Alkyphenol exposure alters steroidogenesis in male lizard podarcis siculus

Background: Nonylphenol (NP) and Octylphenol (OP) are persistent and non-biodegradable environmental contaminants classified as endocrine disruptor chemicals (EDCs). These compounds are widely used in several industrial applications and present estrogen-like properties, which have extensively been studied in aquatic organisms. The present study aimed to verify the interference of these compounds alone, and in mixture, on the reproductive cycle of the male terrestrial vertebrate Podarcis siculus, focusing mainly on the steroidogenesis process. Methods: Male lizards have been treated with different injections of both NP and OP alone and in mixture, and evaluation has been carried out using a histological approach. Results: Results obtained showed that both substances are able to alter both testis histology and localization of key steroidogenic enzymes, such as 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD) and P450 aromatase. Moreover, OP exerts a preponderant effect, and the P450 aromatase represents the major target of both chemicals. Conclusions: In conclusion, NP and OP inhibit steroidogenesis, which in turn may reduce the reproductive capacity of the specimens

Status of coronary disease and results from early endovascular aneurysm repair after preventive percutaneous coronary revascularization

Background: The incidence of coronary artery disease (CAD) is high in patients with an aortic aneurysm but preoperative routine coronary angiography and preventive coronary revascularization are not recommended to reduce cardiac events in patients with severe CAD. Aim: This study evaluated the safeness and efficacy of preventive percutaneous coronary intervention (PCI) in patients with severe CAD scheduled for endovascular aneurysm repair (EVAR). Methods: All patients with descending thoracic aneurysm (DTA) or abdominal aortic aneurysm (AAA) scheduled for EVAR underwent preliminary coronary angiography. Based on coronary angiography results, 917 patients (40.7%) had significant CAD and were treated by percutaneous coronary intervention (PCI; CAD group) and 1337 patients (59.3%) were without or with mild/moderate CAD and were considered as controls (no‐CAD group). To evaluate the safeness and efficacy of preventive PCI in patients with severe CAD undergoing EVAR, groups were compared for hospital and 12‐month cardiac adverse events. Results: CAD was present in 1210 patients (53.6%): significant in 917 patients (38%) and mild to moderate in 293 patients (5.3%). Hospital and 12‐month cardiac events occurred in 15 (1.6%) and 13 (1.4%) CAD group patients and in 9 (0.7%) and 8 (0.4%) no‐CAD group patients (p = .05 and p = .08), respectively. Hospital and 12‐month cardiac deaths occurred in 3 (0.3%) and 2 (0.2%) CAD group patients and in 3 (0.2%) and 2 (0.2%) no‐CAD group patients (p = .9 and p = .9), respectively. Conclusion: The strategy to treat severe CAD preoperatively by PCI and early subsequent EVAR brings a similar outcome to that in patients without or with mild/ moderate CAD

Lenvatinib for the treatment of renal cell carcinoma

Introduction: Renal cell carcinoma (RCC) accounts for 2\u20133% of all solid tumors. Expression of the receptor for the vascular endothelial growth factor (VEGF) is one of the most common features of RCC. Areas covered: Lenvatinib is a novel multi-kinase inhibitor that has been studied in several solid tumors. It has shown promising results in the treatment of RCC, especially when combined with everolimus, In this review, we summarize the available data of lenvatinib for the treatment of advanced/metastatic renal cell carcinoma. Expert opinion: Lenvatinib in combination with everolimus has provided encouraging results in both clinical and laboratory investigations showing that blocking angiogenesis and the mTOR signalling pathway could be a remarkable approach for treating RCC. As an additive to this type of approach it would be interesting in future clinical settings testing also the combination of lenvatinib and everolimus with immune-therapy

Conformational selection underlies recognition of a molybdoenzyme by its dedicated chaperone

Molecular recognition is central to all biological processes. Understanding the key role played by dedicated chaperones in metalloprotein folding and assembly requires the knowledge of their conformational ensembles. In this study, the NarJ chaperone dedicated to the assembly of the membrane-bound respiratory nitrate reductase complex NarGHI, a molybdenum-iron containing metalloprotein, was taken as a model of dedicated chaperone. The combination of two techniques ie site-directed spin labeling followed by EPR spectroscopy and ion mobility mass spectrometry, was used to get information about the structure and conformational dynamics of the NarJ chaperone upon binding the N-terminus of the NarG metalloprotein partner. By the study of singly spin-labeled proteins, the E119 residue present in a conserved elongated hydrophobic groove of NarJ was shown to be part of the interaction site. Moreover, doubly spin-labeled proteins studied by pulsed double electron-electron resonance (DEER) spectroscopy revealed a large and composite distribution of inter-label distances that evolves into a single preexisting one upon complex formation. Additionally, ion mobility mass spectrometry experiments fully support these findings by revealing the existence of several conformers in equilibrium through the distinction of different drift time curves and the selection of one of them upon complex formation. Taken together our work provides a detailed view of the structural flexibility of a dedicated chaperone and suggests that the exquisite recognition and binding of the N-terminus of the metalloprotein is governed by a conformational selection mechanism

Alterações na estrutura florística das espécies comerciais após o manejo florestal comunitário em Anapu, Pará, Brasil.

Estudos sobre florística e estrutura fitossociológica das formações florestais auxiliam a compreensão do funcionamento dos ecossistemas mediante manejo florestal. Objetivou-se, neste estudo, estimar alterações na composição, diversidade e estrutura florística de um fragmento florestal de 545,3 ha, em Anapu, Pará. Foram inventariados 9.604 indivíduos com diâmetro à altura do peito ≥50 cm, e efetivamente explorados 1.218 indivíduos com volume de 6.649,55 m³ de madeira, resultando em uma intensidade de exploração de 15,08 m³/ha. Um indicativo de que a exploração florestal foi eficiente quanto à composição florística é que se mantiveram remanescentes 87,32% do número de indivíduos das 107 espécies inventariadas antes da exploração. Dentre as famílias registradas, Fabaceae foi a que predominou antes e após a exploração. A espécie com maior número de indivíduos e índice de Valor de Cobertura foi o Acapu, enquanto no grupo das espécies exploradas foi a Timborana. A exploração alterou a ordem sequencial do Índice de Valor de Cobertura das espécies da comunidade florestal e resultou em alterações estatisticamente significativas no índice de diversidade e na estrutura da distribuição diamétrica. Por outro lado, mantiveram-se praticamente inalteradas a distribuição equitativa ?J? Pilou (de 0,803 para 0,801) e a similaridade florística superior a 93,2% na comunidade arbórea após a exploração. Conclui-se que mesmo com as boas práticas realizadas pelos assentados do Projeto de Desenvolvimento Sustentável Virola-Jatobá, em conformidade ao atual sistema policíclico de manejo florestal brasileiro, o manejo comunitário não se demonstrou sustentável ecologicamente em vista ao desequilíbrio populacional provocado pela maior pressão de exploração de um reduzido número de espécies florestai

Transcriptional Profile Associated with Clinical Outcomes in Metastatic Hormone-Sensitive Prostate Cancer Treated with Androgen Deprivation and Docetaxel

(1) Background: Androgen deprivation therapy (ADT) and docetaxel (DX) combination is a standard therapy for metastatic hormone-sensitive prostate cancer (mHSPC) patients. (2) Methods: We investigate if tumor transcriptomic analysis predicts mHSPC evolution in a multicenter retrospective biomarker study. A customized panel of 184 genes was tested in mRNA from tumor samples by the nCounter platform in 125 mHSPC patients treated with ADT+DX. Gene expression was correlated with castration-resistant prostate cancer-free survival (CRPC-FS) and overall survival (OS). (3) Results: High expression of androgen receptor (AR) signature was independently associated with longer CRPC-FS (hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.3-0.9; p = 0.015), high expression of estrogen receptor (ESR) signature with longer CRPC-FS (HR 0.6, 95% CI 0.4-0.9; p = 0.019) and OS (HR 0.5, 95% CI 0.2-0.9, p = 0.024), and lower expression of tumor suppressor genes (TSG) (RB1, PTEN and TP53) with shorter OS (HR 2, 95% CI 1-3.8; p = 0.044). ARV7 expression was independently associated with shorter CRPC-FS (HR 1.5, 95% CI 1.1-2.1, p = 0.008) and OS (HR 1.8, 95% CI 1.2-2.6, p = 0.004), high ESR2 was associated with longer OS (HR 0.5, 95% CI 0.2-1, p = 0.048) and low expression of RB1 was independently associated with shorter OS (HR 1.9, 95% CI 1.1-3.2, p = 0.014). (4) Conclusions: AR, ESR, and TSG expression signatures, as well as ARV7, RB1, and ESR2 expression, have a prognostic value in mHSPC patients treated with ADT+DX

The kinase inhibitor SI113 induces autophagy and synergizes with quinacrine in hindering the growth of human glioblastoma multiforme cells

open15noBackground: Glioblastoma multiforme (GBM), due to its location, aggressiveness, heterogeneity and infiltrative growth, is characterized by an exceptionally dismal clinical outcome. The small molecule SI113, recently identified as a SGK1 inhibitor, has proven to be effective in restraining GBM growth in vitro and in vivo, showing also encouraging results when employed in combination with other antineoplastic drugs or radiotherapy. Our aim was to explore the pharmacological features of SI113 in GBM cells in order to elucidate the pivotal molecular pathways affected by the drug. Such knowledge would be of invaluable help in conceiving a rational offensive toward GBM. Methods: We employed GBM cell lines, either established or primary (neurospheres), and used a Reverse-Phase Protein Arrays (RPPA) platform to assess the effect of SI113 upon 114 protein factors whose post-translational modifications are associated with activation or repression of specific signal transduction cascades.Results: SI113 strongly affected the PI3K/mTOR pathway, evoking a pro-survival autophagic response in neurospheres. These results suggested the use of SI113 coupled, for maximum efficiency, with autophagy inhibitors. Indeed, the association of SI113 with an autophagy inhibitor, the antimalarial drug quinacrine, induced a strong synergistic effect in inhibiting GBM growth properties in all the cells tested, including neurospheres. Conclusions: RPPA clearly identified the molecular pathways influenced by SI113 in GBM cells, highlighting their vulnerability when the drug was administered in association with autophagy inhibitors, providing a strong molecular rationale for testing SI113 in clinical trials in associative GBM therapy.openMatteoni S.; Abbruzzese C.; Matarrese P.; De Luca G.; Mileo A.M.; Miccadei S.; Schenone S.; Musumeci F.; Haas T.L.; Sette G.; Carapella C.M.; Amato R.; Perrotti N.; Signore M.; Paggi M.G.Matteoni, S.; Abbruzzese, C.; Matarrese, P.; De Luca, G.; Mileo, A. M.; Miccadei, S.; Schenone, S.; Musumeci, F.; Haas, T. L.; Sette, G.; Carapella, C. M.; Amato, R.; Perrotti, N.; Signore, M.; Paggi, M. G