Association of Helicobacter Pylori Infection with Endothelial Dysfunction in Metabolic Syndrome

Background: Metabolic risk factors play a critical role in metabolic syndrome (MetS), and endothelial dysfunction is important in its development. On the other hand, Helicobacter pylori (H. pylori) infection has an essential role in MetS. The goal of present study was to evaluate the effect of H. pylori infection on endothelial dysfunction in MetS patients. Methods: Based on the International Diabetes Federation (IDF) criteria, 80 MetS patients (59 females and 21 males, mean age: 48.94 ± 10.00 years) were selected. Plasma samples were assayed for H. pylori IgG using the ELISA method. Endothelial function was also evaluated by measuring plasma concentrations of endothelin-1 (ET-1), E-selectin, and intracellular adhesion molecule-1 (ICAM-1) using ELISA method. Also, NO2– and NO3– concentrations were measured by Griess method. Results: Fifty patients (62.5%) had H. pylori infection. Plasma concentrations of ET- 1, NO2–, and NO3– were significantly higher in MetS patients with positive H. pylori infection than in MetS patients with negative H. pylori infection (ET-1: 2.92 ± 2.33 vs 1.9 ± 1.4 pg/ml; P = 0.037; NO2–:19.46 ± 7.11 vs 15.46 ± 4.56 μM; P = 0.003; NO3–: 20.8 ± 10.53 vs 16.85 ± 6.03 μM, P = 0.036). However, plasma concentrations of ICAM-1 and E-selectin did not show any significant difference in the two groups. Conclusion: The results showed a relationship between H. pylori infection and endothelial dysfunction. H. pylori infection can lead to atherosclerosis by causing chronic inflammation and affecting the factors contributing to the MetS

Therapeutic applications of SAMMSON lncRNA inhibition in uveal melanoma

Uveal melanoma is the most common intraocular malignancy in adults. The lack of an effective treatment results in a median survival time less than one year for patients with metastatic disease. Recently, our lab identified the melanoma-specific long non-coding RNA (lncRNA) SAMMSON as a novel therapeutic target in skin melanoma. Analysis of a PAN cancer RNA-sequencing dataset revealed consistent expression of SAMMSON in uveal melanoma tumors. Although SAMMSON expression was lower in uveal compared to skin melanoma, over 90% of uveal melanoma tumors showed detectable SAMMSON expression. Further analysis also revealed SAMMSON expression in conjunctival melanoma, another form of ocular melanoma. To evaluate the therapeutic potential of SAMMSON inhibition in uveal and conjunctival melanoma, we treated 8 representative cell lines with SAMMSON-specific ASOs and observed a strong reduction in cell viability, accompanied by induction of apoptosis. In line with the role of SAMMSON in modulating mitochondrial metabolism, SAMMSON knock down resulted in decreased mitochondrial oxygen consumption. Uveal melanomas are characterized by activated MEK-signaling through mutations in GNA11/GNAQ. Combining SAMMSON-specific ASOs with the MEK-inhibitor Trametinib, induced strong synergistic effects, resulting in a nearly complete abrogation of tumor cells at nanomolar concentrations of Trametinib. The in vivo effects of SAMMSON inhibition, whether or not in combination with Trametinib, are currently being investigated in a uveal melanoma PDX model. Together, our results demonstrate the efficacy of SAMMSON inhibition as a novel treatment option for uveal melanoma and demonstrate its synergism with MEK inhibition making SAMMSON a promising anti-cancer target for uveal melanoma patients

mTor inhibitor GDC-0349 improves ASO induced SAMMSON knock down resulting in enhanced anti-tumor efficacy in uveal melanoma

Uveal melanoma (UM) is the most common intraocular malignancy in adults. The lack of an effective treatment results in a median survival time of less than one year for patients with metastatic disease and shows the high unmet need for the development of effective treatments. Recently, the melanoma-specific lncRNA SAMMSON was shown to be essential for skin melanoma survival. Analysis of a PAN cancer RNA-sequencing dataset revealed consistent expression of SAMMSON in uveal melanoma tumors. Targeting SAMMSON by means of antisense oligonucleotides (ASOs) results in a strong reduction in cell viability with induction of apoptosis of UM cells and slows down tumor growth in multiple UM PDX models. These effects were driven by impaired mitochondrial function and protein translation, resulting in cell death. To identify potential synergistic combinations, we combined SAMMSON knockdown with a library of 2911 FDA-approved drugs and quantified cell viability in a uveal melanoma cell line. The strongest synergy was obtained with the mTOR inhibitor GDC-0349. Combining SAMMSON knockdown with mTOR inhibition resulted in enhanced impairment of mitochondrial function and protein synthesis. Interestingly, we observed a more pronounced knockdown of SAMMSON when combining SAMMSON targeting ASOs with GDC-0349, suggesting mTOR inhibition facilitates ASO uptake in uveal melanoma cells. Further experiments are ongoing to confirm this mechanism. Taken together, these results demonstrate that SAMMSON inhibition in combination with mTOR inhibition could be a novel treatment option for uveal melanoma patients

HDAC inhibition increases HLA class I expression in uveal melanoma

The treatment of uveal melanoma (UM) metastases or adjuvant treatment may imply immunological approaches or chemotherapy. It is to date unknown how epigenetic modifiers affect the expression of immunologically relevant targets, such as the HLA Class I antigens, in UM. We investigated the expression of HDACs and the histone methyl transferase EZH2 in a set of 64 UMs, using an Illumina HT12V4 array, and determined whether a histone deacetylase (HDAC) inhibitor and EZH2 inhibitor modified the expression of HLA Class I on three UM cell lines. Several HDACs (HDAC1, HDAC3, HDAC4, and HDAC8) showed an increased expression in high-risk UM, and were correlated with an increased HLA expression. HDAC11 had the opposite expression pattern. While in vitro tests showed that Tazemetostat did not influence cell growth, Quisinostat decreased cell sur

Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models

PURPOSE ALK-activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1%-2% of cases. Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single-agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data have suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway. EXPERIMENTAL DESIGN We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin, and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient-derived xenografts (PDX). RESULTS Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with high ALK expression. In this PDX, lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth. CONCLUSIONS In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma

Alterations in juvenile diploid and triploid African catfish skin gelatin yield and amino acid composition: effects of chlorpyrifos and butachlor exposures

Skin is a major by-product of the fisheries and aquaculture industries and is a valuable source of gelatin. This study examined the effect of triploidization on gelatin yield and proximate composition of the skin of African catfish (Clarias gariepinus). We further investigated the effects of two commonly used pesticides , chlorpyrifos (CPF) and butachlor (BUC), on the skin gelatin yield and amino acid composition in juvenile full-sibling diploid and triploid African catfish. In two separate experiments, diploid and triploid C. gariepinus were exposed for 21 days to graded CPF [mean measured: 10, 16, or 31 mg/L] or BUC concentrations [Mean measured: 22, 44, or 60 mg/L]. No differences in skin gelatin yield, amino acid or proximate compositions were observed between diploid and triploid control groups. None of the pesticide treatments affected the measured parameters in diploid fish. In triploids, however, gelatin yield was affected by CPF treatments while amino acid composition remained unchanged. Butachlor treatments did not alter any of the measured variables in triploid fish. To our knowledge, this study is the first to investigate changes in the skin gelatin yield and amino acid composition in any animal as a response to polyploidization and/or contaminant exposure