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Fibrosis is a chronic disease characterized by excessive extracellular matrix production, which leads to disruption of organ function. Fibroblasts are key effector cells of this process, responding chiefly to the pleiotropic cytokine transforming growth factor-β1 (TGF-β1), which promotes fibroblast to myofibroblast differentiation. We found that extracellular nutrient availability profoundly influenced the TGF-β1 transcriptome of primary human lung fibroblasts and that biosynthesis of amino acids emerged as a top enriched TGF-β1 transcriptional module. We subsequently uncovered a key role for pyruvate in influencing glutaminase (GLS1) inhibition during TGF-β1-induced fibrogenesis. In pyruvate-replete conditions, GLS1 inhibition was ineffective in blocking TGF-β1-induced fibrogenesis, as pyruvate can be used as the substrate for glutamate and alanine production via glutamate dehydrogenase (GDH) and glutamic-pyruvic transaminase 2 (GPT2), respectively. We further show that dual targeting of either GPT2 or GDH in combination with GLS1 inhibition was required to fully block TGF-β1-induced collagen synthesis. These findings embolden a therapeutic strategy aimed at additional targeting of mitochondrial pyruvate metabolism in the presence of a glutaminolysis inhibitor to interfere with the pathological deposition of collagen in the setting of pulmonary fibrosis and potentially other fibrotic conditions.

The increasing energy demand and the ever more pressing need for clean technologies of energy conversion pose one of the most urgent and complicated issues of our age. Thermoelectricity, namely the direct conversion of waste heat into electricity, is a promising technique based on a long-standing physical phenomenon, which still has not fully developed its potential, mainly due to the low efficiency of the process. In order to improve the thermoelectric performance, a huge effort is being made by physicists, materials scientists and engineers, with the primary aims of better understanding the fundamental issues ruling the improvement of the thermoelectric figure of merit, and finally building the most efficient thermoelectric devices. In this Roadmap an overview is given about the most recent experimental and computational results obtained within the Italian research community on the optimization of composition and morphology of some thermoelectric materials, as well as on the design of thermoelectric and hybrid thermoelectric/photovoltaic devices., (Creative Commons Attribution license.)

Objectives: A previous pilot study showed that pravastatin supplementation improved pregnancy outcomes in women with obstetric antiphospholipid syndrome (OAPS) that developed placental insufficiency despite standard of care treatment low molecular weight heparin plus low dose aspirin (LMWH + LDA). In this study we investigated the mechanism behind the beneficial effects of the triple therapy LMWH + LDA + pravastatin in improving uteroplacental vascular function and reducing pregnancy complications in OAPS. We hypothesized that nitric oxide (NO) is involved in the vasculoprotective effects of the triple therapy. A mouse model of OAPS that resembles the clinical scenario was used to test this hypothesis., Methods: Eleven women with OAPS that developed preeclampsia (PE) and/or intrauterine growth restriction (IUGR) associated with uteroplacental vascular dysfunction despite treatment with LMWH + LDA participated in this study after given informed written consent. Seven women were supplemented with pravastatin at the time abnormal uterine artery Dopplers were detected and 4 remained on LMWH + LDA treatment only. Wire myography was used to identify the mechanisms underpinning the protective effects of the triple therapy in the mouse model of OAPS., Results: The triple therapy increased serum NO levels, diminished uteroplacental vessels resistance improving placental function and prolonged pregnancies compared to conventional treatment LMWH + LDA, leading to live births in women with OAPS. Comparable to the observations in women, the triple therapy protected pregnancies in OAPS-mice, increasing placental perfusion and pregnancy outcomes. A synergistic vasculoprotective effect of the triple therapy on uterine arteries and aorta was demonstrated in OAPS-mice. LMWH + LDA showed a partial protection on endothelial function. Addition of pravastatin increase eNOS synthesis, expression and activity/signaling leading to a significant increment in nitric oxide (NO) generation, resulting in improved placental vascular function and total protection of pregnancies., Conclusion: LMWH + LDA + PRAV increased serum NO levels and significantly improved placental haemodynamics and maternal and neonatal outcomes in women and mice with OAPS. A role for eNOS/NO in mediating the placental vasculoprotective effects in OAPS-mice was demonstrated, strengthening the concept that impaired NO production is a crucial mediator in the pathogenesis of OAPS and a potential target for pharmacological interventions. The efficacy of pravastatin supplementation should be confirmed in a larger clinical trial., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The differentiation of fibroblasts into a transient population of highly activated, extracellular matrix (ECM)-producing myofibroblasts at sites of tissue injury is critical for normal tissue repair. Excessive myofibroblast accumulation and persistence, often as a result of a failure to undergo apoptosis when tissue repair is complete, lead to pathological fibrosis and are also features of the stromal response in cancer. Myofibroblast differentiation is accompanied by changes in cellular metabolism, including increased glycolysis, to meet the biosynthetic demands of enhanced ECM production. Here, we showed that transforming growth factor-β 1 (TGF-β 1 ), the key pro-fibrotic cytokine implicated in multiple fibrotic conditions, increased the production of activating transcription factor 4 (ATF4), the transcriptional master regulator of amino acid metabolism, to supply glucose-derived glycine to meet the amino acid requirements associated with enhanced collagen production in response to myofibroblast differentiation. We further delineated the signaling pathways involved and showed that TGF-β 1 -induced ATF4 production depended on cooperation between canonical TGF-β 1 signaling through Smad3 and activation of mechanistic target of rapamycin complex 1 (mTORC1) and its downstream target eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). ATF4, in turn, promoted the transcription of genes encoding enzymes of the de novo serine-glycine biosynthetic pathway and glucose transporter 1 (GLUT1). Our findings suggest that targeting the TGF-β 1 -mTORC1-ATF4 axis may represent a novel therapeutic strategy for interfering with myofibroblast function in fibrosis and potentially in other conditions, including cancer., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Placental ischemic disease and adverse pregnancy outcomes are frequently observed in patients with antiphospholipid syndrome (APS). Despite the administration of conventional antithrombotic treatment a significant number of women continue to experience adverse pregnancy outcomes, with uncertain prevention and management. Efforts to develop effective pharmacological strategies for refractory obstetric APS cases will be of significant clinical benefit for both mothers and fetuses. Although the antimalarial drug, hydroxychloroquine (HCQ) is increasingly used to treat pregnant women with APS, little is known about its efficacy and mechanism of action of HCQ. Because complement activation plays a crucial and causative role in placental ischemia and abnormal fetal brain development in APS we hypothesised that HCQ prevents these pregnancy complications through inhibition of complement activation. Using a mouse model of obstetric APS that closely resembles the clinical condition, we found that HCQ prevented fetal death and the placental metabolic changes -measured by proton magnetic resonance spectroscopy in APS-mice. Using 111 In labelled antiphospholipid antibodies (aPL) we identified the placenta and the fetal brain as the main organ targets in APS-mice. Using this same method, we found that HCQ does not inhibit aPL binding to tissues as was previously suggested from in vitro studies. While HCQ did not affect aPL binding to fetal brain it prevented fetal brain abnormal cortical development. HCQ prevented complement activation in vivo and in vitro. Complement C5a levels in serum samples from APS patients and APS-mice were lower after treatment with HCQ while the antibodies titres remained unchanged. HCQ prevented not only placental insufficiency but also abnormal fetal brain development in APS. By inhibiting complement activation, HCQ might also be an effective antithrombotic therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: For almost 3 years, Radiologists and Physicists from Padova and Ferrara Universities have collaborated together, with the aim of collecting and comparing experimental data useful to define the most significant parameters for quality controls in digital mammography. Successively, radiologists and physicists working in other sites where a digital mammography unit was installed joined the work-group., Materials and Methods: In this study we report the results obtained from measurements of linearity, uniformity, short- and long-term reproducibility, AEC stability performed on 5 digital equipment by using a simple test object. X-ray beam quality and tube yield were preliminarily checked in such a way that possible uncertainties of digital system responses could be separated from those due to differences among X-ray tubes., Results: Results showed that the equipment considered, comparable in terms of both beam quality (HVL) and tube yield, always displayed linear response and reproducibility errors lower than 5%. Uniformity was very good and the grey level compensation as a function of exposure parameters remained within 5%. Differences in choice of parameters by exposure control system (AOP) were emphasised, especially for crossing between track/filter combinations (from Mo/Mo to Mo/Rh and from Mo/Rh to Rh/Rh); those differences were attributed to the +/-2 mm tolerance of breast thickness measurement (mechanically obtained) greater than the AOP tolerance (+/-1 mm)., Discussion and Conclusions: Obtained results can be useful, as comparison and reference values, for users employing a digital mammography unit of the same kind reported in this paper. Moreover, the same results could be used as "orientation" also by other users having different digital mammography technologies, whose operation should be nevertheless specifically studied and understood in order to find the most useful parameters for quality controls. The acquired experience clearly showed us that years of investigations will be necessary in order to be able to write reliable protocols. This should induce people to contemplate the necessity of not improvising "theoretical" protocols, that are unreliable and dangerous for their negative clinical implications.

The authors describe an afterloading brachytherapy to treat oral cavity carcinomas. Catheters for arterial/venous catheterization are inserted percutaneously in the target volume. The internal needles are then removed and replaced with iridium wires inside tubes to form wire loops. This technique has proven to be simple, quick and safe.

Flexible 192Ir wire implants are commonly used for the treatment of some types of cancer in the oral cavity. A modified technique of plastic tubes is here presented which aims at correctly positioning the active wires with thin plastic templates. Possible sources of error are examined and their consequences on the dose distribution around the implant are analyzed. In most cases control dosimetry matches the provisions satisfactorily. It may be thus concluded that the use of templates allows good and reproducible results to be obtained in the brachytherapy of the oral cavity.