Chemotherapy-induced high expression of IL23A enhances efficacy of anti-PD-1 therapy in TNBC by co-activating the PI3K-AKT signaling pathway of CTLs.

Treatment of advanced triple-negative breast cancer (TNBC) is a great challenge in clinical practice. The immune checkpoints are a category of immunosuppressive molecules that cancer could hijack and impede anti-tumor immunity. Targeting immune checkpoints, such as anti-programmed cell death 1 (PD-1) therapy, is a promising therapeutic strategy in TNBC. The efficacy and safety of PD-1 monoclonal antibody (mAb) with chemotherapy have been validated in TNBC patients. However, the precise mechanisms underlying the synergistic effect of chemotherapy and anti-PD-1 therapy have not been elucidated, causing the TNBC patients that might benefit from this combination regimen not to be well selected. In the present work, we found that IL-23, an immunological cytokine, is significantly upregulated after chemotherapy in TNBC cells and plays a vital role in enhancing the anti-tumor immune response of cytotoxic T cells (CTLs), especially in combination with PD-1 mAb. In addition, the combination of IL-23 and PD-1 mAb could synergistically inhibit the expression of Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), which is a regulatory subunit of PI3K and inhibit p110 activity, and promote phosphorylation of AKT in TNBC-specific CTLs. Our findings might provide a molecular marker that could be used to predict the effects of combination chemotherapy therapy and PD-1 mAb in TNBC.

Effect of Influenza Vaccination on Rate of Influenza Virus Infection in Chinese Military Personnel, 2015-2016: A Cluster Randomized Trial.

Influenza is a major cause of morbidity and mortality. The protective effect of a trivalent influenza vaccine (TIV) is undetermined in military personnel. We conducted an open-label, cluster randomized trial on active-duty servicemen of Beijing, Tianjin, and Shijiazhuang, who were randomly assigned to receive either a single dose of TIV or no treatment, according to cluster randomized sampling. The subjects were then followed for a maximum of six months to assess the incidence of laboratory-confirmed influenza. A total of 5445 subjects in 114 clusters received one dose of TIV before the 2015/2016 influenza season. Laboratory-confirmed influenza was identified in 18 in the vaccine group compared with 87 in the control group (6031 subjects in 114 clusters), resulting in a vaccine effectiveness (VE) of 76.4% (95%CI: 60.7 to 85.8) against laboratory-confirmed influenza. Influenza-like illness was diagnosed in 132 in the vaccine group compared with 420 in the control group, resulting in a VE of 64.1% (95%CI: 56.2 to 70.6). The estimated VE against influenza B viruses was 80.5% (95%CI: 65.6 to 88.9) and 8.6% (95%CI: -241 to 75.5) against influenza A viruses. In conclusion, the trivalent influenza vaccine is moderately effective, highly immunogenic, and generally safe to use in healthy male military servicemen.

Identification and validation of a novel mitochondrion-related gene signature for diagnosis and immune infiltration in sepsis.

Background: Owing to the complex pathophysiological features and heterogeneity of sepsis, current diagnostic methods are not sufficiently precise or timely, causing a delay in treatment. It has been suggested that mitochondrial dysfunction plays a critical role in sepsis. However, the role and mechanism of mitochondria-related genes in the diagnostic and immune microenvironment of sepsis have not been sufficiently investigated. Methods: Mitochondria-related differentially expressed genes (DEGs) were identified between human sepsis and normal samples from GSE65682 dataset. Least absolute shrinkage and selection operator (LASSO) regression and the Support Vector Machine (SVM) analyses were carried out to locate potential diagnostic biomarkers. Gene ontology and gene set enrichment analyses were conducted to identify the key signaling pathways associated with these biomarker genes. Furthermore, correlation of these genes with the proportion of infiltrating immune cells was estimated using CIBERSORT. The expression and diagnostic value of the diagnostic genes were evaluated using GSE9960 and GSE134347 datasets and septic patients. Furthermore, we established an in vitro sepsis model using lipopolysaccharide (1 µg/mL)-stimulated CP-M191 cells. Mitochondrial morphology and function were evaluated in PBMCs from septic patients and CP-M191 cells, respectively. Results: In this study, 647 mitochondrion-related DEGs were obtained. Machine learning confirmed six critical mitochondrion-related DEGs, including PID1, CS, CYP1B1, FLVCR1, IFIT2, and MAPK14. We then developed a diagnostic model using the six genes, and receiver operating characteristic (ROC) curves indicated that the novel diagnostic model based on the above six critical genes screened sepsis samples from normal samples with area under the curve (AUC) = 1.000, which was further demonstrated in the GSE9960 and GSE134347 datasets and our cohort. Importantly, we also found that the expression of these genes was associated with different kinds of immune cells. In addition, mitochondrial dysfunction was mainly manifested by the promotion of mitochondrial fragmentation (p<0.05), impaired mitochondrial respiration (p<0.05), decreased mitochondrial membrane potential (p<0.05), and increased reactive oxygen species (ROS) generation (p<0.05) in human sepsis and LPS-simulated in vitro sepsis models. Conclusion: We constructed a novel diagnostic model containing six MRGs, which has the potential to be an innovative tool for the early diagnosis of sepsis.

A High-Quality Nomogram for Predicting Lung Metastasis in Newly Diagnosed Stage IV Thyroid Cancer: A Population-Based Study.

Introduction: Lung metastasis (LM) implies a very dismal event in patients with thyroid cancer. We aimed to construct a nomogram to predict LM for newly diagnosed stage IV thyroid cancer. Methods: A total of 1407 stage IV thyroid cancer patients were gathered from the surveillance, epidemiology, and end results (SEER) database. Pearson's Chi-squared test or Fisher's exact test was used to identify LM-related factors, and logistic regression analysis was employed to identify independent risk parameters of LM, which were included to establish a nomogram model by R software. The discriminative ability and predictive accuracy of the nomogram were assessed using the area under the curve (AUC) and calibration plots. Cox regression analysis and Kaplan-Meier analysis were applied to evaluate the clinical utility of this model. A simulation trial was conducted to verify the health economic value of this nomogram in predicting TCLM. Results: Five variables were found to be independent risk predictors of LM, including grade, histology, N stage, bone metastasis, and liver metastasis. The results of the AUC and calibration curves demonstrated that the nomogram exhibited outstanding performance for predicting the risk of LM patients both internally and externally. The LM prediction risk was an independent prognostic factor for stage IV thyroid cancer patients [P = .009, hazard ratio (HR): 1.812, 95% CI: 1.163-2.824]. Conclusion: We successfully developed a predictive model for stage IV thyroid cancer, which provides important information for identifying patients at high risk of LM and implementing early preventive interventions to improve their outcomes.

A high-quality model for predicting the prognosis of breast neuroendocrine carcinoma to help clinicians decide on appropriate treatment methods: A population-based analysis.

BACKGROUND: Breast neuroendocrine carcinoma (NEC) is a rare malignancy with unclear treatment options and prognoses. This study aimed to construct a high-quality model to predict overall survival (OS) and breast cancer-specific survival (BCSS) and help clinicians choose appropriate breast NEC treatments. PATIENTS AND METHODS: A total of 378 patients with breast NEC and 349,736 patients with breast invasive ductal carcinoma (IDC) were enrolled in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2018. Propensity score matching (PSM) was performed to balance the clinical baseline. Prognostic factors determined by multivariate Cox analysis were included in the nomogram. C-index and calibration curves were used to verify the performance of the nomogram. RESULTS: Nomograms were constructed for the breast NEC and breast IDC groups after PSM. The C-index of the nomograms ranged from 0.834 to 0.880 in the internal validation and 0.818-0.876 in the external validation, indicating that the nomogram had good discrimination. The risk stratification system showed that patients with breast NEC had worse prognoses than those with breast IDC in the low-risk and intermediate-risk groups but had a similar prognosis that those in the high-risk group. Moreover, patients with breast NEC may have a better prognosis when undergoing surgery plus chemotherapy than when undergoing surgery alone or chemotherapy alone. CONCLUSIONS: We established nomograms with a risk stratification system to predict OS and BCSS in patients with breast NEC. This model could help clinicians evaluate prognosis and provide individualized treatment recommendations for patients with breast NEC.

MDN1 Mutation Is Associated With High Tumor Mutation Burden and Unfavorable Prognosis in Breast Cancer.

Background: Breast cancer (BRCA) is the most common cancer worldwide and a serious threat to human health. MDN1 mutations have been observed in several cancers. However, the associations of MDN1 mutation with tumor mutation burden (TMB) and prognosis of BRCA have not been investigated. Methods: Genomic, transcriptomic, and clinical data of 973 patients with BRCA from The Cancer Genome Atlas (TCGA) database were analyzed. The clinical attributes of BRCA based on the MDN1 mutation status were assessed by comparing TMB and tumor infiltrating immune cells. Gene ontology analysis and gene set enrichment analysis (GSEA) were conducted to identify the key signaling pathways associated with MDN1 mutation. Moreover, univariate and multivariate Cox regression analyses were performed to assess the association between prognostic factors and survival outcomes. Finally, nomograms were used to determine the predictive value of MDN1 mutation on clinical outcomes in patients with BRCA. Results: MDN1 was found to have a relatively high mutation rate (2.77%). Compared to the MDN1 wild-type patients, the TMB value was significantly higher in MDN1 mutant patients (p < 0.001). Prognostic analysis revealed that MDN1 mutant patients had a worse survival probability than MDN1 wild-type patients (hazard ratio = 2.91; 95% CI:1.07-7.92; p = 0.036). GSEA revealed samples with MDN1 mutation enriched in retinol metabolism, drug metabolism cytochrome P450, glucuronidation, miscellaneous transport, and binding event pathways. Conclusion: MDN1 mutation was found to be associated with high TMB and inferior prognosis, suggesting that MDN1 mutation may play a potential role in prognosis prediction and immunotherapy guidance in BRCA.

An effective tool for predicting survival in breast cancer patients with de novo lung metastasis: Nomograms constructed based on SEER.

Background & objectives: An effective tool for forecasting the survival of BCLM is lacking. This study aims to construct nomograms to predict overall survival (OS) and breast cancer-specific survival (BCSS) in breast cancer patients with de novo lung metastasis, and to help clinicians develop appropriate treatment regimens for breast cancer lung metastasis (BCLM) individuals. Methods: We gathered clinical data of 2,537 patients with BCLM between 2010 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. Cox regression analysis was employed to identify independent prognostic parameters for BCLM, which were integrated to establish nomograms by R software. The discriminative ability and predictive accuracy of the nomograms were assessed using the concordance index (C-index), receiver operating characteristic (ROC) curves, and calibration plots. Kaplan-Meier analyses were applied to evaluate the clinical utility of the risk stratification system and investigate the survival benefit of primary site surgery, chemotherapy, and radiotherapy for BCLM patients. Results: Two nomograms shared common prognostic indicators including age, marital status, race, laterality, grade, AJCC T stage, subtype, bone metastasis, brain metastasis, liver metastasis, surgery, and chemotherapy. The results of the C-index, ROC curves, and calibration curves demonstrated that the nomograms exhibited an outstanding performance in predicting the prognosis of BCLM patients. Significant differences in the Kaplan-Meier curves of various risk groups corroborated the nomograms' excellent stratification. Primary site surgery and chemotherapy remarkably improved OS and BCSS of BCLM patients whether the patients were at low-risk or high-risk, but radiotherapy did not. Conclusions: We successfully developed prognostic stratification nomograms to forecast prognosis in BCLM patients, which provide important information for indicating prognosis and facilitating individualized treatment regimens for BCLM patients.

Predicting the survival benefit of local surgery in patients aged 70 years or older with stage IV breast cancer: A population-based analysis.

PURPOSE: The aim of this study was to establish individualized nomograms to predict survival outcomes in older female patients with stage IV breast cancer who did or did not undergo local surgery, and to determine which patients could benefit from surgery. METHODS: A total of 3,129 female patients with stage IV breast cancer aged ≥70 years between 2010 and 2015 were included in the Surveillance, Epidemiology, and End Results program. Multivariate Cox regression analysis was used to identify risk factors for overall survival (OS) and breast cancer-specific survival (BCSS). Survival analysis was performed using the Kaplan-Meier plot and log-rank test. Nomograms and risk stratification models were constructed. RESULTS: Patients who underwent surgery had better OS (HR = 0.751, 95% CI [0.668-0.843], P < 0.001) and BCSS (HR = 0.713, 95% CI [0.627-0.810], P < 0.001) than patients who did not undergo surgery. Patients with human epidermal growth factor receptor 2-positive, lung or liver metastases may not benefit from surgery. In the stratification model, low-risk patients benefited from surgery (OS, HR = 0.688, 95% CI [0.568-0.833], P < 0.001; BCSS, HR = 0.632, 95% CI [0.509-0.784], P < 0.001), while patients in the high-risk group had similar outcomes (OS, HR = 0.920, 95% CI [0.709-1.193], P = 0.509; BCSS, HR = 0.953, 95% CI [0.713-1.275], P = 0.737). CONCLUSION: Older female patients with stage IV breast cancer who underwent surgery had better OS and BCSS than those who did not in each specific subgroup. Patients in low- or intermediate-risk group benefit from surgery while those in the high-risk group do not.

Tip60 Suppresses Cholangiocarcinoma Proliferation and Metastasis via PI3k-AKT.

BACKGROUND/AIMS: Aberrant expression of Tip60 is associated with progression in many cancers. However, the role of Tip60 in cancer progression remains contradictory. The aim of this study was to investigate the clinical significance, biological functions and underlying mechanisms of Tip60 deregulation in cholangiocarcinoma (CCA) for the first time. METHODS: Quantitative real-time PCR (QRT-PCR), western blotting and immunohistochemistry staining (IHC) were carried out to measure Tip60 expression in CCA tissues and cell lines. Kaplan-Meier analysis and the log-rank test were used for survival analysis. In vitro, cell proliferation was evaluated by flow cytometry and CCK-8, colony formation, and EDU assays. Migration/ invasion was evaluated by trans-well assays. Phosphokinase array was used to confirm the dominant signal regulated by Tip60. Tumor growth and metastasis were demonstrated in vivo using a mouse model. RESULTS: Tip60 was notably downregulated in CCA tissues, which was associated with greater tumor size, venous invasion, and TNM stage. Down-regulation of Tip60 was associated with tumor progression and poorer survival in CCA patients. In vitro and in vivo studies demonstrated that Tip60 suppressed growth and metastasis throughout the progression of CCA. We further identified the PI3K/AKT pathway as a dominant signal of Tip60 and suggested that Tip60 regulated CCA cell proliferation and metastasis via PT3K-AKT pathway. Pearson analysis revealed that PTEN was positively correlated with the Tip60 level in CCA tissues. CONCLUSION: Tip60, as a tumor suppressor in CCA via the PI3K/AKT pathway, might be a promising therapeutic target or prognostic marker for CCA.

Suppression of miR-16 promotes tumor growth and metastasis through reversely regulating YAP1 in human cholangiocarcinoma.

BACKGROUND & AIMS: Aberrant expression of microRNAs is associated with many cancers progression. Many studies have shown that miR-16 is down-regulated in many cancers. However, its role in cholangiocarcinoma (CCA) is unknown. METHODS: Quantitative real-time PCR (qRT-PCR) was developed to measure miR-16 expression in CCA tissues and cell lines. CCK-8, colony formation and transwell assays were used to reveal the role of miR-16 in CCA cell proliferation and malignant transformation in vitro. The loss-and-gain function was further validated by subcutaneous xenotransplantation and tail vein injection xenotransplantation model in vivo. Dual-luciferase reporter assay was performed to validate the relationship of miR-16 with YAP1. RESULTS: MiR-16 was notably downregulated in CCA tissues, which was associated with tumor size, metastasis, and TNM stage. Both in vitro and in vivo studies demonstrated that miR-16 could suppress proliferation, invasion and metastasis throughout the progression of CCA. We further identified YAP1 as a direct target gene of miR-16 and found that miR-16 could regulate CCA cell growth and invasion in a YAP1-dependent manner. In addition, YAP1 was markedly upregulated in CCA tissues, which was reversely correlated with miR-16 level in tissue samples. Besides, Down-regulation of miR-16 was remarkably associated with tumor progression and poor survival in CCA patients through a Kaplan-Meier survival analysis. CONCLUSIONS: miR-16, as a novel tumor suppressor in CCA through directly targeting YAP1, might be a promising therapeutic target or prognosis biomarker for CCA.

miR-940 Suppresses Tumor Cell Invasion and Migration via Regulation of CXCR2 in Hepatocellular Carcinoma.

Aim. To investigate the expression of miR-940 in the hepatocellular carcinoma (HCC) and its impact on function and biological mechanism in the HCC cells. Methods. Quantitative RT-PCR analysis was used to quantify miR-940 expression in 46 cases of tissues and cells. Transfection of HCC cell lines was performed by miR-940 mimics; the abilities of invasion and migration were assessed through Transwell array. Western blot represents the alteration in expression of CXCR2 by miR-940 mimics. Results. miR-940 expression was decreased significantly in the HCC tissues and the relevant cell lines. miR-940 upregulation suppressed the invasion and migration of HCC cells in vitro. Furthermore, the CXCR2 was downregulated to suppress invasion and migration after miR-940 mimics. Moreover, decreased miR-940 expression was negatively correlated with Edmondson grade (P = 0.008), tumor microsatellite or multiple tumors (P = 0.04), vascular invasion (P = 0.035), and recurrence and metastasis (P = 0.038). Kaplan-Meier analysis demonstrated that decreased miR-940 expression contributed to poor overall survival (P < 0.05). Conclusions. Our findings present that miR-940 acts as a pivotal adaptor of CXCR2 and its transcription downregulated CXCR2 expression to decrease HCC invasion and migration in vitro. Our study suggests that miR-940 may be a novel poor prognostic biomarker for HCC.

Safety, immunogenicity and cross-reactivity of a Northern hemisphere 2013-2014 seasonal trivalent inactivated split influenza virus vaccine, Anflu®.

Anflu® is a seasonal trivalent inactivated split-virion influenza vaccine manufactured by Sinovac Biotech Co., Ltd. The objectives of this study were to evaluate the safety of Anflu® (2013-14 formulation: H1N1, H3N2 and BYAM) in infants and adults and its immunogenicity and cross-reactivity against mismatched influenza B lineage and avian influenza A(H7N9) viruses (hereafter BVIC and H7N9, respectively) in adults. In this phase IV open label trial, infants 6-35 months old (n=61) each received two injections with 28 days apart; adults 18-60 yrs old (n=60) and elderly >60 yrs old (n=61) each received one injection. Information of adverse events was collected through safety observation and follow-up visits. Pre- and post-immune blood samples (day 0 and 21) were collected from subjects ≥18 yrs old to detect hemagglutination inhibition antibody titers and calculate seroprotection rates (SPRs) and seroconversion rates (SCRs). The overall adverse reaction incidence was 1.6% (3/182), and no serious adverse event was reported during the study period. For subjects ≥18 yrs old, the SCRs, SPRs, and the geometric mean titers (GMTs) met the European criteria for all three strains. In addition, the point estimations of SCR, SPR and GMT for BVIC also met the European criteria. Six subjects were seroconverted against H7N9; however the serological results did not meet the European criteria. In conclusion, the results showed a satisfactory safety and immunogenicity profile of Anflu® and cross-reactivity against BVIC, but did not demonstrate cross-reactivity against H7N9 (Clinicaltrials.gov ID: NCT02269852).