Current Molecular Medicine - Volume 17, Issue 8, 2017

Immunotherapy aims to amplify the anticancer immune response through reactivation of the lymphocytic response raised against several tumor neo-antigens. To obtain an effective immune response, this therapeutic approach requires that a number of immunological checkpoints be passed, such as the activation of excitatory costimulatory signals or the avoidance of coinhibitory molecules. Among the immune checkpoints, the interaction of the membrane-bound ligand PD-1 and its receptor PD-L1 has received much attention because of remarkable efficacy in numerous clinical trials for various cancer types, including non-small cell lung cancer (NSCLC). However, several limitations exist with these therapeutic agents when used as monotherapy, with objective responses observed in only 30–40% of patients, with the majority of patients demonstrating innate resistance, and approximately 25% of responders later demonstrating disease progression. Recent developments in the understanding of cancer immunology have the potential to identify mechanisms of innate and acquired resistance to immune checkpoint inhibitors through translational research in human samples. This review focuses on the biological basic principles for immunological checkpoint blockade, and highlights the current status and the perspectives of this therapeutic approach in NSCLC patients.

The growing evidence shows that LIM and SH3 Domain Protein 1 (LASP1) is a multi-functional protein that plays important role in forming cytoskeleton and prognostic marker in different cancers. LASP1 expression is correlated with the grade, size, and the metastasis of tumor in clinical samples. And the upregulation of LASP1 facilitates tumor cells proliferation, migration, and invasion perhaps through the interaction with cytoskeleton and increased nuclear translocation. The underlying mechanism of LASP1 on tumor is still in the initial stage; therefore, the signaling pathways in various tumors are specifically summarized to deepen the biological understanding of LASP1. This article systematically summarizes the current status of knowledge regarding the contribution of LASP1 in physiological and pathological processes, especially the progress in tumor. This article also gives an emphasized overview of LASP1 on the correlation with tumor microenvironment.

Today, there are more than 32 million patients with diabetes in the Middle East (ME), the number is expected to double by 2040. In contrast to Europe and North America and despite the high prevalence of diabetes in ME, epidemiological data about incident and types of diabetes in the region is very limited. Maturity-onset diabetes of the young (MODY) is a subtype of monogenic diabetes representing 2-5% of all diabetes patients. The disease is autosomal dominant mode of inheritance characterized by β-cell malfunction below the age of 35 years. To date, there are 15 different MODY forms that have been identified; each has a distinct genetic etiology. It is very common that MODY is misdiagnosed between with type 1 or type 2 diabetes. Hence, accurate genetic diagnosis is crucial to individualize the treatment and to improve glycaemia control. New technologies such as next-generation sequencing (NGS) offer an excellent alternative to screen and identify causative MODY mutations. In this review, we summarize the main clinical and genetic characteristics for each MODY form. In addition, we shed light on MODY studies that have been executed in the ME region.

Background: Cerebral ischemia reperfusion (CIR) injury is the main pathological mechanism of ischemia stroke, and oxidative stress (OS) plays a vital role during the process of CIR. Recent studies have found that OS can activate MAPK pathway, which mainly functions as a mediator of cellular stresses. It revealed that H2S may exhibit multiple biological functions as a neuroprotector through protecting against OS-induced neuronal injury. But how H2S can attenuate ischemia/reoxygenation injury through MAPK signaling is not clear. The protective mechanism of exogenous hydrogen sulfide (H2S) on oxygen glucose deprivation/reoxygenation (OGD/R) at physiological doses in SH-SY5Y cells were investigated in this study. Methods: DCFH- DA probe is used to measure intracellular ROS, Real-time PCR and Western blot are used to detect the levels of p38 MAPK, ERK3 and Nrf2. CCK-8 is used to detect cell viability. Results: Comparing with the normal control group, the expressions of ERK3, p38MAPK and Nrf2 mRNA in other three groups were downregulated at the beginning of 24h. After 24h, the expressions of ERK3, p38MAPK and Nrf2 were upregulated significantly compared with the normal control group. When the cells were pretreated with 200μM NaHS at the beginning of 24h, the expressions of ERK3, p38MAPK and Nrf2 were decreased much more significantly than OGD/R and NaHS groups. Conclusion: The present study demonstrated that exogenous H2S exerts a protective effect against OGD/R-induced injury by enhancing the activation of the ERK3, p38MAPK and Nrf2 mRNA.

Background: Little is known about the pathogenesis of acute lung injury (ALI) complicated with acute aortic dissection (AAD). Objective: We aim to investigate the roles of macrophages-derived matrix metalloproteinase 9 (MMP9) in the development of ALI complicated with AAD and factors involved in the recruitment of macrophages. Methods: This study included three parts: (i) Determination of serum MMPs, angiotensin II (AngII) and MCP-1 in patients with AAD complicated with ALI or AAD only, non-ruptured chronic aortic aneurysm patients or healthy volunteers using ELISA method. (ii) A novel AAD complicated with ALI model was established by infusing angiotensin II (AngII) to immature rats treated with β-aminopropionitrile monofumarate (BAPN) to identify the potential roles of MMP9 and MCP-1 in AAD complicated with ALI. (iii) Cultured pulmonary microvascular endothelial cell (PMVEC) line was used to investigate how AngII was involved in the release of MCP-1 in rat pulmonary vascular endothelial cells. Results: Serum MMP9, AngII and MCP-1 were remarkably elevated in patients with AAD complicated with ALI. The MMP9 expressed in pulmonary tissues was derived from macrophages. In the animal model, the release of MMP9 from macrophages finally resulted in ALI, while inhibition of MMP9 and MCP-1 contributed to decreased incidence of AAD complicated with ALI. In vitro experiments indicated that AngII triggered overexpression of MCP-1 in PMVECs by activating NF-ΚB signaling pathway. Conclusion: AAD complicated with ALI is highly associated with the macrophages infiltrating the pulmonary interstitial tissue and released MMP9 in response to angiotensin II. MCP-1 is closely related to the recruitment of macrophages.

Background: Several SNPs were identified through GWAS for their association with type 2 diabetes which has implications to pancreatic β-cell physiology. Objective: We aimed to study the role of risk alleles of TCF7L2, KCNJ11, CDKN2A, CDKAL1, IGF2BP2, SLC30A8 and KCNQ1 along with pharmacokinetic variants in response to sulfonylureas. Method: We performed a prospective study on 209 newly diagnosed subjects; treatment naive T2D subjects were recruited. Individuals were started with glibenclamide monotherapy and followed-up for 12 weeks. Genotyping was done, using PCR-RFLP and TETRA-ARMS PCR and confirmed by DNA sequencing. Results: In univariate regression analysis, KCNJ11 (rs5219) was only the predictor for glibenclamide treatment failure. Conclusion: The present data suggests a possible role of KCNJ11 gene in altered response to glibenclamide.