Current Molecular Medicine - Volume 18, Issue 4, 2018

Background: Exacerbated proliferation of cancer cells in nascent tumors leads to the genesis of a hypoxic microenvironment, which is associated with poor patient prognosis, because these stress conditions enhance migratory, invasive and metastatic capacities of tumor cells. These changes are associated with the induction of the hypoxia-inducible factors (HIFs, mainly HIF1α) and increased expression of target genes, including Caveolin-1 (CAV1). Results from our group have shown that CAV1 expression in metastatic cancer cells promotes cell migration/invasion in vitro and metastasis in vivo in a manner dependent on tyrosine-14 phosphorylation by src family kinases. Here, we evaluated whether hypoxia-induced expression of CAV1 was required for hypoxia-dependent migration and invasion in cancer cells. Methods: B16-F10 murine melanoma and HT29(US) colon adenocarcinoma cells were exposed to hypoxia (1% O2). CAV1 expression was evaluated by western blotting. Endogenous CAV1 and HIF1α were knocked-down using different shRNA constructs. Cell migration and invasion were evaluated in Boyden Chamber and Matrigel assays, respectively. Results: We observed that hypoxia increased CAV1 protein levels in a HIF1 α- dependent manner, in B16-F10 and HT29(US) cells. Importantly, hypoxia-dependent migration of both tumor cell lines was blocked upon CAV1 knock-down. Likewise, pharmacological inhibition of HIF prevented hypoxia-induced migration and invasion in B16-F10 cells. Finally, hypoxia-induced migration was also blocked by the src-family kinase inhibitor 4-amino-5-(4-chloro-phenyl)-7-(t-butyl) pyrazolo3,4-dpyrimidine (PP2), an inhibitor of CAV1 phosphorylation. Conclusion: Hypoxia induced migration and invasion of metastatic cancer cells require HIF1α-dependent induction of CAV1 expression and src family kinase activation.

Background: IFNL4 polymorphisms are associated with circulating IFN-λ3, and higher plasma IFN-λ3 are associated with higher production of antibodies to HBV surface antigen (anti-HBs). The IFNL4 rs8099917 T allele and anti-HBs development in response to HBV vaccine are associated with better survival in hemodialysis (HD) patients. Objective: To show whether plasma IFN-λ3 is also a predictor of survival in HD patients. Methods: Plasma IFN-λ3 was measured in 135 HD patients who were followed-up for 2.6 years. Survival probability was tested using the Kaplan-Meier method and the Cox proportional hazard model. Results: Plasma IFN-λ3 (ng/L) was 116.8 (20.4–227.5) in survivors on HD (n=89, 65.9%), 75.1 (36.0-228.8) in deceased patients (n=37, 27.4%), and 109.0 (40.0–232.7) in subjects submitted to kidney transplantation (n=9, 6.7%). IFN-λ3 was lower in deceased patients than that in all remaining patients (P=0.039) and patients who continued HD without transplantation (P=0.028). IFN-λ3 and anti-HBs titers were correlated (r=0.587, P<0.000001). Patients showing IFN-λ3 >126.1 ng/L (3rd tertile) presented better survival compared with patients with IFN-λ3 in the 1st (<73.8 ng/L, P=0.005) and 2nd (≥73.8 - <126.1 ng/L, P=0.013) tertiles. Each decrease in IFN-λ3 per 10 ng/L was associated with a hazard ratio equal to 1.076 (95%CI 1.015–1.140, P=0.013). In multivariate analysis, the independent predictors of survival were age (P=0.008), dialysis modality (P=0.038), circulating IFN-λ3 (P=0.044), and diabetic nephropathy (P=0.047), but not gender, dialysis duration prior to the study, mean arterial pressure, BMI, CRP, albumin, 25(OH)D, or anti-HBs. Conclusion: Circulating IFN-λ3 is a promising predictor of HD patient survival.

The mammalian target of rapamycin (mTOR) regulates multiple pathophysiological processes, such as cell development, angiogenesis, autophagy, as well as innate-adaptive immune responses. Numerous studies have demonstrated that mTOR signaling plays an important role in the process of atherosclerosis (AS) itself or AS-related diseases. The activation of mTOR signaling contributes to the endothelium dysfunction and the formation of foam cells via enhancing the process from monocyte to macrophage in the initial stage of atherosclerosis. The activation of mTOR signaling not only promotes the formation of the fatty streak (more foam cells), and migration and proliferation of vascular smooth muscle cells in the early lesion of AS, but also facilitates the formation of vulnerable plaque and replication of vascular smooth muscle cells in the late lesion of AS. Moreover, it has been found the role of the upstream and downstream components of mTOR signaling pathway in the formation of AS. Thus, the mTOR inhibitors may be a promising target for the prevention and treatment of AS.

The concept of minimodeling is defined as a kind of focal bone formation that features the absence of preceding bone absorption by osteoclasts. In the process of minimodeling, osteogenetic and osteoclastic activities are decoupled. Linear boundary between old bone and new bone can be discovered. Frost et al. presumed that minimodeling in trabeculae can continue throughout life. The concept of minimodeling is not new, however its function and nature are still imperfectly understood. Our review will focus on minimodeling-based formation in 5 aspects below: 1. compare the minimodeling with remodeling regarding 10 items; 2. describe the histological observation to characterize remodeling and minimodeling formation sites; 3. present evidence of bone anabolic agents which start bone minimodeling; 4. discuss the mechanism and target cells involved in bone minimodeling; 5. interpretate the increased osteogenic potential and trabecular connectivity with minimodeling-based formation; 6. Depict modeling patterns of the bone implant interface and peri-implant osteogenesis in osteoporosis. This review provides an in-depth knowledge regarding minimodeling comprehensively and its potential contributions in skeletal homeostasis and application prospect in improving the success rate of dental implant in osteoporosis.

Intracerebral hemorrhage (ICH), which accounts for 10% of all strokes, leads to higher morbidity and mortality compared with other stroke subtypes. Hypertension has been recognized as a major risk factor for ICH. Current antihypertensive options have not been fully effective for either prevention of ICH or ameliorating its complications. Therefore, attempts should be made to use novel antihypertensive medications for more effective management of blood pressure (BP) in the acute phase of ICH. Imidazoline receptor (IR) agonists can potentially be effective agents for BP control with the adjunctive ability to attenuate post-ICH brain injury. IR agonists render neuroprotective effects including inhibition of inflammatory reactions, apoptotic cell death, excitotoxicity, and brain edema. Given these properties, the present review aims to focus on the application of IR agonists for managing BP in ICH patients.

Gastrointestinal stromal tumours are the most common mesenchymal tumours of the gastrointestinal tract. Despite similar mutation pattern of activating mutations in KIT or PDGFRA receptors in 85% of cases, they demonstrate significantly heterogeneous clinical behaviour and pathological characteristics. This heterogeneity opens the question of the role of other factors and mechanisms of regulation in the development of GIST. Additional mutations in downstream effectors of GIST related signalling pathways or aberrant expression of non-coding RNAs may be additional contributing factors, the latter being increasingly recognized in carcinogenesis in general. Recently, a substantial progress has been achieved in understanding the functional roles of lncRNAs in GIST suggesting their potential employment as biomarkers and therapeutic targets in GIST. Moreover, some miRNAs have recently been found to be able to sensitize cells to imatinib, which could be an attractive option to overcome the resistance to the drug, which hampers the efficacy of GIST treatment. Therefore, the advantage can be taken of both coding and non-coding parts of the genome in order to significantly improve prognostication and help find personalized therapy for patients, depending on a subtype of GIST and personal characteristics.

Multiple myeloma (MM) is characterized by the clonal proliferation of malignant plasma B-lymphocytes and even as of today, it is an incurable disease. MM accounts for approximately 10% of all hematologic cancers. Its molecular pathogenesis is poorly understood, but the bone marrow microenvironment of tumor cells and genetic factors have apparent roles in the process. Accurate diagnosis is important to properly identify and stratify the disease, however, MM identification steps are time-consuming and expensive. Thus, development of early molecular diagnostic methods is of high importance in order to start proper therapies as early in the disease progression as possible, given the nature of the poor survival rates/remission periods. Molecular diagnostics via analytical omics represents one of the promising toolsets to speed up the diagnostic process. In this paper, we critically review the utilization of state of the art, high sensitivity analytical omics approaches (genomics, proteomics, metabolomics, lipidomics and glycomics) in MM diagnostics at the molecular level.