Proof of concept nanotechnological approach to in vitro targeting of malignant melanoma for enhanced immune checkpoint inhibition.

Immunotherapies, including immune checkpoint inhibitors, have limitations in their effective treatment of malignancies. The immunosuppressive environment associated with the tumor microenvironment may prevent the achievement of optimal outcomes for immune checkpoint inhibitors alone, and nanotechnology-based platforms for delivery of immunotherapeutic agents are increasingly being investigated for their potential to improve the efficacy of immune checkpoint blockade therapy. In this manuscript, nanoparticles were designed with appropriate size and surface characteristics to enhance their retention of payload so that they can transmit their loaded drugs to the tumor. We aimed to enhance immune cell stimulation by a small molecule inhibitor of PD-1/PD-L1 (BMS202) using nanodiamonds (ND). Melanoma cells with different disease stages were exposed to bare NDs, BMS202-NDs or BMS202 alone for 6 h. Following this, melanoma cells were co-cultured with freshly isolated human peripheral blood mononuclear cells (hPBMCs). The effects of this treatment combination on melanoma cells were examined on several biological parameters including cell viability, cell membrane damage, lysosomal mass/pH changes and expression of γHA2X, and caspase 3. Exposing melanoma cells to BMS202-NDs led to a stronger than normal interaction between the hPBMCs and the melanoma cells, with significant anti-proliferative effects. We therefore conclude that melanoma therapy has the potential to be enhanced by non-classical T-cell Immune responses via immune checkpoint inhibitors delivered by nanodiamonds-based nanoparticles.

Pharmacogenetic association between NAT2 gene polymorphisms and isoniazid induced hepatotoxicity: trial sequence meta-analysis as evidence.

Hepatotoxicity is a severe problem generally faced by tuberculosis (TB) patients. It is a well-known adverse reaction due to anti-TB drugs in TB patients undergoing long-term treatment. The studies published previously have explored the connection of N-acetyltransferase 2 (NAT2) gene polymorphisms with isoniazid-induced hepatotoxicity, but the results obtained were inconsistent and inconclusive. A comprehensive trial sequence meta-analysis was conducted employing 12 studies comprising 3613 controls and 933 confirmed TB cases using the databases namely, EMBASE, PubMed (Medline) and Google Scholar till December 2017. A significant association was observed with individuals carrying variant allele at position 481C>T (T vs. C: P = 0.001; OR = 1.278, 95% CI = 1.1100-1.484), at position 590G>A (A vs. G: P = 0.002; OR = 1.421, 95% CI = 1.137-1.776) and at position 857G>A (A vs. G: P = 0.0022; OR = 1.411, 95% CI = 1.052-1.894) to higher risk of hepatotoxicity vis-à-vis wild-type allele. Likewise, the other genetic models of NAT2 gene polymorphisms have also shown increased risk of hepatotoxicity. No evidence of publication bias was observed. These results suggest that genetic variants of NAT2 gene have significant role in isoniazid induced hepatotoxicity. Thus, NAT2 genotyping has the potential to improve the understanding of the drug-enzyme metabolic capacity and help in early predisposition of isoniazid-induced hepatotoxicity.

Correction: Hasona, N.A. and Elasbali, A. Evaluation of Electrolytes Imbalance and Dyslipidemia in Diabetic Patients. Med. Sci. 2016, 4, 7.

The authors wish to make the following correction to their paper [1]. In the discussion section, the sentence "Regarding the lipid profile, the present results revealed a significant increase (p < 0.001) in the serum levels of cholesterol, triglycerides and HDL-cholesterol in all diabetics relative to all non-diabetic subjects". This should be changed to "Regarding the lipid profile, the present results revealed a significant increase (p < 0.001) in the serum levels of cholesterol and triglycerides and a significant decrease in HDL-cholesterol in all diabetics relative to all non-diabetic subjects".[...].

Evaluation of Electrolytes Imbalance and Dyslipidemia in Diabetic Patients.

Electrolytes and Lipids have always played significant roles, and changes in their concentrations gives good indications of disease progression in a number of non-communicable diseases. Diabetes mellitus is the most common metabolic disorder in the community. Diabetics may suffer from electrolyte disorders due to complications of diabetes mellitus and the medication they receive. Serum glucose, electrolytes (Na⁺, K⁺, Cl- and Ca++), and lipid profiles (total cholesterol, triglyceride, and HDL-c) were determined in 100 diabetics and in non-diabetic subjects. All the diabetic patients had a significant (p < 0.001) increase in glucose, total cholesterol, triglyceride, chloride and calcium levels. There was significant (p < 0.001) decrease in the serum levels of Na⁺ and K⁺ in all diabetics. It was concluded that differences in lipids and electrolytes found in diabetics may have great potential as a diagnostic tool in clinical practice and have a significant effect upon the risk of contracting many diseases.

The normal cellular prion protein and its possible role in angiogenesis.

Cellular Prion Protein (PrPc) is a ubiquitous glycoprotein present on the surface of endothelial cells. Resting vascular endothelial cells show minimum expression of PrPc and can constitutively release PrPc. PrPc participates in cell survival, differentiation and angiogenesis. During development, neonatal brain endothelial cells transiently express PrPc. Our group recently reported upregulation of PrPc in microvessels from ischemic brain regions in stroke patients. Ischemia/hypoxia induces PrPc expression through the activation of extracellular signal-regulated kinase (ERK). All these data suggest that PrPc plays an important role in angiogenic responses. In addition, PrPc participates in cellular function in the central nervous system, since PrPc is also highly expressed in neurons. PrPc binds copper, suggesting a role in copper metabolism. PrPc also protects cells against oxidative stress and it seems to be involved in neuroprotection. Several studies have demonstrated that PrPc prevents cells from apoptosis and subsequent tissue damage. Moreover, PrPc plays an important role in the immune response. Here, we review the multiple functions of PrPc with a special attention to its recently reported role in angiogenesis.