Endothelial to mesenchymal transition (EndoMT) in the pathogenesis of Systemic Sclerosis-associated pulmonary fibrosis and pulmonary arterial hypertension. Myth or reality?

Systemic Sclerosis (SSc) is a systemic autoimmune disease characterized by progressive fibrosis of skin and multiple internal organs and severe functional and structural microvascular alterations. SSc is considered to be the prototypic systemic fibrotic disorder. Despite currently available therapeutic approaches SSc has a high mortality rate owing to the development of SSc-associated interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH), complications that have emerged as the most frequent causes of disability and mortality in SSc. The pathogenesis of the fibrotic process in SSc is complex and despite extensive investigation the exact mechanisms have remained elusive. Myofibroblasts are the cells ultimately responsible for tissue fibrosis and fibroproliferative vasculopathy in SSc. Tissue myofibroblasts in SSc originate from several sources including expansion of quiescent tissue fibroblasts and tissue accumulation of CD34+ fibrocytes. Besides these sources, myofibroblasts in SSc may result from the phenotypic conversion of endothelial cells into activated myofibroblasts, a process known as endothelial to mesenchymal transition (EndoMT). Recently, it has been postulated that EndoMT may play a role in the development of SSc-associated ILD and PAH. However, although several studies have described the occurrence of EndoMT in experimentally induced cardiac, renal, and pulmonary fibrosis and in several human disorders, the contribution of EndoMT to SSc-associated ILD and PAH has not been generally accepted. Here, the experimental evidence supporting the concept that EndoMT plays a role in the pathogenesis of SSc-associated ILD and PAH will be reviewed

Role of growth factors in the pathogenesis of tissue fibrosis in systemic sclerosis.

The most severe clinical and pathologic manifestations of systemic sclerosis (SSc) are the result of a fibrotic process characterized by the excessive and often progressive deposition of collagen and other connective tissue macromolecules in skin and numerous internal organs. The mechanisms involved in the initiation and progression of the remarkable fibrotic process in SSc remain largely unknown. Extensive recent studies have indicated that a variety of polypeptide growth factors play a crucial role in this process. The most commonly implicated growth factors include transforming growth factor beta (TGF-β), connective tissue growth factor (CTGF), platelet derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Here, the experimental evidence supporting the participation of various growth factors in the pathogenesis of the fibrotic process in SSc and the molecular mechanisms involved will be reviewed

Molecular mechanisms of endothelial to mesenchymal cell transition (EndoMT) in experimentally induced fibrotic diseases.

Several recent studies have demonstrated that endothelial to mesenchymal transition (EndoMT), a newly recognized type of cellular transdifferentiation may be an important source of myofibroblasts during the development of experimentally induced pulmonary, cardiac and kidney fibrosis. EndoMT is a complex biological process induced by members of the transforming growth factor (TGF-β) family of regulatory polypeptides in which endothelial cells adopt a mesenchymal or myofibroblastic phenotype acquiring motile and contractile properties and initiating expression of mesenchymal cell products such as α smooth muscle actin (α-SMA) and type I collagen. Although these experimental studies provide compelling evidence for the participation of EndoMT in the development of experimentally-induced fibrotic processes the precise role of EndoMT in the pathogenesis of human fibrotic disorders requires confirmation and validation from studies of human clinical pathologic conditions. Such confirmation should lead to a change in the paradigm of the origin of profibrogenic myofibroblasts involved in human fibrotic diseases. Further understanding of the molecular mechanisms and the regulatory pathways involved in EndoMT may lead to the development of novel therapeutic approaches for the incurable and often devastating fibrotic disorders

Budget Impact Analysis of Brivaracetam Adjunctive Therapy for Partial-Onset Epileptic Seizures in Valencia Community, Spain

[EN] Background and Objective More than 30% of patients with epilepsy have inadequate control of seizures with drug therapy. The goal of this study is to determine the budget impact (BI) of the introduction of brivaracetam to the portfolio of approved drugs in Spain as adjunctive therapy for the treatment of partial-onset epilepsy in patients over 16 years old with a 5-year time horizon in the Valencia Community, a Spanish region with a population of 5 million. Methods The BI model compares the pharmaceutical expenditure on antiepileptics in two scenarios: with and without brivaracetam. It assumes that the introduction and increased use of brivaracetam will lead to a proportional decrease in consumption of coexisting adjunctive antiepileptics and calculates the evolution of the consumption of brivaracetam over 5 years (2016-2020). The model was designed from the perspective of the Spanish National Health System. Data on the candidate population, consumption of antiepileptics, market share and pharmaceutical expenditure were obtained from real-world data. Finally, a sensitivity analysis was carried out on the set of variables involved in the evolution of costs using a Monte-Carlo simulation. Results The model estimates that the target population eligible for adjunctive antiepileptics will hold at around 2352 between 2016 and 2020. Annual expenditure on antiepileptics is approximately a,notsign3.6 million. The number of patients eligible for treatment with brivaracetam would increase from 42 to 179 and annual savings of 0.09-0.37% would be created, representing a,notsign 41,873 over 5 years (0.23% of the total budget). The sensitivity analysis corroborates that the probability of achieving savings with brivaracetam is around 84%. Conclusions Brivaracetam is a therapeutic alternative that allows savings for the health system in patients with non-controlled epilepsy in monotherapy, having a fixed, predictable annual cost (independent of dose) from the first day of treatment as the lack of need for titration means the patient is within a range of therapeutic doses from the first dose.This work was supported partially by the Instituto de Salud Carlos III-Ministerio de Economia y Competitividad and the European Union (FEDER [Fonds Europeen de Developpement Economique et Regional (European Fund for Economic and Regional Development)] funds)-FIS PI12/00037.Barrachina Martínez, I.; Vivas-Consuelo, D.; Piera-Balbastre, A. (2018). Budget Impact Analysis of Brivaracetam Adjunctive Therapy for Partial-Onset Epileptic Seizures in Valencia Community, Spain. Clinical Drug Investigation. 38(4):353-363. https://doi.org/10.1007/s40261-017-0615-zS353363384World Health Organization (2017). 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Exposure to polychlorinated biphenyl (PCB) congeners measured shortly after giving birth and subsequent risk of maternal breast cancer before age 50

Discrete windows of susceptibility to toxicants have been identified for the breast, including in utero, puberty, pregnancy, and postpartum. We tested the hypothesis that polychlorinated biphenyls (PCBs) measured during the early postpartum predict increased risk of maternal breast cancer diagnosed before age 50. We analyzed archived early postpartum serum samples collected from 1959 to 1967, an average of 17 years before diagnosis (mean diagnosis age 43 years) for 16 PCB congeners in a nested case–control study in the Child Health and Development Studies cohort (N = 112 cases matched to controls on birth year). We used conditional logistic regression to adjust for lipids, race, year, lactation, and body mass. We observed strong breast cancer associations with three congeners. PCB 167 was associated with a lower risk (odds ratio (OR), 75th vs. 25th percentile = 0.2, 95 % confidence interval (95 % CI) 0.1, 0.8) as was PCB 187 (OR, 75th vs. 25th percentile = 0.4, 95 % CI 0.1, 1.1). In contrast, PCB 203 was associated with a sixfold increased risk (OR, 75th vs. 25th percentile = 6.3, 95 % CI 1.9, 21.7). The net association of PCB exposure, estimated by a post-hoc score, was nearly a threefold increase in risk (OR, 75th vs. 25th percentile = 2.8, 95 % CI 1.1, 7.1) among women with a higher proportion of PCB 203 in relation to the sum of PCBs 167 and 187. Postpartum PCB exposure likely also represents pregnancy exposure, and may predict increased risk for early breast cancer depending on the mixture that represents internal dose. It remains unclear whether individual differences in exposure, response to exposure, or both explain risk patterns observed

Estimating the Underwater Diffuse Attenuation Coefficient with a Low-Cost Instrument: The KdUINO DIY Buoy

A critical parameter to assess the environmental status of water bodies is the transparency of the water, as it is strongly affected by different water quality related components (such as the presence of phytoplankton, organic matter and sediment concentrations). One parameter to assess the water transparency is the diffuse attenuation coefficient. However, the number of subsurface irradiance measurements obtained with conventional instrumentation is relatively low, due to instrument costs and the logistic requirements to provide regular and autonomous observations. In recent years, the citizen science concept has increased the number of environmental observations, both in time and space. The recent technological advances in embedded systems and sensors also enable volunteers (citizens) to create their own devices (known as Do-It-Yourself or DIY technologies). In this paper, a DIY instrument to measure irradiance at different depths and automatically calculate the diffuse attenuation Kd coefficient is presented. The instrument, named KdUINO, is based on an encapsulated low-cost photonic sensor and Arduino (an open-hardware platform for the data acquisition). The whole instrument has been successfully operated and the data validated comparing the KdUINO measurements with the commercial instruments. Workshops have been organized with high school students to validate its feasibility

A new solution suggesting the need for a new equation

When Victoria Hale first came up with the notion of starting the Institute for OneWorld Health (iOWH), some cautioned that the idea of a non-profit pharmaceutical company developing drugs to treat neglected diseases was a proven loser. The more direct among them might also have inquired why a successful scientist, trained in being analytic, consistent and logical, would undertake such an evidently hopeless project. Yet a few years later, iOWH has not only achieved its first drug approval (i.e. Paramomycin for the treatment of leishmaniasis or ‘black fever’, approved for use in India), it has also seen that same drug included in WHO’s Essential Medicines list, and has research results in the New England Journal of Medicine. This turnaround raises a question: Did skeptics fail to grasp Hale’s clever insights, misjudge the depth of her commitment, or underestimate the extent of her potential good fortune? Put more simply, is Hale’s a story of smarts, guts, and luck

Coupled Natural Fusion Enzymes in a Novel Biocatalytic Cascade Convert Fatty Acids to Amines

[Image: see text] Tambjamine YP1 is a pyrrole-containing natural product. Analysis of the enzymes encoded in the Pseudoalteromonas tunicata “tam” biosynthetic gene cluster (BGC) identified a unique di-domain biocatalyst (PtTamH). Sequence and bioinformatic analysis predicts that PtTamH comprises an N-terminal, pyridoxal 5′-phosphate (PLP)-dependent transaminase (TA) domain fused to a NADH-dependent C-terminal thioester reductase (TR) domain. Spectroscopic and chemical analysis revealed that the TA domain binds PLP, utilizes l-Glu as an amine donor, accepts a range of fatty aldehydes (C(7)–C(14) with a preference for C(12)), and produces the corresponding amines. The previously characterized PtTamA from the “tam” BGC is an ATP-dependent, di-domain enzyme comprising a class I adenylation domain fused to an acyl carrier protein (ACP). Since recombinant PtTamA catalyzes the activation and thioesterification of C(12) acid to the holo-ACP domain, we hypothesized that C(12) ACP is the natural substrate for PtTamH. PtTamA and PtTamH were successfully coupled together in a biocatalytic cascade that converts fatty acids (FAs) to amines in one pot. Moreover, a structural model of PtTamH provides insights into how the TA and TR domains are organized. This work not only characterizes the formation of the tambjamine YP1 tail but also suggests that PtTamA and PtTamH could be useful biocatalysts for FA to amine functional group conversion