrier (BBB) severely impedes the permeation of chemotherapy drugs, thereby reducing their efficacy. Consequently, it is essential to develop novel GBM treatment methods. A novel kind of pericyte immunotherapy known as chimeric antigen receptor T (CAR-T) cell treatment uses CAR-T cells to target and destroy tumor cells without the aid of the antigen with great specificity and in a manner that is not major histocompatibility complex (MHC)-restricted. It has emerged as one of the most promising therapy techniques with positive clinical outcomes in hematological cancers, particularly leukemia. Due to its efficacy in hematologic cancers, CAR-T cell therapy could potentially treat solid tumors, including GBM. On the other hand, CAR-T cell treatment has not been as therapeutically effective in treating GBM as it has in treating other hematologic malignancies. CAR-T cell treatments for GBM have several challenges. This paper reviewed the use of CAR-T cell therapy in hematologic tumors and the selection of targets, difficulties, and challenges in GBM.

RNA-sequencing transcriptome analysis of Avicennia marina (Forsk.) Vierh. leaf epidermis defines tissue-specific transcriptional response to salinity treatment.

Avicennia marina (Forsk.) Vierh. is a typical mangrove plant. Its epidermis contains salt glands, which can secrete excess salts onto the leaf surfaces, improving the salt tolerance of the plants. However, knowledge on the epidermis-specific transcriptional responses of A. marina to salinity treatment is lacking. Thus, physiological and transcriptomic techniques were applied to unravel the salt tolerance mechanism of A. marina. Our results showed that 400 mM NaCl significantly reduced the plant height, leaf area, leaf biomass and photosynthesis of A. marina. In addition, 1565 differentially expressed genes were identified, of which 634 and 931 were up- and down-regulated. Based on Kyoto Encyclopedia of Genes and Genomes metabolic pathway enrichment analysis, we demonstrated that decreased gene expression, especially that of OEE1, PQL2, FDX3, ATPC, GAPDH, PRK, FBP and RPE, could explain the inhibited photosynthesis caused by salt treatment. Furthermore, the ability of A. marina to cope with 400 mM NaCl treatment was dependent on appropriate hormone signalling and potential sulfur-containing metabolites, such as hydrogen sulfide and cysteine biosynthesis. Overall, the present study provides a theoretical basis for the adaption of A. marina to saline habitats and a reference for studying the salt tolerance mechanism of other mangrove plants.

Myeloid leukemia factor 1: A "double-edged sword" in health and disease.

The occurrence and development of malignancies are closely related to abnormal cell cycle regulation. Myeloid leukemia factor 1 (MLF1) is a small nucleocytoplasmic shuttling protein associated with cell cycle exit, apoptosis, and certain immune functions. Therefore, it is pertinent to explore the role of MLF1 in health and diseases. Studies to date have suggested that MLF1 could act as a double-edged sword, regulating biochemical activities directly or indirectly. In hematopoietic cells, it serves as a protective factor for the development of lineages, and in malignancies, it serves as an oncogenesis factor. The diversity of its functions depends on the binding partners, including tumor inhibitors, scaffolding molecules, mitochondrial membrane proteins, and transcription factors. Emerging evidence indicates that MLF1 influences immune responses as well. This paper reviews the structure, biological function, and research progress on MLF1 in health and diseases to provide new insights for future research.

Relapsed/refractory diffuse large B cell lymphoma with cardiac involvement: A case report and literature review.

Background: Hematological malignancies of the heart (CHMs) are extremely rare, and include leukemia, lymphoma infiltration, and multiple myeloma with extramedullary manifestations. Cardiac lymphoma can be divided into primary cardiac lymphoma (PCL) and secondary cardiac lymphoma (SCL). Compared to PCL, SCL is relatively more common. Histologically, the most frequent SCL is diffuse large B-cell lymphoma (DLBCL). The prognosis of lymphoma in patients with cardiac involvement is extremely poor. CAR T-cell immunotherapy has been recently become a highly effective treatment for relapsed or refractory diffuse large B-cell lymphoma. To date, there are no guidelines that provide a clear consensus on the management of patients with secondary heart or pericardial involvement. We report a case of relapsed/refractory DLBCL that secondarily affected the heart. Case presentation: A male patient was diagnosed with double-expressor DLBCL based on biopsies of mediastinal and peripancreatic masses and fluorescence in situ hybridization. The patient received first-line chemotherapy and anti-CD19 CAR T cell immunotherapy, but developed heart metastases after 12 months. Considering his physical condition and economic situation of the patient, two cycles of multiline chemotherapies were administered, followed by CAR-NK cell immunotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) at another hospital. After achieving a six-month survival, the patient died of severe pneumonia. Conclusion: The response of our patient emphasizes the importance of early diagnosis and timely treatment to improve the prognosis of SCL and serves as an important reference for SCL treatment strategies.

ATG5 Knockdown Attenuates Ischemia‒Reperfusion Injury by Reducing Excessive Autophagy-Induced Ferroptosis.

Autophagy has been described to be both protective and pathogenic in cerebral ischemia/reperfusion (I/R) injury. The underlying association between autophagy and ferroptosis in ischemic stroke has not yet been clearly investigated. The purpose of this study was to explore the role of autophagy-related gene 5 (ATG5) in experimental ischemic stroke. After injection of ATG5 shRNA lentivirus, mice underwent surgery for transient middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia. The infarct volume, neurological function, apoptosis, reactive oxygen species (ROS), autophagy, and ferroptosis levels were evaluated. After MCAO, ATG5-knockdown mice had a smaller infarct size and fewer neurological deficits than wild-type mice. The levels of apoptosis and ROS in ischemic mouse brains were alleviated through ATG5 knockdown. The expression of LC3 I/II was reduced through ATG5 knockdown after MCAO. Additionally, the expression of beclin1 and LC3 II was increased after I/R, but the increase was counteracted by preconditioning with ATG5 knockdown. After ischemic stroke, the levels of Fe2+ and malondialdehyde (MDA) were increased, but they were reduced by ATG5 knockdown. Similarly, the expression of glutathione peroxidase 4 (GPX4) and glutathione (GSH) was decreased by I/R but elevated by ATG5 knockdown. The present study shows that ATG5 knockdown attenuates autophagy-induced ferroptosis, which may offer a novel potential approach for ischemic stroke treatment.

Effects of inflammation and oxidative stress on postoperative delirium in cardiac surgery.

The past decade has witnessed unprecedented medical progress, which has translated into cardiac surgery being increasingly common and safe. However, complications such as postoperative delirium remain a major concern. Although the pathophysiological changes of delirium after cardiac surgery remain poorly understood, it is widely thought that inflammation and oxidative stress may be potential triggers of delirium. The development of delirium following cardiac surgery is associated with perioperative risk factors. Multiple interventions are being explored to prevent and treat delirium. Therefore, research on the potential role of biomarkers in delirium as well as identification of perioperative risk factors and pharmacological interventions are necessary to mitigate the development of delirium.

Comprehensive evaluation of breast cancer immunotherapy and tumor microenvironment characterization based on interleukin genes-related risk model.

Breast cancer (BRCA) is the most prevalent malignancy and the leading cause of death in women. Interleukin (IL) genes are critical in tumor initiation and control. Nevertheless, the prognosis value of the IL in BRCA remains unclear. We collected data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and 94 IL genes were identified from GeneCard. Based on the random forest (RF), least absolute shrinkage and selection operator (LASSO) analysis, and multivariate Cox regression analysis, we constructed an IL signature. GSE22219, GSE25065, and GSE21653 were derived as validation sets. The expression differences in the tumor microenvironment (TME), immunotherapy, and chemosensitivity of BRCA between the high- and low-risk groups were evaluated. Overall, 21 IL genes were selected to construct an IL risk model, of which IL18BP, IL17D, and IL23A were the first time identified as prognostic genes in BRCA. IL score could distinguish BRCA patients with inferior outcomes, and AUC of it was 0.70, 0.76, and 0.72 for 1-,3- and 5- years, respectively, which was also verified in GSE22219, GSE25065, and GSE21653 cohorts. Meanwhile, compared to luminal A and luminal B, HER2-positive and TNBC had significantly higher IL score. Besides, the high-risk group had a significantly higher prevalence of TP53 and TTN but a lower prevalence of PIK3CA, as well as higher tumor mutation burden (TMB) and neoantigen level. High- and low-risk groups exhibited notable differences in immunomodulators and tumor infiltrates immune cells (TIICs), and the high-risk group had significantly lower Tumor Immune Dysfunction and Exclusion (TIDE) score. Additionally, the high-risk group has more responders to immune or anti-HER2 combination therapy, whereas the low-risk group has higher sensitivity to docetaxel and paclitaxel. Consequently, we constructed a reliable risk model based on the IL genes, which can provide more information on both the risk stratification and personalizing management strategies for BRCA.

APOL4, a Novel Immune-Related Prognostic Biomarker for Glioma.

Glioma is the common, most aggressive and poorest prognostic tumor type in the brain. More and more biomarkers associated with glioma treatment, prognosis, and immunity are being discovered. Here, we aimed to explore the underlying biological functions and prognostic predictive value of Apolipoprotein L4 (APOL4) in glioma. We downloaded the expression data of APOL4 and clinical information from several databases and used R software for preprocessing. The clinical significance of APOL4 in a glioma outcome was explored by the Cox regression analysis and Kaplan-Meier survival analysis. In addition, immune infiltrates and microenvironmental indicators were assessed by CIBERSORT and TIMER. GO and KEGG analyses were used to analyze the potential functions of APOL4 in gliomas. APOL4 expression was increased in glioma specimens compared to normal tissues and correlated dramatically with the WHO grade. A survival analysis showed a shorter overall survival (OS) in glioma patients with APOL4 overexpression, and a Cox regression analysis showed that APOL4 was an independent prognostic factor for the OS of glioma patients. GSEA, GO, and KEGG enrichment analyses showed remarkable enrichment in immune-related pathways. APOL4 expression was positively correlated with immune infiltration (including DC cells, neutrophils, CD8+ T cells, B cells, macrophages, CD4+ T cells, etc.) and microenvironmental parameters (including immune, stromal, and ESTIMATE scores) in gliomas. Glioma patients with a higher expression of APOL4 may be more sensitive to immune checkpoint inhibitors (ICI). In conclusion, these findings suggest that APOL4 is associated with the tumor grade and immune infiltrates; APOL4 may be a new and potential biomarker for therapeutic and prognostic evaluations that may further suggest the therapeutic efficacy of immunotherapy.

A Diuretic Response is Associated with the Early Prognosis of Patients Undergoing Repeat Tricuspid Valve Surgery Due to Severe Tricuspid Regurgitation After Left-Sided Valvular Surgery.

OBJECTIVE: To analyze the factors affecting the early prognosis of patients undergoing repeat tricuspid valve surgery due to severe tricuspid regurgitation after left-sided valvular surgery. METHOD: We retrospectively analyzed 76 patients undergoing repeat tricuspid valve surgery due to severe tricuspid regurgitation after left-sided valvular surgery at Peking University International Hospital between October 2017 and February 2021. Patients were divided into two groups, according to preoperative weight control and whether the adjusted diuretic dose exceeded 40 mg of furosemide (or the equivalent dose). The factors affecting the early prognosis were analyzed through postoperative follow up. RESULTS: Thirty-five male patients (46.1%), aged 57±13 years, were enrolled in the study. For the patients who received a preoperative same dose of furosemide ≥40 mg/day and a same dose of furosemide <40 mg/day, the baseline data basically were the same. There were 76 patients (100%) who were followed up. Endpoint events during the follow up were as follows: Six patients (7.9%) died, two patients (2.6%) were admitted to the hospital or transferred to the intensive care unit due to cardiac insufficiency, and other conditions such as severe tricuspid regurgitation on repeat ultrasound, bilateral lower extremity edema, and inability to reduce or stop diuretics were found in five cases (6.6%). Compared with the group with the same dose of furosemide <40 mg/day group, the ≥40 mg/day group had a higher incidence of endpoints (12, 27.3% vs. 1, 3.1%, P = 0.006). CONCLUSION: In patients undergoing repeat tricuspid valve surgery due to severe tricuspid regurgitation after left-sided valvular surgery, a diuretic response was associated with surgical prognosis. Compared with the low-dose furosemide group, the high-dose group (≥40 mg/) had a significantly increased incidence of early events.

MS4A6A is a new prognostic biomarker produced by macrophages in glioma patients.

MS4A6A has been recognized as being associated with aging and the onset of neurodegenerative disease. However, the mechanisms of MS4A6A in glioma biology and prognosis are ill-defined. Here, we show that MS4A6A is upregulated in glioma tissues, resulting in unfavorable clinical outcomes and poor responses to adjuvant chemotherapy. Multivariate Cox regression analysis suggested that MS4A6A expression can act as a strong and independent predictor for glioma outcomes (CGGA1: HR: 1.765, p < 0.001; CGGA2: HR: 2.626, p < 0.001; TCGA: HR: 1.415, p < 0.001; Rembrandt: HR: 1.809, p < 0.001; Gravendeel: HR: 1.613, p < 0.001). A protein-protein interaction (PPI) network revealed that MS4A6A might be coexpressed with CD68, CD163, and macrophage-specific signatures. Enrichment analysis showed the innate immune response and inflammatory response to be markedly enriched in the high MS4A6A expression group. Additionally, single-cell RNA sequencing (scRNA-seq) analysis revealed distinctive expression features for MS4A6A in macrophages in the glioma immune microenvironment (GIME). Immunofluorescence staining confirmed colocalization of CD68/MS4A6A and CD163/MS4A6A in macrophages. Correlation analysis revealed that MS4A6A expression is positively related to the tumor mutation burden (TMB) of glioma, displaying the high potential of applying MS4A6A to evaluate responsiveness to immunotherapy. Altogether, our research indicates that MS4A6A upregulation may be used as a promising and effective indicator for adjuvant therapy and prognosis assessment.

Risk Factors for Postoperative Acute Kidney Injury in Patients Undergoing Redo Cardiac Surgery Using Cardiopulmonary Bypass.

Objective: This paper aimed to investigate the incidence and risk factors of postoperative acute kidney injury (AKI) in adult patients undergoing redo cardiac surgery with cardiopulmonary bypass (CPB), and explore the impact of AKI on early outcomes. Methods: A total of 116 patients undergoing redo cardiac surgery with CPB between November 2017 and May 2021 were included. Patients were divided into two groups, AKI group and non-AKI group, according to the Kidney Disease Improving Global Outcomes criteria. Perioperative variables were retrospectively collected and analyzed. Risk factors for the development of AKI were investigated by univariate and multiple logistic regression models. Clinical outcomes were also compared between the groups. Results: Postoperative AKI occurred in 63 patients (54.3%), among whom renal replacement therapy was required in 12 patients (19.0%). The mechanical ventilation time (AKI: 43.00 (19.00, 72.00) hours; non-AKI: 18.00 (15.00, 20.00) hours; p < 0.001), ICU length of stay (AKI: 4.00 (2.00, 6.00) days; non-AKI: 3.00 (2.00, 4.00) days; p = 0.010), hospital length of stay since operation (AKI: 12.00 (8.00, 18.00) days; non-AKI: 9.00 (7.00, 12.50) days; p = 0.024), dialysis (AKI: 12.00 (19.05%); non-AKI: 0 (0%); p = 0.001), reintubation (AKI: 7.00 (11.11%); non-AKI: 0 (0%); p = 0.035), and hospital mortality (AKI: 8.00 (12.70%); non-AKI: 0 (0%); p = 0.020) were all higher in the AKI group than in the non-AKI group. Multivariate analysis revealed that high aspartate aminotransferase (OR, 1.028, 95% CI, 1.003 to 1.053, p = 0.025), coronary angiogram within 2 weeks before surgery (OR, 3.209, 95% CI, 1.307 to 7.878, p = 0.011) and CPB time (OR, 1.012, 95% CI, 1.005 to 1.019, p = 0.001) were independent risk factors for postoperative AKI. Conclusions: High aspartate aminotransferase, coronary angiogram within 2 weeks before surgery and CPB time seem to be associated with an increased incidence of postoperative AKI in patients with redo cardiac surgery.