The phosphoinositide 3 kinase AKT mammalian target of rapamycin (PI3K-AKTmTOR) signaling pathway is an important in the aetiology of pancreatic cancer (PC) and is frequently activated in PC. It is then associated with a poorer prognosis. Aberrant activation of this pathway is involved in cell metabolism and survival, cell cycle progression, regulation of apoptosis, protein synthesis, and genomic instability. Several agents have been developed to target the Akt/PI3K pathways, including PI3K inhibitors, (e.g. LY294002, Wortmannin), PI3K/mTOR inhibitors (e.g. BEZ235), or Akt inhibitors (e.g. perifosine, MK2206), which have been tested alone or in combinations with DNA-targeted agents (e.g., gemcitabine and fluorouracil) in pancreatic ductal adenocarcinoma (PDAC). However, due to their unfavorable pharmaceutical activities, toxicity, and crossover inhibition of other lipid and protein kinases, these compounds have not been used in clinical studies. In this review, we focus on the progress in the development of Akt, PI3K and mTOR inhibitors for clinical applications, together with the need for the development of in PDAC and the need for the identification of predictive biomarkers and combination strategies with less toxicity in counteracting the mechanisms of resistance to the therapy.

Cervical cancer (CC) is one of the most common cancers among females, and it is most notable in developing countries. The exact etiology of CC is poorly understood; but, smoking, oral contraceptives, immunosuppression, and infection with human papillomavirus (HPV) may increase the risk of CC. There is also an association between CC and oxidative stress. Oxidative stress is caused by a disturbed oxidant‐antioxidant balance in favor of the former, leading to an excessive generation of free radicals, particularly reactive oxygen species (ROS), and subsequently to biological damages. Thus, redox enzymatic and nonenzymatic regulators are required to maintain the redox homeostasis. Dysregulated antioxidants system and the pathogenic role of oxidative stress in CC have been investigated in several clinical and preclinical studies. In this study, we reviewed studies that have addressed the cross‐talk between oxidative stress and CC pathogenesis and resistance to therapy.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a very poor prognosis, and excessive resistance to chemotherapy. MicroRNAs have been shown to play important roles in PDAC oncogenesis as they can act as both oncogenes and tumor suppressor molecules. Altered expression of specific microRNAs in PDAC has diagnostic and prognostic implications. There is growing body of evidence showing the important role of miR-486-5p and miR-938 for discrimination of PDAC patients from healthy subjects and those with chronic pancreatitis. Additionally the diagnostic features of miR-486-5p were comparable with CA 19-9 for the detection of PDAC patients, suggesting its diagnostic value as a blood-based miRNA in PDAC, although further investigations are warranted for validation of this marker. In addition to these applications, several studies have suggested therapeutic potential of some miRNAs in PDAC. In particular, modulations of let-7, miR-29a, miR-17-5p, miR-365, miR-181b, miR-21, miR-221 and miR-96 are reported to be associated with tumor response. Moreover, enforced expression of miR-17-92 inhibits tumourigenicity and increased chemoresistance in PDAC cancer stem cells via TGF-β1 pathway, while overexpression of miR-96 suppresses cell proliferation, migration, and invasion in a manner associated with KRAS downregulation. In this review we attempt to give an overview about recent preclinical and clinical studies that have addressed the potential use of circulating microRNAs as diagnostic and prognostic biomarkers, their use as therapeutic targets and finally, we discuss the possible role of microRNAs in PDAC chemoresistance.

Thrombin initiates proinflammatory signaling responses through activation of protease-activated receptors (PARs) in in vitro and in vivo systems. Proinflammatory signaling function of thrombin increases secretion of proinflammatory cytokines and chemokines, triggers vascular permeability, promotes leukocyte migration, and induces adhesion molecule expression. Thrombin as a potent signaling molecule is strongly implicated in a number of proinflammatory disorders including severe sepsis, cancer, cardiovascular disease, and of special interest in this review neurodegenerative disorders. This review summarizes the role of thrombin in the pathogenesis of central nervous system (CNS) inflammatory diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), promoting greater understanding and clinical management of these diseases. J. Cell. Physiol. 232: 482-485, 2017. © 2016 Wiley Periodicals, Inc.

No abstract

Interferons (INFs) elicit antiviral responses in tumor cells upon binding to cell surface receptors. Oncolytic virotherapy (OV) is an effective antitumor therapeutic approach which in combination with standard radiotherapy or chemotherapy regimens potentiates treatment responses in cancer patients. However, oncolytic viruses are susceptible to the IFN-induced antiviral state in the tumor microenvironment. A number of studies have, therefore, investigated the effects of combined therapy of IFN signaling pharmacological inhibitors with oncolytic viruses, which result in improved virus replication and oncolysis. This review summarizes the current knowledge of the mechanisms of interferon-mediated tumor resistance to oncolytic virotherapy and provides new insights regarding the effectiveness of combinatorial treatment strategies to attenuate INF-induced OV resistance for greater clinical significance in the treatment of cancer patients. J. Cell. Biochem. 118: 1994-1999, 2017. © 2017 Wiley Periodicals, Inc.

Background. Osteosarcoma, the most frequent osteogenic malignancy, has become a serious public health challenge due to its high morbidity rates and metastatic potential. Recently, the neurokinin-1 receptor (NK-1R) is proved to be a promising target in cancer therapy. This study is aimed at determining the effect of aprepitant, a safe and Food and Drug Administration (FDA) approved NK-1R antagonist, on osteosarcoma cell migration and metastasis, and to explore its underlying mechanism of action. Methods. Colorimetric MTT assay was employed to assess cell viability and cytotoxicity. A wound-healing assay was used to examine migration ability. The desired genes’ protein and mRNA expression levels were measured by western blot assay and quantitative real-time PCR (qRT-PCR), respectively. Gelatinase activity was also measured by zymography. Results. We found that aprepitant inhibited MG-63 osteosarcoma cell viability in a dose-dependent manner. We also observed that aprepitant inhibited the migrative phenotype of osteosarcoma cells and reduced the expression levels and activities of matrix metalloproteinases (MMP-2 and MMP-9). Aprepitant also reduced the expression of an angiogenic factor, VEGF protein, and NF-κB as an important transcriptional regulator of metastasis-related genes. Conclusion. Collectively, our observations indicate that aprepitant modulates the metastatic behavior of human osteosarcoma cells, which may be applied to an effective therapeutic approach for patients with metastatic osteosarcoma.

WNT/B-CATENIN signaling pathway is one of the key dysregulated pathways in different tumor types, which regulate the expression of several genes involved in cell proliferation, differentiation, and survival. This pathway is being modulated by sex-determining region Y-box (SOX) family genes. The functions of these genes are suggested as tumor suppressor or oncogene. SOX genes transcribe a group of transcription factors that play important roles in embryonic development and carcinogenesis. Among them, SOX15 is recently been identified as a novel tumor suppressor in pancreatic and esophagus cancers with a potential role in modulating Wnt/b-catenin signaling. This report summarizes the current knowledge about Wnt/b-catenin signaling pathway and its cross talk with SOX15 with particular emphasis on the value of SOX gene expression as prognostic or predictive biomarker in cancer.