Sharp estimates on the first eigenvalue of the p-Laplacian with negative Ricci lower bound

We complete the picture of sharp eigenvalue estimates for the p-Laplacian on a compact manifold by providing sharp estimates on the first nonzero eigenvalue of the nonlinear operator $\Delta_p$ when the Ricci curvature is bounded from below by a negative constant. We assume that the boundary of the manifold is convex, and put Neumann boundary conditions on it. The proof is based on a refined gradient comparison technique and a careful analysis of the underlying model spaces.Comment: Sign mistake fixed in the proof of the gradient comparison theorem (theorem 5.1 pag 10), and some minor improvements aroun

Rectifiability and upper Minkowski bounds for singularities of harmonic Q-valued maps

In this article we prove that the singular set of Dirichlet-minimizing Q-valued functions is countably .m2/-rectifiable and we give upper bounds for the .m2/-dimensional Minkowski content of the set of singular points with multiplicity Q

What is the impact on health and wellbeing of interventions that foster respect and social inclusion in community-residing older adults? A systematic review of quantitative and qualitative studies

BackgroundMany interventions have been developed to promote respect and social inclusion among older people, but the evidence on their impacts on health has not been synthesised. This systematic review aims to appraise the state of the evidence across the quantitative and qualitative literature.MethodsEligible studies published between 1990 and 2015 were identified by scanning seven bibliographic databases using a pre-piloted strategy, searching grey literature and contacting experts. Studies were included if they assessed the impact (quantitatively) and/or perceived impact (qualitatively) of an intervention promoting respect and social inclusion on the physical or mental health of community-residing people aged 60 years and older. Titles and abstracts were screened for eligibility by one reviewer. A second reviewer independently screened a 10% random sample. Full texts were screened for eligibility by one reviewer, with verification by another reviewer. Risk of bias was assessed using standardised tools. Findings were summarised using narrative synthesis, harvest plots and logic models to depict the potential pathways to health outcomes.ResultsOf the 27,354 records retrieved, 40 studies (23 quantitative, 6 qualitative, 11 mixed methods) were included. All studies were conducted in high and upper middle-income countries. Interventions involved mentoring, intergenerational and multi-activity programmes, dancing, music and singing, art and culture and information-communication technology. Most studies (n = 24) were at high or moderate risk of bias. Music and singing, intergenerational interventions, art and culture and multi-activity interventions were associated with an overall positive impact on health outcomes. This included depression (n = 3), wellbeing (n = 3), subjective health (n = 2), quality of life (n = 2), perceived stress and mental health (n = 2) and physical health (n = 2). Qualitative studies offered explanations for mediating factors (e.g. improved self-esteem) that may lead to improved health outcomes and contributed to the assessment of causation.ConclusionsWhilst this review suggests that some interventions may positively impact on the health outcomes of older people, and identified mediating factors to health outcomes, the evidence is based on studies with heterogeneous methodologies. Many of the interventions were delivered as projects to selected groups, raising important questions about the feasibility of wider implementation and the potential for population-wide benefits.Systematic review registrationPROSPERO registration number CRD42014010107

Improved efficacy response attributed to diagnostic selection – Interim results of the phase 1 experience from ALKA-372-001

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Validation of an Engineered Cell Model for In Vitro and In Vivo HIF-1 alpha Evaluation by Different Imaging Modalities

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Combined characterization of a pituitary adenoma and a subcutaneous lipoma in a MEN1 patient with a whole gene deletion

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary disorder associated with mutations of the MEN1 gene, which is characterized by combined tumors of the parathyroid glands, pancreatic islet cells, and the anterior pituitary. A significant number of patients with the clinical features of MEN1, however, do not show MEN1 mutations upon direct sequencing. We describe a young woman who fulfilled the clinical and biochemical criteria for MEN1 syndrome, but DNA sequencing did not indicate any MEN1 mutations. She developed a prolactin-secreting pituitary macroadenoma, primary hyperparathyroidism with parathyroid hyperplasia, pancreatic lesions, and two subcutaneous lipomas. Array comparative genomic hybridization (aCGH) analysis of peripheral blood DNA revealed a heterozygous germline deletion at 11q13.1 that spanned at least 22.23 kilobases and contained the entire MEN1 gene. Integrated aCGH and cytogenetic analyses of the adenoma and lipoma tissues revealed somatic inactivation of the wild-type MEN1 allele by different routes: the second hit of MEN1 recessive oncogenesis leading to adenoma implied a loss of heterozygosity, whereas a balanced translocation deleting the wild-type MEN1 allele primed the lipoma development. These findings show that aCGH is a valuable means of optimizing genetic testing in MEN1 patients which complements other technologic approaches to elucidating the pathologic mechanisms of MEN1 tumors

[18F](2S,4R)-4-Fluoroglutamine as a New Positron Emission Tomography Tracer in Myeloma

The high glycolytic activity of multiple myeloma (MM) cells is the rationale for use of Positron Emission Tomography (PET) with 18F-fluorodeoxyglucose ([18F]FDG) to detect both bone marrow (BM) and extramedullary disease. However, new tracers are actively searched because [18F]FDG-PET has some limitations and there is a portion of MM patients who are negative. Glutamine (Gln) addiction has been recently described as a typical metabolic feature of MM cells. Yet, the possible exploitation of Gln as a PET tracer in MM has never been assessed so far and is investigated in this study in preclinical models. Firstly, we have synthesized enantiopure (2S,4R)-4-fluoroglutamine (4-FGln) and validated it as a Gln transport analogue in human MM cell lines, comparing its uptake with that of 3H-labelled Gln. We then radiosynthesized [18F]4-FGln, tested its uptake in two different in vivo murine MM models, and checked the effect of Bortezomib, a proteasome inhibitor currently used in the treatment of MM. Both [18F]4-FGln and [18F]FDG clearly identified the spleen as site of MM cell colonization in C57BL/6 mice, challenged with syngeneic Vk12598 cells and assessed by PET. NOD.SCID mice, subcutaneously injected with human MM JJN3 cells, showed high values of both [18F]4-FGln and [18F]FDG uptake. Bortezomib significantly reduced the uptake of both radiopharmaceuticals in comparison with vehicle at post treatment PET. However, a reduction of glutaminolytic, but not of glycolytic, tumor volume was evident in mice showing the highest response to Bortezomib. Our data indicate that [18F](2S,4R)-4-FGln is a new PET tracer in preclinical MM models, yielding a rationale to design studies in MM patients

APache Is an AP2-Interacting Protein Involved in Synaptic Vesicle Trafficking and Neuronal Development

Synaptic transmission is critically dependent on synaptic vesicle (SV) recycling. Although the precise mechanisms of SV retrieval are still debated, it is widely accepted that a fundamental role is played by clathrin-mediated endocytosis, a form of endocytosis that capitalizes on the clathrin/adaptor protein complex 2 (AP2) coat and several accessory factors. Here, we show that the previously uncharacterized protein KIAA1107, predicted by bioinformatics analysis to be involved in the SV cycle, is an AP2-interacting clathrin-endocytosis protein (APache). We found that APache is highly enriched in the CNS and is associated with clathrin-coated vesicles via interaction with AP2. APache-silenced neurons exhibit a severe impairment of maturation at early developmental stages, reduced SV density, enlarged endosome-like structures, and defects in synaptic transmission, consistent with an impaired clathrin/AP2-mediated SV recycling. Our data implicate APache as an actor in the complex regulation of SV trafficking, neuronal development, and synaptic plasticity

The clock is ticking on schizophrenia: a study protocol for a translational study integrating phenotypic, genomic, microbiome and biomolecular data to overcome disability

Background: Shared biological factors may play a role in both the cognitive deficits and the increased prevalence of metabolic syndrome observed in individuals with Schizophrenia (SCZ). These factors could entail disturbances in tryptophan (Trp) to both melatonin (MLT) and kynurenine (Kyn) metabolic pathways, as well as inflammation and alterations in the gut microbiome composition. Methods: The present research project aims to investigate this hypothesis by recruiting 170 SCZ patients from two different recruitment sites, assessing their cognitive functions and screening for the presence of metabolic syndrome. Additionally, we plan to assess the impact of a 3-month cognitive remediation therapy on 30 of these patients. We will analyze clinical data alongside serum biomarkers and gene expression related to the Trp- to MLT and Kyn metabolic pathways, markers of inflammatory and composition of the gut microbiome. The association between Trp-MLT-Kyn levels, expression levels of selected genes, inflammatory markers and clinical phenotypes will be analyses in the context of general linear models. Discussion: This project has the potential to identify some typical SCZ symptomatic clusters that will be more stringently associated with variations in the Trp-MLT-Kyn/inflammatory system and with a better response to cognitive remediation therapy. Moreover, in a future perspective, it may highlight a group of patients who may benefit from a pharmacological treatment aiming at reinstating the physiological Trp to MLT and Kyn system. Therefore, it has the potential to move research toward a personalized approach for SCZ management

Amplification of the MET Receptor Drives Resistance to Anti-EGFR Therapies in Colorectal Cancer.

EGF receptor (EGFR)-targeted monoclonal antibodies are effective in a subset of metastatic colorectal cancers. Inevitably, all patients develop resistance, which occurs through emergence of KRAS mutations in approximately 50% of the cases. We show that amplification of the MET proto-oncogene is associated with acquired resistance in tumors that do not develop KRAS mutations during anti-EGFR therapy. Amplification of the MET locus was present in circulating tumor DNA before relapse was clinically evident. Functional studies show that MET activation confers resistance to anti-EGFR therapy both in vitro and in vivo. Notably, in patient-derived colorectal cancer xenografts, MET amplification correlated with resistance to EGFR blockade, which could be overcome by MET kinase inhibitors. These results highlight the role of MET in mediating primary and secondary resistance to anti-EGFR therapies in colorectal cancer and encourage the use of MET inhibitors in patients displaying resistance as a result of MET amplification. SIGNIFICANCE: Amplification of the MET proto-oncogene is responsible for de novo and acquired resistance to anti-EGFR therapy in a subset of colorectal cancers. As multiple anti-MET therapeutic strategies are available, these findings offer immediate novel opportunities to design clinical studies