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Non‐small cell lung cancer (NSCLC) is one of the most common types of cancer in the world and has a 5‐year survival rate of ~20%. Immunotherapies have shown promising results leading to durable responses, however, they are only effective for a subset of patients. To determine the best therapeutic approach, a thorough and in‐depth profiling of the tumour microenvironment (TME) is required. The TME is a complex network of cell types that form an interconnected network, promoting tumour cell initiation, growth and dissemination. The stroma, immune cells and endothelial cells that comprise the TME generate a plethora of cytotoxic or cytoprotective signalling pathways. In this review, we discuss immunotherapeutic targets in NSCLC tumours and how the TME may influence patients' response to immunotherapy. [ABSTRACT FROM AUTHOR]

End-stage renal disease patients on chronic hemodialysis (HD) patients are at risk for both hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, and they may coexist. To de-termine the prevalence and clinical impact of HBV and HCV infection, we studied poly chain reaction (PCR) and reverse transcription (RT)-PCR on the blood samples of 90 HD patients in Kerman, Iran. ELISA test was used to detect anti-HBc, anti-HBs and HBsAg. We found that 30 out of 90 (33.3%) patients were PCR-RT-PCR positive for HCV-RNA. No HBV-DNA (0%) was detected through the PCR study in both positive and negative HCV-RNA patient groups. Though none of the samples was HBsAg positive, 10 (33.3%) HCV-RNA positive patients were anti-HBc positive, and 12 (40.7%) were anti-HBs positive. We conclude that prevalence of hepatitis C infection is high in HD patients in our region, but not associated with active HBV infection.

This report analyzes nuclear receptor (NR) subfamily 4A's potential role in treating those diagnosed with breast cancer. Here we reviewed the current literature on NR4 family members. We also examined the relative gene expression of the NR4A receptor subfamily in the basal, HER2 (human epidermal growth factor receptor 2) positive, luminal A, and luminal B subtypes using data from tumor samples in The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). These data showed a positive link between NR4A1-NR4A3 expression and increased overall survival and relapse-free survival in breast cancer patients. In addition, we observed that high expression of NR4A1, NR4A2, and NR4A3 led to better survival. Furthermore, NR4A family genes seem to play an essential regulatory role in glycolysis and oxidative phosphorylation in breast cancer. The novel prognostic role of the NR4A1–NR4A3 receptors implicates these receptors as important mediators controlling breast cancer metabolic reprograming and its progression. The review establishes a strong clinical basis for the investigation of the cellular, molecular, and physiological roles of NR4A genes in breast cancer. [ABSTRACT FROM AUTHOR]

• Updating UNO limiters for working on wavelet-based adapted centered and non-centered cells. • Providing of the first-order systems of generalized saturated thermo-elastic media. • The first-order systems include Cartesian coordinates and asymmetric spherical coordinate. The uniformly non-oscillatory (UNO) limiters with second-order accuracy are updated to handle nonuniform cell obtained from wavelet-based cell adaptation. These limiters are then used in the cell-adaptive second-order Kurganov-Tadmor (KT) central high resolution scheme. Over the adapted cells, the performance of the UNO limiters are compared with the generalized MINMOD (GMM) limiter with the total variation diminishing (TVD) feature, by measuring error of reconstruction of some functions and also by numerical solution of some benchmark partial differential equations (PDEs). Then, unified forms of generalized fully-coupled saturated thermo-poro-elastic systems are presented as first-order hyperbolic-parabolic systems in the 2D Cartesian and the asymmetric spherical coordinates. For these systems, corresponding flux, source (load), diffusion and nonlinear terms are derived. It is shown that in the case of the asymmetric spherical coordinate, due to the geometry, considerable complexities are introduced in the load (source) and flux terms. Finally, the coupled 1D and 2D systems are simulated by the adaptive central KT scheme with the GMM and UNO limiters. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma (GBM), the most aggressive and common form of glioma, accounts for over 13,000 death per year in the United States which indicates the importance of developing novel strategies for the treatment of this fatal malignancy. Although Arsenic trioxide (ATO) hinders the growth and survival of GBM cells, the requirement of concentrations higher than 4 µM for triggering apoptotic cell death has questioned its safety profile. Since the NF-κB signaling pathway plays a crucial role in tumorigenesis and chemo-resistance, targeting this oncogenic pathway may sensitize GBM cells to lower concentrations of ATO. Methods: Anti-tumor effects of ATO as monotherapy and in combination with Bay 11-7082 were determined using MTT, crystal violet staining, Annexin V/PI staining and scratch assays. Quantitative reverse transcription-PCR (qRT-PCR) analysis was applied to elucidate the molecular mechanisms underlying the anti-tumor activity of this combination therapy. Results: Our results revealed that ATO and Bay 11-7082 synergistically inhibited the proliferation and survival of GBM cells. Also, it was revealed that NF-κB inhibition using Bay 11-7082 enhanced the inhibitory effects of ATO on migration of GBM cells via suppressing the expression of NF-κB target genes such as TWIST, MMP2, ICAM-1, and cathepsin B. Furthermore, combination treatment of GBM cells with ATO and Bay 11-7082 significantly induce apoptotic cell death coupled with downregulation of NF-κB anti-apoptotic target genes including Bcl-2 and IAP family members. Conclusions: Altogether, these findings suggest that combination therapy with ATO and Bay 11-7082 may be a promising strategy for the treatment of GBM. [ABSTRACT FROM AUTHOR]

Posttranscriptional regulation is a mechanism for the cells to control gene regulation at the RNA level. In this process, RNA‐binding proteins (RBPs) play central roles and orchestrate the function of RNA molecules in multiple steps. Accumulating evidence has shown that the aberrant regulation of RBPs makes contributions to the initiation and progression of tumorigenesis via numerous mechanisms such as genetic changes, epigenetic alterations, and noncoding RNA‐mediated regulations. In this article, we review the effects caused by RBPs and their functional diversity in the malignant transformation of cancer cells that occurs through the involvement of these proteins in various stages of RNA regulation including alternative splicing, stability, polyadenylation, localization, and translation. Besides this, we review the various interactions between RBPs and other crucial posttranscriptional regulators such as microRNAs and long noncoding RNAs in the pathogenesis of cancer. Finally, we discuss the potential approaches for targeting RBPs in human cancers. [ABSTRACT FROM AUTHOR]

A little number of current autophagy inhibitors may have beneficial effects on the acute myeloid leukemia (AML) patients. However, there is a strong need to figure out which settings should be activated or inhibited in autophagy pathway to prevail drug resistance and also to improve current treatment options in leukemia. Therefore, this study aimed to compare the effects of well‐known inhibitors of autophagy (as 3‐MA, BafA1, and HCQ) in leukemia KG‐1 and HL‐60 cells exposed to arsenic trioxide (ATO) and/or all‐trans retinoic acid (ATRA). Cell proliferation and cytotoxicity of cells were examined by MTT assay. Autophagy was studied by evaluating the development of acidic vesicular organelles, and the autophagosomes formation was investigated by acridine orange staining and transmission electron microscopy. Moreover, the gene and protein expressions levels of autophagy markers (ATGs, p62/SQSTM1, and LC‐3B) were also performed by qPCR and western blotting, respectively. The rate of apoptosis and cell cycle were evaluated using flow cytometry. We compared the cytotoxic and apoptotic effects of ATO and/or ATRA in both cell lines and demonstrated that some autophagy markers upregulated in this context. Also, it was shown that autophagy blockers HCQ and/or BafA1 could potentiate the cytotoxic effects of ATO/ATRA, which were more pronounced in KG‐1 cells compared to HL‐60 cell line. This study showed the involvement of autophagy during the treatment of KG‐1 and HL‐60 cells by ATO/ATRA. This study proposed that therapy of ATO/ATRA in combination with HCQ can be considered as a more effective strategy for targeting leukemic KG‐1 cells. [ABSTRACT FROM AUTHOR]

Generation of induced pluripotent stem cells (iPSCs) has been described as a powerful method to dedifferentiate the specialized cells to pluripotency. However, obtaining cancer-specific iPS cells (iPCs) encounters several barriers. The generation of iPCs provides valuable experimental platforms to mimic oncogenesis and offers potentials regarding drug screening. To overcome the difficulties regarding the iPC generation, we aimed at optimizing the generation of iPCs from glioblastoma multiform (GBM) cell lines and at understanding the potential barriers ahead of this process. The T731, T653, and mouse embryonic fibroblast cells were transduced by using retroviral plasmids encoding Oct4, Sox2, and Klf4. The cells were cultured on a layer of feeder cells for 14 days in iPS media and the obtained colonies were then picked and expanded to be evaluated for pluripotency markers by alkaline phosphatase staining, qRT-PCR, and Western blotting. Our findings confirmed resistance in cancer cells to achieve the pluripotency markers. In addition to designing technical tricks to obviate the barriers ahead of iPC generation, we suggested the small molecule PD98059 to enhance the efficiency of iPC generation from GBM cell lines. The resulting iPCs can further be used as a platform to study the mechanism of cancer formation and as a tool for drug screening for the treatment of patients with GBM. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer (EOC) has exhibited marginal improvement in survival rate, despite advances in surgical debulking and chemotherapy regimens. Although the majority of EOC patients achieve a clinical remission after induction therapy, over 80% relapse and succumb to chemoresistant disease. In this regard, it is of paramount importance to elucidate molecular mechanisms and signaling pathways which promote therapy resistance in EOC in order to devise novel and more effective treatment strategies. In this study, we showed that activation of nuclear factor-κB (NF-κB) is significantly higher in therapy-resistant EOC cells compared to chemosensitive counterparts, which was positively associated with resistance to cisplatin, carboplatin, paclitaxel and erlotinib. Bay 11-7082, a highly selective NF-κB inhibitor, reduced cell proliferation, clonogenicity and anoikis resistance in the therapy-resistant EOC cells and induced apoptotic cell death. Moreover, Bay 11-7082 decreased the expression of pro-survival, inflammatory and metastatic genes and synergistically increased anti-proliferative efficacy of cisplatin, carboplatin, paclitaxel and erlotinib. Altogether, these findings suggest that NF-κB is an attractive therapeutic target in EOC to be exploited in translational oncology and Bay 11-7082 is a potential anti-cancer drug to overcome chemoresistance and inhibit proliferation of the EOC cells. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) remains one of the most fatal human malignancies due to its high angiogenic and infiltrative capacities. Even with optimal therapy including surgery, radiotherapy and temozolomide, it is essentially incurable. GBM is among the most neovascularised neoplasms and its malignant progression associates with striking neovascularisation, evidenced by vasoproliferation and endothelial cell hyperplasia. Targeting the pro-angiogenic pathways is therefore a promising anti-glioma strategy. Here we show that tivozanib, a pan-inhibitor of vascular endothelial growth factor (VEGF) receptors, inhibited proliferation of GBM cells through a G2/M cell cycle arrest via inhibition of polo-like kinase 1 (PLK1) signalling pathway and down-modulation of Aurora kinases A and B, cyclin B1 and CDC25C. Moreover, tivozanib decreased adhesive potential of these cells through reduction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Tivozanib diminished GBM cell invasion through impairing the proteolytic cascade of cathepsin B/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase-2 (MMP-2). Combination of tivozanib with EGFR small molecule inhibitor gefitinib synergistically increased sensitivity to gefitinib. Altogether, these findings suggest that VEGFR blockade by tivozanib has potential anti-glioma effects in vitro. Further in vivo studies are warranted to explore the anti-tumour activity of tivozanib in combinatorial approaches in GBM.

Breast cancer (BC) is the most frequently diagnosed malignancy in women and a major public health concern. The Hippo pathway is an evolutionarily conserved signaling pathway that serves as a key regulator for a wide variety of biological processes. Hippo signaling has been shown to have both oncogenic and tumor-suppressive functions in various cancers. Core components of the Hippo pathway consist of various kinases and downstream effectors such as YAP/TAZ. In the current report, differential expression of Hippo pathway elements as well as the correlation of Hippo pathway mRNAs with various clinicopathologic characteristics, including molecular subtypes, receptor status, and methylation status, has been investigated in BC using METABRIC and TCGA datasets. In this review, we note deregulation of several Hippo signaling elements in BC patients. Moreover, we see examples of negative correlations between methylation of Hippo genes and mRNA expression. The expression of Hippo genes significantly varies between different receptor subgroups. Because of the clear associations between mRNA expression and methylation status, DNA methylation may be one of the mechanisms that regulate the Hippo pathway in BC cells. Differential expression of Hippo genes among various BC molecular subtypes suggests that Hippo signaling may function differently in different subtypes of BC. Our data also highlights an interesting link between Hippo components' transcription and ER negativity in BC. In conclusion, substantial deregulation of Hippo signaling components suggests an important role of these genes in breast cancer. [Display omitted] • Hippo signaling has been shown to have both oncogenic and tumor-suppressive functions in various cancers. • The expression of Hippo genes significantly varied between different breast cancer subtypes. • DNA methylation could be one of the mechanisms that regulate the Hippo pathway in breast cancer cells. • The expression of Hippo genes significantly varied between different receptor subgroups. [ABSTRACT FROM AUTHOR]

R273 --> 815.8 --> Background: Treatment of patients with triple‐negative breast cancer (TNBC) has been challenging due to the absence of well‐defined molecular targets and high invasive and proliferative capacities of these cells. Current treatments against TNBC have shown minimal activity due to the high recurrence rate in the patients. There is, therefore, a pressing need for novel and efficacious therapies against TNBC. Here, we found a novel small molecule inhibitor with potent anti‐tumor activity against TNBC cells. Methods: Anti‐proliferative effects of NSC small molecule inhibitor were determined using 2D and 3D culture cell proliferation assays. Using proteomics, NGS and enrichment analysis, we globally investigated top regulatory pathways affected by this compound in TNBC cells. Subsequently, we validated the proteomics and NGS analysis data using seahorse and enzymatic assays. Finally, we showed the inhibitor anti‐tumor effects in vivo. Data were evaluated in triplicate against untreated control cells. Data were graphed and analyzed using GraphPad Prism Software 8.0 using one‐way ANOVA and the unpaired two‐tailed Student's t‐test. Results: In this report, we showed that a novel NSC small molecule inhibitor reduced the proliferation of TNBC cells. Proteomic analysis confirmed a significant metabolic reprograming including suppression of glycolysis and oxidative phosphorylation after treatment. Furthermore, we found that treatment with NSC small molecule inhibitor impaired glycolysis and oxidative phosphorylation via modulating the activity of metabolic regulator enzymes. Conclusions: Altogether, our data indicate that NSC small molecule inhibitor may exhibit anti‐tumor activity in TNBC cells and provide a rationale for further investigation of the potential of NSC small molecule inhibitor as an attractive therapeutic drug for TNBC. Further in‐depth investigations are required to evaluate the exact targets and mechanism of this potent small molecule inhibitor, and its anti‐neoplasm effects on TNBC in vivo. [ABSTRACT FROM AUTHOR]

Nischarin (Nisch) is a cytosolic scaffolding protein that harbors tumor-suppressor-like characteristics. Previous studies have shown that Nisch functions as a scaffolding protein and regulates multiple biological activities. In the current study, we prepared a complete Nisch knockout model, for the first time, by deletion of exons 5 and 6. This knockout model was confirmed by Qrt–PCR and Western blotting with products from mouse embryonic fibroblast (MEF) cells. Embryos and adult mice of knockouts are significantly smaller than their wild-type counterparts. Deletion of Nisch enhanced cell migration, as demonstrated by wound type and transwell migration assays. Since the animals were small in size, we investigated Nisch's effect on metabolism by conducting several assays using the Seahorse analyzer system. These data indicate that Nisch null cells have lower oxygen consumption rates, lower ATP production, and lower levels of proton leak. We examined the expression of 15 genes involved in lipid and fat metabolism, as well as cell growth, and noted a significant increase in expression for many genes in Nischarin null animals. In summary, our results show that Nischarin plays an important physiological role in metabolic homeostasis. [ABSTRACT FROM AUTHOR]