Detailed Modeling of Cork-Phenolic Ablators in Preparation for the Post-flight Analysis of the QARMAN Re-entry CubeSat

This work deals with the analysis of the cork P50, an ablative thermal protection material (TPM) used for the heat shield of the qarman Re-entry CubeSat. Developed for the European Space Agency (ESA) at the von Karman Institute (VKI) for Fluid Dynamics, qarman is a scientifc demonstrator for Aerothermodynamic Research. The ability to model and predict the atypical behavior of the new cork-based materials is considered a critical research topic. Therefore, this work is motivated by the need to develop a numerical model able to respond to this demand, in preparation to the post-fight analysis of qarman. This study is focused on the main thermal response phenomena of the cork P50: pyrolysis and swelling. Pyrolysis was analyzed by means of the multi-physics Computational Fluid Dynamics (CFD) code argo, developed at Cenaero. Based on a unifed fow-material solver, the Volume Averaged Navier–Stokes (VANS) equations were numerically solved to describe the interaction between a multi-species high enthalpy fow and a reactive porous medium, by means of a high-order Discontinuous Galerkin Method (DGM). Specifcally, an accurate method to compute the pyrolysis production rate was implemented. The modeling of swelling was the most ambitious task, requiring the development of a physical model accounting for this phenomenon, for the purpose of a future implementation within argo. A 1D model was proposed, mainly based on an a priori assumption on the swelling velocity and the resolution of a nonlinear advection equation, by means of a Finite Diference Method (FDM). Once developed, the model was successfully tested through a matlab code, showing that the approach is promising and thus opening the way to further developments

Hepatitis C virus infection and development of type 2 diabetes mellitus: Systematic review and meta-analysis of the literature

Type 2 diabetes mellitus (T2DM) is an endocrine disorder encompassing multifactorial mechanisms, and chronic hepatitis C virus infection (CHC) is a multifaceted disorder, associated with extrahepatic manifestations, including endocrinological disorders. CHC and T2DM are associated, but the subject remains controversial. We performed a systematic review and meta-analysis evaluating such association, searching on PubMed until February 29, 2016. Inclusion criteria were: 1) presence of at least one internal control group age- and gender-matched (non-hepatopathic controls; and/or hepatopathic, not HCV-positive, controls); 2) sufficient data to calculate odds ratio and relative risk. Exclusion criteria were: 1) literature reviews on the topic; 2) publications regarding special populations [human immunodeficiency virus and human T-lymphotropic virus-1 coinfections, hepatocellular carcinoma (HCC), post-transplantation DM, gender selection]; 3) no clear differentiation among HCV patients with CHC, cirrhosis or HCC. Data from each study were independently extracted by two reviewers and cross-checked by AA. Our systematic review returned 544 records, and 33 were included in our meta-analysis. HCV infection is associated with an increased risk of T2DM independently from the severity of the associated liver disease, in CHC and cirrhotic HCV patients. As expected T2DM risk is higher in cirrhotic HCV patients, than CHC, and the prevalence of HCV infection in T2DM patients is higher than in non-diabetic controls. Regarding HBV infection prevalence, no difference exists in diabetic and non-diabetic subjects. An unequivocal CHC and T2DM association was shown. A proactive, integrated approach to HCV and T2DM therapies should maximize benefits of both diseases treatment

Emerging Therapeutic Approaches for the Most Aggressive Epithelial Thyroid Cancers

The majority of epithelial thyroid carcinomas (TC) have a differentiated (DTC) histotype and include the papillary (PTC) and the follicular (FTC) TC which, ensuing dedifferentiation, generate the aggressive poorly differentiated (PDTC) and anaplastic (ATC) TC. Although derived from the same cell type, each TC shows specific histological features, biological behavior, and degree of differentiation because of different genetic alterations. Total thyroidectomy, followed by adjuvant therapy with 131I, is the treatment of choice for most patients affected by DTC. The prognosis of DTC patients is favorable, with 10‐year survival rate of nearly 90%. However, one third of them face the morbidity of disease recurrence and TC‐related deaths. The worst outcomes are encountered in patients with PDTC and ATC. The latter, in particular, has a mean survival time of few months from the diagnosis, which is not influenced by current anticancer treatments. Following the progress made in the comprehension of the underlying molecular mechanisms deregulated in TC progression, novel therapeutic approaches have come to light. Here, we will attempt to review new targeted therapies, which are currently being exploited in preclinical and clinical studies, with tyrosine kinase inhibitors as well as with emerging inhibitors of mitotic kinases, in PDTC and ATC

Antineoplastic Effects of PPARγ Agonists, with a Special Focus on Thyroid Cancer

Peroxisome Proliferator-Activated Receptor-γ (PPARγ) is a ligand-activated nuclear hormone receptor that functions as transcription factor and plays an important role in lipid metabolism and insulin sensitization. Recent studies have shown that PPARγ is overexpressed in many tumor types, including cancers of breast, lung, pancreas, colon, glioblastoma, prostate and thyroid differentiated/anaplastic cancers. These data suggest a role of PPARγ in tumor development and/or progression. PPARγ is emerging as a growth-limiting and differentiation-promoting factor, and it exerts a tumor suppressor role. Moreover, naturally-occurring and synthetic PPARγ agonists promote growth inhibition and apoptosis. Thiazolidinediones (TZDs) are synthetic agonists of PPARγ that were developed to treat type II diabetes. These compounds also display anticancer effects which appear mainly to be independent of their PPARγ agonist activity. Various preclinical and clinical studies strongly suggest a role for TZDs both alone and in combination with existing chemotherapeutic agents, for the treatment of cancer. Differentiation therapy involves the use of agents with the ability to induce differentiation in cells that have lost this ability, i.e. cancer cells, targeting pathways capable of re-activating blocked terminal differentiation programs. PPARγ agonists have been shown to induce differentiation in solid tumors such as thyroid differentiated/ anaplastic cancers and sarcomas. However, emerging data suggest that chronic use of TZDs is associated with increased risk of adverse cardiovascular events. The exploration of newer PPARγ agonists can help in unveiling the underlying mechanisms of these drugs, providing new molecules that are able to treat cancer, without increasing the cardiovascular risk of neoplastic patients

Sorafenib and Thyroid Cancer

Sorafenib (Nexavar) is a multikinase inhibitor, which has demonstrated both anti-proliferative and anti-angiogenic properties in vitro and in vivo, inhibiting the activity of targets present in the tumor cell [c-RAF (proto-oncogene serine/threonine-protein kinase), BRAF, V600EBRAF, c-KIT, and FMS-like tyrosine kinase 3] and in tumor vessels (c-RAF, vascular endothelial growth factor receptor-2, vascular endothelial growth factor receptor-3, and platelet-derived growth factor receptor β). For several years, sorafenib has been approved for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma. After previous studies showing that sorafenib was able to inhibit oncogenic RET mutants, V600EBRAF, and angiogenesis and growth of orthotopic anaplastic thyroid cancer xenografts in nude mice, some clinical trials demonstrated the effectiveness of sorafenib in advanced thyroid cancer. Currently, the evaluation of the clinical safety and efficacy of sorafenib for the treatment of advanced thyroid cancer is ongoing. This article reviews the anti-neoplastic effect of sorafenib in thyroid cancer. Several completed (or ongoing) studies have evaluated the long-term efficacy and tolerability of sorafenib in patients with papillary and medullary aggressive thyroid cancer. The results suggest that sorafenib is a promising therapeutic option in patients with advanced thyroid cancer that is not responsive to traditional therapeutic strategies

Cabozantinib in Thyroid Cancer

Cabozantinib is an oral once-daily multitarget tyrosine kinase inhibitor of MET, VEGFR2, RET, acting against KIT, AXL, FLT3 and Tie-2. Cabozantinib has shown anti-cancer effects in preclinical and clinical models of cancers derived from both epithelial and mesenchymal origins [prostate cancer, non small lung cancer, medullary thyroid cancer (MTC) and differentiated thyroid cancer (DTC), renal cell carcinoma, etc.]. In a Phase III clinical study, cabozantinib improved PFS (11.2 months versus 4.0 months in the placebo group) of patients with MTC (independently of age, bone metastases, RET status and prior treatment). Cabozantinib was approved in 2012 by FDA for metastatic MTC and in 2013 by EMA. Cabozantinib has been also evaluated in metastatic DTC patients, because they have activation on tyrosine kinases, including MET, VEGFR2 and RET, suggesting the possible use of cabozantinib in metastatic DTC. Actually, two Phase II trials of cabozantinib in DTC patients resistant to RAI are ongoing. To increase the antineoplastic effect of cabozantinib, and to overcome the occurrence of drug resistance, combination studies with other anticancer agents are ongoing. In conclusion, cabozantinib has shown to exert an important therapeutic effect in patients with MTC improving PFS. In DTC patients, cabozantinib has shown promising results

The safety and efficacy of vandetanib in the treatment of progressive medullary thyroid cancer

Introduction: Traditional therapies for advanced or metastatic progressive medullary thyroid cancer (pMTC) are poor effective. Several TKIs have been tested in clinical trials in pMTC patients. Areas covered: This paper reviews efficacy and safety of vandetanib in the treatment of pMTC. Expertcommentary: Vandetanib (trade name CAPRELSA® [Vandetanib]) has been shown to improve progression-free survival (30.5 vs 19.3 months in controls) in pMTC patients. Vandetanib is approved by FDA and EMA for metastatic MTC in adults; in adolescents and children with metastatic or locally advanced MTC, vandetanib seems to be effective. The most common adverse events in vandetanib-treated patients are: diarrhea, rash, folliculitis, nausea, QTc prolongation, hypertension and fatigue. In patients with aggressive differentiated thyroid cancer, vandetanib has shown promising results. Further research is needed to determine the ideal targeted therapy, based on tumor molecular characterization and host factors, to obtain the best response in terms of survival and quality of life

New Targeted Therapies for Thyroid Cancer

The increasing incidence of thyroid cancer is associated with a higher number of advanced disease characterized by the loss of cancer differentiation and metastatic spread. The knowledge of the molecular pathways involved in the pathogenesis of thyroid cancer has made possible the development of new therapeutic drugs able to blockade the oncogenic kinases (BRAF V600E, RET/PTC) or signaling kinases [vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptors (PDGFR)] involved in cellular growth and proliferation. Some clinical trials have been conducted showing the ability of targeted therapies (sorafenib, sunitinib, axitinib, imanitib, vandetanib, pazopanib, gefitinib) in stabilizing the course of the disease. Until now, however, no consensus guidelines have been established for patient selection and more data on toxicities and side effects are needed to be collected

Advancements in the treatment of hypothyroidism with L-T4 liquid formulation or soft gel capsule: an update

INTRODUCTION: The most recent advance concerning levothyroxine (L-T4) therapy is the development of novel oral formulations: the liquid preparation, and the soft gel capsule. AREAS COVERED: This review evaluates the most recent clinical studies about these new formulations. The liquid formulation has been shown to overcome: the food and beverages intereference with L-T4 tablets absorption, caused by food or coffee at breakfast; malabsorption induced by the increased gastric pH, resulting from atrophic gastritis, or due to proton-pump inhibitors; and malabsorption after bariatric surgery. The use of liquid L-T4 has been studied also in pregnancy, newborns and infants, suggesting a better bioequivalence than tablets. Finally, liquid L-T4 is more active than tablets in the control of thyroid-stimulating hormone (TSH) in hypothyroid patients without malabsorption, drug interference, or gastric disorders, leading to a hypothesized higher absorption of liquid L-T4 also in these patients. Few studies have evaluated soft gel L-T4 with promising results in patients with malabsorption related to coffee or gastritis. EXPERT OPINION: Liquid L-T4 (and soft gel capsules) are more active than the tablet L-T4 in the control of TSH in hypothyroid patients with gastric disorders, malabsorption, or drug interference, but also in patients without absorption disorders