Loss of HRD functional phenotype impedes immunotherapy and can be reversed by HDAC inhibitor in ovarian cancer.

In recent years, homologous recombination deficiency (HRD) has not achieved the expected substantial promotion of immunotherapeutic efficacy in ovarian cancer. This study aims to explore the role of HRD functional phenotype as a powerful biomarker in identifying HRD patients who may benefit from immunotherapy. HRD functional phenotype, namely HRD-EXCUTE, was defined as the average level of the 15 hub genes upregulated in HRD ovarian cancer. A decision tree was plotted to evaluate the critical role of HRD-EXCUTE in HRD patients. Agents inducing HRD-EXCUTE were identified by CMAP web (Connectivity Map). The mechanisms and immunotherapeutic effect of PARPi and HDACi in promoting HRD-EXCUTE was examined in vitro and in vivo. The decision tree plotted on the basis of HRD and HRD-EXCUTE indicated the HRD patients without the HRD functional phenotype were largely unresponsive to immunotherapy, which was validated by the immunotherapeutic cohorts. Furthermore, loss of HRD-EXCUTE in the HRD patients attenuated immunogenicity and inhibited immune cells in tumor microenvironment. Moreover, Niraparib combined with Entinostat induced HRD-EXCUTE by activating the cGAS-STING pathway and increasing the histone acetylation. The combination therapy could enhance the cytotoxicity of immune cells, and promote pro-immune cells infiltrating into ascites, resulting in inhibited ovarian cancer growth. The HRD functional phenotype HRD-EXCUTE was set up as a potent biomarker to identify whether HRD patients can benefit from immunotherapy. Loss of HRD-EXCUTE in HRD patients were largely insensitive to immunotherapy. The combination of PARPi with HDACi could improve the efficacy of the PARPi-based immunotherapy in ovarian cancer by augmenting the HRD functional phenotype.

A Krasnoselskii-Mann Algorithm With an Improved EM Preconditioner for PET Image Reconstruction.

This paper presents a preconditioned Krasnoselskii-Mann (KM) algorithm with an improved EM preconditioner (IEM-PKMA) for higher-order total variation (HOTV) regularized positron emission tomography (PET) image reconstruction. The PET reconstruction problem can be formulated as a three-term convex optimization model consisting of the Kullback-Leibler (KL) fidelity term, a nonsmooth penalty term, and a nonnegative constraint term which is also nonsmooth. We develop an efficient KM algorithm for solving this optimization problem based on a fixed-point characterization of its solution, with a preconditioner and a momentum technique for accelerating convergence. By combining the EM precondtioner, a thresholding, and a good inexpensive estimate of the solution, we propose an improved EM preconditioner that can not only accelerate convergence but also avoid the reconstructed image being "stuck at zero." Numerical results in this paper show that the proposed IEM-PKMA outperforms existing state-of-the-art algorithms including, the optimization transfer descent algorithm and the preconditioned L-BFGS-B algorithm for the differentiable smoothed anisotropic total variation regularized model, the preconditioned alternating projection algorithm, and the alternating direction method of multipliers for the nondifferentiable HOTV regularized model. Encouraging initial experiments using clinical data are presented.

Association Between 12 Polymorphisms of VEGF/Hypoxia/Angiogenesis Pathway Genes and Risk of Urogenital Carcinomas: A Meta-Analysis Based on Case-Control Studies.

Objective: Previous studies indicated potential associations between polymorphisms in genes of VEGF/hypoxia/angiogenesis pathway and risk of urogenital carcinomas However, the results were controversial and inconclusive. Here, we conducted an in-depth meta-analysis to investigate the precise associations between polymorphisms in VEGF/hypoxia/angiogenesis related genes and risk of urogenital carcinomas. Methods: We searched PubMed, Web of Science, EMBASE, and Cochrane Library to identify all eligible publications. Pooled odds ratios (ORs) corresponding with the 95% confidence intervals (CIs) were calculated to evaluate their associations. Subgroup analysis was conducted to further ascertain such relationship and investigate sources of heterogeneity. Results: In the end, a total of 96 case-control studies fulfilled the inclusion criteria were enrolled for 12 polymorphisms in 4 VEGF/hypoxia/angiogenesis related genes. The pooled results showed eNOS-rs2070744 polymorphism conferred a significantly increased overall risk of urogenital carcinomas in allele, homozygote, and recessive models, respectively. In addition, eNOS-Intron 4a/b VNTR polymorphism was identified related to an increased risk of urogenital carcinomas in recessive model. And VEGF-rs699947 polymorphism was also identified an increased risk of renal cell carcinoma (RCC) in allelic, heterozygote, dominant, homozygote, and recessive models. Conclusion: To conclude, eNOS-rs2070744 and eNOS-Intron 4a/b VNTR polymorphisms are risk factors for urogenital carcinomas. VEGF-rs699947 polymorphism was also identified as an increased risk factor for renal carcinoma.

ß-catenin, leucine-rich repeat-containing G protein-coupled receptor 5 and GATA-binding factor 6 are associated with the normal mucosa-adenoma-adenocarcinoma sequence of colorectal tumorigenesis.

In the present study, the expression of ß-catenin, leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) and GATA6 was investigated during the transition from normal mucosa through to adenoma and adenocarcinoma in colorectal tissue sections obtained from 65 patients with a pathological diagnosis of colorectal adenocarcinoma and a history of adenoma. Immunohistochemical staining of ß-catenin, LGR5 and GATA6 was performed and evaluated. The nuclear expression of ß-catenin and the cytoplasmic expression of LGR5 and GATA6 were increased in samples as they progressed from normal mucosa to adenoma and adenocarcinoma. However, membrane-bound ß-catenin and nuclear GATA6 expression decreased. Positive correlations were observed between the expression of LGR5 and cytoplasmic GATA6 in adenoma (P=0.0005; rs=0.48) and adenocarcinoma samples (P=0.007; rs=0.38): However, no significant association was observed in normal mucosa (P=0.399). The expression of nuclear ß-catenin was significantly increased in the serosal layer compared with the invasive layers of the colorectal wall in samples of adenocarcinoma (P=0.042). The results of the present study suggest that the nuclear expression of ß-catenin and LGR5 and the cytoplasmic expression of GATA6 function together during the development of colorectal carcinoma.

Transforming growth factor-ß1 contributes to oxaliplatin resistance in colorectal cancer via epithelial to mesenchymal transition.

Transforming growth factor-ß1 (TGF-ß1), secreted by main components of tumor microenvironment, is considered to be closely associated with cancer development and chemoresistance. The present study aimed to analyze the effects and mechanisms underlying TGF-ß1-induced chemoresistance to oxaliplatin (LOH) in human colorectal cancer (CRC) cell lines. The cytotoxic effects of LOH subsequent to TGF-ß1 treatment were assessed in three CRC cell lines by MTT assay. In addition, epithelial to mesenchymal transition (EMT), DNA damage and apoptosis assays were performed to evaluate the mechanisms of drug resistance in vitro. It was revealed that an exposure of CRC cells to TGF-ß1 induced EMT. This was followed by a decrease in the levels of DNA damage and LOH-induced apoptotic cell death at certain TGF-ß1 concentrations compared with untreated cells, which was responsible for LOH resistance. TGF-ß1 leads to resistance to LOH in CRC cells, primarily through EMT. These data not only provide insight into the understanding of the chemoresistant mechanisms, but also may guide the clinical applications of reducing EMT to enhance the sensitivity to chemotherapy, by targeting TGF-ß1.

High Expression of Long Noncoding RNA MALAT1 Indicates a Poor Prognosis and Promotes Clinical Progression and Metastasis in Bladder Cancer.

BACKGROUND: Recent studies have demonstrated that the expression of long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes cancer cell proliferation, invasion, and metastasis in many tumor types, but the association between bladder cancer and MALAT1 remains unknown. MATERIALS: The expression of MALAT1 was tested by in situ hybridization (ISH) in 120 bladder cancer specimens. The association between MALAT1 expression and clinicopathological features and prognosis of the patients with bladder cancer was analyzed. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify the relationship between the expression of MALAT1 and progression and metastasis of bladder cancer. RESULTS: ISH showed that high MALAT1 expression was associated with advanced histological grade, high tumor stage, and positive lymph nodes. Kaplan-Meier survival analysis and Cox regression analysis indicated that high tumor stage, positive lymph nodes, and high MALAT1 expression were independent prognostic indicators for overall survival (OS) of patients with bladder cancer. qRT-PCR showed that the expression of MALAT1 in bladder cancer tissues was 2.85 times higher than those measured in adjacent normal tissues (P < .001). The expression of MALAT1 was 2.673 ± 0.254 in non-muscle-invasive bladder cancer and 2.987 ± 0.381 in muscle-invasive bladder cancer (P = .018). In bladder cancer specimens with positive lymph nodes, MALAT1 expression was 3.167 ± 0.297 versus 2.896 ± 0.329 in bladder cancer specimens with negative lymph nodes (P = .020). CONCLUSION: High MALAT1 expression could serve as an independent prognostic factor for OS of patients with bladder cancer and could be considered as a potential therapeutic target of bladder cancer.

Validation of the chinese version of the EORTC QLQ-CR29 in patients with colorectal cancer.

AIM: To assess the validity and reliability of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal Cancer 29 (EORTC QLQ-CR29) in Chinese patients with colorectal cancer (CRC). METHODS: From March 2014 to January 2015, 356 patients with CRC from four different hospitals in China were enrolled in the study, and all patients self-administered the EORTC QLQ-CR29 and the quality of life core questionnaire (EORTC QLQ-C30). Evaluation of the scores was based on the Karnofsky Performance Scale (KPS). The reliability and validity of the questionnaires were assessed by Cronbach's α coefficient, the Spearman correlation test and Wilcoxon rank sum test. RESULTS: The EORTC QLQ-CR29 showed satisfactory reliability (α > 0.7), although the urinary frequency and blood and mucus in stool dimensions had only moderate reliability (α = 0.608). The multitrait scaling analyses showed good convergent (r > 0.4) and discriminant validity. Significant differences were obtained for each item in the different KPS subgroups (KPS ≤ 80; KPS > 80). Body image and most single-item dimensions showed statistically significant differences in patients with a stoma compared with the rest of the patients. CONCLUSION: The EORTC QLQ-CR29 exhibits high validity and reliability in Chinese patients with CRC, and can therefore be recommended as a valuable tool for the assessment of quality of life in these patients.