Upper bounds for the eigenvalues of Hessian equations

We prove some upper bounds for the Dirichlet eigenvalues of a class of fully nonlinear elliptic equations, namely the Hessian equationsComment: 15 pages, 1 figur

Post-acute delivery of erythropoietin induces stroke recovery by promoting perilesional tissue remodelling and contralesional pyramidal tract plasticity

The promotion of post-ischaemic motor recovery remains a major challenge in clinical neurology. Recently, plasticity-promoting effects have been described for the growth factor erythropoietin in animal models of neurodegenerative diseases. To elucidate erythropoietin's effects in the post-acute ischaemic brain, we examined how this growth factor influences functional neurological recovery, perilesional tissue remodelling and axonal sprouting of the corticorubral and corticobulbar tracts, when administered intra-cerebroventricularly starting 3 days after 30 min of middle cerebral artery occlusion. Erythropoietin administered at 10 IU/day (but not at 1 IU/day), increased grip strength of the contralesional paretic forelimb and improved motor coordination without influencing spontaneous locomotor activity and exploration behaviour. Neurological recovery by erythropoietin was associated with structural remodelling of ischaemic brain tissue, reflected by enhanced neuronal survival, increased angiogenesis and decreased reactive astrogliosis that resulted in reduced scar formation. Enhanced axonal sprouting from the ipsilesional pyramidal tract into the brainstem was observed in vehicle-treated ischaemic compared with non-ischaemic animals, as shown by injection of dextran amines into both motor cortices. Despite successful remodelling of the perilesional tissue, erythropoietin enhanced axonal sprouting of the contralesional, but not ipsilesional pyramidal tract at the level of the red and facial nuclei. Moreover, molecular biological and histochemical studies revealed broad anti-inflammatory effects of erythropoietin in both hemispheres together with expression changes of plasticity-related molecules that facilitated contralesional axonal growth. Our study establishes a plasticity-promoting effect of erythropoietin after stroke, indicating that erythropoietin acts via recruitment of contralesional rather than of ipsilesional pyramidal tract projection

Soil carbon investigation in three pedoclimatic and agronomic settings of northern Italy

Sustainable agricultural management is needed to promote carbon (C) sequestration in soil, prevent loss of soil fertility, and reduce the release of greenhouse gases. However, the influence of agronomic practices on soil C sequestration depends on the existing pedoclimatic features. We characterized the soils of three farms far away each other in the Emilia-Romagna region (Northern Italy): an organic farm in the Northern Apennines, a biodynamic farm, and a conventional farm on the Po Plain. The total, inorganic, and organic carbon in soil, as well as the distinct humic fractions were investigated, analyzing both the elemental and isotopic (13C/12C) composition. In soils, organic matter appears to be variously affected by mineralization processes induced by microorganisms that consume organic carbon. In particular, organic carbon declined in farms located in the plain (e.g., organic carbon down to 0.75 wt%; carbon stock0-30 cm down to 33 Mg/ha), because of the warmer climate and moderately alkaline environment that enhance soil microbial activity. On the other hand, at the mountain farm, the minimum soil disturbance, the cold climate, and the neutral conditions favored soil C sequestration (organic carbon up to 4.42 wt%; carbon stock0-30 cm up to 160 Mg/ha) in humified organic compounds with long turnover, which can limit greenhouse gas emissions into the atmosphere. This work shows the need for thorough soil investigations, to propose tailored best-practices that can reconcile productivity and soil sustainability

Primary Tumor Resection for Metastatic Colorectal, Gastric and Pancreatic Cancer Patients: In Search of Scientific Evidence to Inform Clinical Practice

The management of the primary tumor in metastatic colorectal, gastric and pancreatic cancer patients may be challenging. Indeed, primary tumor progression could be associated with severe symptoms, compromising the quality of life and the feasibility of effective systemic therapy, and might result in life-threatening complications. While retrospective series have suggested that surgery on the primary tumor may confer a survival advantage even in asymptomatic patients, randomized trials seem not to definitively support this hypothesis. We discuss the evidence for and against primary tumor resection for patients with metastatic gastrointestinal (colorectal, gastric and pancreatic) cancers treated with systemic therapies and put in context the pros and cons of the onco-surgical approach in the time of precision oncology. We also evaluate current ongoing trials on this topic, anticipating how these will influence both research and everyday practice

Dystonia-ataxia syndrome with permanent torsional nystagmus caused by ECHS1 deficiency

Biallelic mutations in ECHS1, encoding the mitochondrial enoyl-CoA hydratase, have been associated with mitochondrial encephalopathies with basal ganglia involvement. Here, we describe a novel clinical presentation consisting of dystonia-ataxia syndrome with hearing loss and a peculiar torsional nystagmus observed in two adult siblings. The presence of a 0.9-ppm peak at MR spectroscopy analysis suggested the accumulation of branched-chain amino acids. Exome sequencing in index probands identified two ECHS1 mutations, one of which was novel (p.V82L). ECHS1 protein levels and residual activities were reduced in patients' fibroblasts. This paper expands the phenotypic spectrum observed in patients with impaired valine catabolism

Loss of the nucleoporin Aladin in central nervous system and fibroblasts of Allgrove Syndrome

Allgrove syndrome (AS) is a rare disease with broad neurological involvement. Neurodegeneration can affect spinal motor neurons, Purkinje cells, striatal neurons, and the autonomic system. The mechanisms that lead to neuronal loss are still unclear. Recessive mutations in the AAAS gene affect the encoded protein Aladin, which would normally localize to the cytoplasmic face of the nuclear membrane as part of the nuclear pore complex (NPC). While the NPC is known to be a key factor for nucleo-cytoplasmic transport, the precise role of Aladin has not been elucidated yet. Here, we explored the consequences of the homozygous AAAS mutation c.464G>A (p.R155H) in central nervous system tissues and fibroblasts of a novel AS patient presenting motor neuron disease, cerebellar ataxia, and autonomic dysfunction. Neuropathological analyses showed severe loss of motor neurons and Purkinje cells, with significant reduction in the perinuclear expression of Aladin. A reduced amount of protein was detected in the nuclear membrane fraction of the patient's brain. RNA analysis revealed a significant reduction of the transcript AAAS-1, while the AAAS-2 transcript was upregulated in fibroblasts. To our knowledge, this is the first study to demonstrate the effects of AAAS mutations in human central nervous system

Baseline computed-tomography (CT)-evaluated sarcopenia predicts toxicity from first-line chemotherapy in metastatic gastric cancer (mGC) patients

Introduction: The impact of sarcopenia as a predictor of poor prognosis and its association with chemotherapy toxicity have been explored in different cancer types but remain controversial in mGC. Our aim was to explore the correlation between sarcopenia, evaluated at baseline CT scan, and toxicity and efficacy of first-line therapy. Methods: We retrospectively analyzed pre-treatment CT scans from 78 mGC patients treated with first-line doublet chemotherapy comprising oxaliplatin and 5-fluorouracil/leucovorin or capecitabine (trastuzumab was administered in case of HER2-positive disease). Sarcopenia was defined according to previously published criteria (Martin L et al. J Clin Oncol 2013) by the use of the skeletal muscle index (SMI) and body mass index (BMI), according to gender-specific cut-off values. SMI was calculated as follows: cross-sectional skeletal muscle area (SMA) measured at the level of the third lumbar vertebra / (height)2 (m2). Toxicities were graded according to NCI CTCAE v.4.0. Association between the presence of sarcopenia and different adverse events was evaluated by Chi-square test. Correlation with response rate (RR, evaluated according to RECIST criteria 1.1), progression-free survival (PFS) and overall survival (OS) was assessed by the use of the log-rank test. Results: Sarcopenia was evident in 34 (44%) patients. We observed a significant association between the presence of sarcopenia at baseline assessment and a higher risk of severe (i.e. grade 3-4) neutropenia (38% versus 18%; p = 0.048) and a higher risk of any grade mucosal toxicities (56% versus 34%; p = 0.045). None of the other investigated clinical factors (comprising age, gender, performance status, sites of metastases and previous surgery on primary tumor) was associated with the risk of toxicity. Neither sarcopenia nor the other evaluated clinical parameters were associated with outcome as measured by RR, PFS, and OS: the only exception was performance status, which was confirmed a major prognostic determinant in terms of PFS and OS. Conclusion: Our experience identified sarcopenia as a potential determinant of the risk of hematologic and mucosal toxicities from first-line platinum plus fluoropyrimidine chemotherapy in mGC patients. Sarcopenia was apparently not associated with benefit from treatment and survival, but larger studies are needed to address this issue. Strategies aiming at improving the nutritional status of mGC patients are warranted to optimize the risk-to-benefit ratio of available treatments

Endothelin receptor B antagonists decrease glioma cell viability independently of their cognate receptor

Background: Endothelin receptor antagonists inhibit the progression of many cancers, but research into their influence on glioma has been limited. Methods: We treated glioma cell lines, LN-229 and SW1088, and melanoma cell lines, A375 and WM35, with two endothelin receptor type B (ETRB)-specific antagonists, A-192621 and BQ788, and quantified viable cells by the capacity of their intracellular esterases to convert non-fluorescent calcein AM into green-fluorescent calcein. We assessed cell proliferation by labeling cells with carboxyfluorescein diacetate succinimidyl ester and quantifying the fluorescence by FACS analysis. We also examined the cell cycle status using BrdU/propidium iodide double staining and FACS analysis. We evaluated changes in gene expression by microarray analysis following treatment with A-192621 in glioma cells. We examined the role of ETRB by reducing its expression level using small interfering RNA (siRNA). Results: We report that two ETRB-specific antagonists, A-192621 and BQ788, reduce the number of viable cells in two glioma cell lines in a dose- and time-dependent manner. We describe similar results for two melanoma cell lines. The more potent of the two antagonists, A-192621, decreases the mean number of cell divisions at least in part by inducing a G2/M arrest and apoptosis. Microarray analysis of the effects of A-192621 treatment reveals up-regulation of several DNA damage-inducible genes. These results were confirmed by real-time RT-PCR. Importantly, reducing expression of ETRB with siRNAs does not abrogate the effects of either A-192621 or BQ788 in glioma or melanoma cells. Furthermore, BQ123, an endothelin receptor type A (ETRA)-specific antagonist, has no effect on cell viability in any of these cell lines, indicating that the ETRB-independent effects on cell viability exhibited by A-192621 and BQ788 are not a result of ETRA inhibition. Conclusion: While ETRB antagonists reduce the viability of glioma cells in vitro, it appears unlikely that this effect is mediated by ETRB inhibition or cross-reaction with ETRA. Instead, we present evidence that A-192621 affects glioma and melanoma viability by activating stress/DNA damage response pathways, which leads to cell cycle arrest and apoptosis. This is the first evidence linking ETRB antagonist treatment to enhanced expression of DNA damage-inducible genes

predicting her2 status in esophagogastric cancer development and validation of an easy to use nomogram

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Association between dietary patterns and renal function in a cross-sectional study using baseline data from the ELSA-Brasil cohort

Previous analyses of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) identified four main dietary patterns (DP). The aim of this study was to explore the association between the previously defined DP and renal function (RF). A crosssectional study using the ELSA-Brasil baseline data was carried out. DP (‘‘traditional’’, ‘‘fruits and vegetables’’, ‘‘bakery’’, and ‘‘low sugar/low fat), metabolic syndrome (MS) using the Joint Interim Statement criteria, microalbuminuria (MA), and glomerular filtration rate (eGFR) through the CKD-EPI equation were evaluated. Abnormal RF was defined as eGFRo60 mL min–1 (1.73 m2 ) –1 and MAX3.0 mg/dL. Factors associated with RF were determined and mediation analysis was performed to investigate the association between DP, MS, and RF. A total of 15,105 participants were recruited, with a mean age of 52±9 years; 8,134 participants (54%) were females. The mediation analysis identified indirect associations between ‘‘bakery’’ and ‘‘fruits and vegetables’’, and both were associated with decreased eGFR and albuminuria in both genders, compared with ‘‘traditional’’ and ‘‘low sugar/low fat’’ patterns in the general population. There was a direct association of the ‘‘bakery’’ pattern with MA in men (OR: 1.17, 95%CI: 1.92–1.48). The ‘‘fruits and vegetables’’ pattern also showed a direct association with reduced eGFR in women (OR: 1.65, 95%CI: 1.28–2.12), although there was no significance after adjustment. The ‘‘fruits and vegetables’’ and ‘‘bakery’’ DPs were associated with renal dysfunction. The only independent, direct association was between ‘‘bakery’’ DP and MA in men, raising concerns about DP and renal damage in men