Vascular ophthalmological side effects associated with antiviral therapy for chronic hepatitis C are related to vascular endothelial growth factor levels.

We have screened for the incidence of vascular ophthalmological side effects (VOSE) in chronic hepatitis C (CHC) patients undergoing pegylated interferon (peg-IFN) plus ribavirin (RBV) therapy and sought evidence for angiogenesis activation. Thirty-four CHC patients were prospectively evaluated (18 patients with 180 microg/week of peg-IFN-alpha2a plus 800mg/day of RBV and 16 with 1.5 microg/kg/week of peg-IFN-alpha2b plus 800-1,200mg/day of RBV). Complete ophthalmological evaluation and serum vascular endothelial growth factor (VEGF) levels were assessed before and at the end of therapy. Thirteen patients (38.2%) developed VOSE, eight (23.5%) featured subconjunctival haemorrhage, and five (14.7%) had evidence of retinopathy - all were unrelated to age, sex, genotype, the type of antiviral schedule used and response to therapy. At the end of treatment, the VOSE group had significantly higher serum VEGF levels than the group of patients without detectable side effects (median 281 [range 106-386] vs 117 [83-225] pg/ml, P=0.05). These differences increased when VEGF values were corrected by platelet count. In the VOSE group, baseline VEGF and VEGF/platelet values were also significantly higher (164 [55-260] vs 64 [21-172] pg/ml, P=0.046; and 0.920 [0.217-1.543] vs 0.320 [0.100-0.661] pg/10(6) platelets, P=0.024, respectively]. In a multivariate model VEGF/platelet values at end of treatment and hepatic fibrosis stage were the only predictors of VOSE development. In 3 out of 13 patients visual acuity was affected and 2 had residual lesions in the follow-up. In this exploratory study, antiviral therapy of CHC frequently induces VOSE, apparently through an activation of angiogenesis.

Prolonged cholestasis after raloxifene and fenofibrate interaction: A case report.

Assigning causality in drug-induced liver injury is challenging particularly when more than one drug could be responsible. We report a woman on long-term therapy with raloxifen who developed acute cholestasis shortly after starting fenofibrate. The picture evolved into chronic cholestasis. We hypothesized that an interaction at the metabolic level could have triggered the presentation of hepatotoxicity after a very short time of exposure to fenofibrate in this patient. The findings of an overexpression of vascular endothelial growth factor in the liver biopsy suggest that angiogenesis might play a role in the persistence of toxic cholestasis.

Whole-exome sequencing analysis in twin sibling males with an anterior cruciate ligament rupture.

Familial predisposition is among the major genetic risk factors for non-contact musculoskeletal tissue injuries. Personal genome sequence shows that different polymorphism profiles may account for the number and the degree of injuries and the recovery time. Genotyping studies allow investigation into genome factors with potential impact on pathogenesis of non-contact ligament injuries. We have studied a family with twin sibling males surgically diagnosed of an anterior cruciate ligament non-contact rupture and non-affected progenitors (father and mother) were subjected to whole exome sequencing (WES) analysis. WES analysis previously carried out on 16 individuals, without ACL injury medical records, were also included in this study for single nucleotide variants (SNVs) and small insertions and deletions detection (indels), variant filtering and to prioritize variants relative to the disease. WES analysis to identify SNVs and indels was performed using open web-based bioinformatics tools. A set of 11 new variants shared by family members can be associated to ACL non-contact injury, including SerpinA11, ARSI, NOCHT4, EPB41, FDFT1, POMC, KIF26A, OLFML2B, ATG7, FAH and WDR6. All of them, except ATG7 and WDR6, have shown a damaging predictive pattern by combinatorial standard predictive scores. In combination to the identified SNVs of EPB41 and SerpinA11 genes, ACTL7A gene showed a predicted deleterious variant reinforcing the idea these variants impact on of fibroblast-like cells deformability and ECM misbalance, Differential gene expression and RNA sequencing analysis will help to understand the combined participation of these protein coding genes in ACL non-contact injuries.

Overproduction of VEGF concomitantly expressed with its receptors promotes growth and survival of melanoma cells through MAPK and PI3K signaling.

Vascular endothelial growth factor (VEGF) is an important mediator of tumor-associated angiogenesis, and consequently it has been associated with metastasis. We report here that the overexpression of VEGF(165) in melanoma xenografts promotes an acceleration of tumor growth and an increase in angiogenesis as well as the spontaneous metastasis formation. In addition, VEGF receptors (VEGFR)1, VEGFR2 and neurophilin-1 are expressed in A375 melanoma cells. Forced overexpression of VEGF in these cells induces cell growth and triggers survival activity in serum-starved cultures, by a mechanism dependent on the mitogen-activating protein kinase signaling pathway. Furthermore, these effects are dependent MEK 1/2 activity. Kinase domain region-specific tyrosine kinase inhibitors dramatically reduced DNA synthesis to 20% with respect to the controls, although they did not completely suppress either the p44 or p42-phosphorylated forms of extracellular signal-regulated protein kinase. These inhibitors also provoked a decrease in Akt phosphorylation. We observed a dramatic reduction in survival after treatment with phosphatidylinositol 3'-kinase (PI3K)-specific inhibitor in the presence of specific tyrosinase inhibitors. We suggest that the overproduction of VEGF(165) concomitantly expressed with its receptors favors cell growth and survival of melanoma cells through MAPK and PI3K signaling pathways. These data support the involvement in melanoma growth and survival of a VEGF-dependent internal autocrine loop mechanism, at least in vitro.