Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma.

SHH Medulloblastoma (SHH-MB) is a pediatric brain tumor characterized by an inappropriate activation of the developmental Hedgehog (Hh) signaling. SHH-MB patients treated with the FDA-approved vismodegib, an Hh inhibitor that targets the transmembrane activator Smoothened (Smo), have shown the rapid development of drug resistance and tumor relapse due to novel Smo mutations. Moreover, a subset of patients did not respond to vismodegib because mutations were localized downstream of Smo. Thus, targeting downstream Hh components is now considered a preferable approach. We show here that selective inhibition of the downstream Hh effectors HDAC1 and HDAC2 robustly counteracts SHH-MB growth in mouse models. These two deacetylases are upregulated in tumor and their knockdown inhibits Hh signaling and decreases tumor growth. We demonstrate that mocetinostat (MGCD0103), a selective HDAC1/HDAC2 inhibitor, is a potent Hh inhibitor and that its effect is linked to Gli1 acetylation at K518. Of note, we demonstrate that administration of mocetinostat to mouse models of SHH-MB drastically reduces tumor growth, by reducing proliferation and increasing apoptosis of tumor cells and prolongs mouse survival rate. Collectively, these data demonstrate the preclinical efficacy of targeting the downstream HDAC1/2-Gli1 acetylation in the treatment of SHH-MB

A close connection: Alzheimer’s disease and type 2 diabetes

In the recent years a growing body of evidence links insulin resistance and insulin action to neurodegenerative diseases, especially Alzheimer’s disease (AD). The importance of insulin in ageing as well as its role in cognition and other aspects of normal brain functions are well established. The hippocampus and cerebral cortex-distributed insulin and insulin receptor (IR) have been shown to be involved in brain cognitive functions. Conversely, deterioration of IR signaling is involved in agingrelated brain degeneration such as in AD and cognitive impairment in type 2 diabetes patients. Insulin administration, while maintaining euglycemia, improves memory in both healthy adults and Alzheimer’s disease patients. In the present review, some common links between AD and type 2 diabetes are presented. Furthermore, several biochemical aspects existing in both pathologies are highlighted

EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers

The involvement of the MET oncogene in de novo and acquired resistance of non-small cell lung cancers (NSCLC) to tyrosine kinase inhibitors (TKIs) has been reported, but the precise mechanism by which MET overexpression contributes to TKI-resistant NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression and their dysregulation has been implicated in tumorigenesis. To understand the role of microRNAs in TKI-resistant NSCLC, we examined TK receptor-mediated microRNA changes. Here we report that miR-30b/c and miR-221/222, modulated by both EGF and MET receptors, and miR-103, -203, controlled only by MET, play important roles in gefitinib-induced apoptosis and epithelial-mesenchymal transition (EMT) of NSCLC cells, in vitro and in vivo, by inhibiting the expression of Bim, APAF-1, PKC-ε and SRC genes. The finding suggests that modulation of specific microRNAs may provide a therapeutic approach for future treatment of NSCLC

Practical and clinical utility of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine. A post hoc analysis of the randomized, sham-controlled, double-blind PRESTO trial

Background: The PRESTO study of non-invasive vagus nerve stimulation (nVNS; gammaCore®) featured key primary and secondary end points recommended by the International Headache Society to provide Class I evidence that for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 h post stimulation. Here, we examined additional data from PRESTO to provide further insights into the practical utility of nVNS by evaluating its ability to consistently deliver clinically meaningful improvements in pain intensity while reducing the need for rescue medication. Methods: Patients recorded pain intensity for treated migraine attacks on a 4-point scale. Data were examined to compare nVNS and sham with regard to the percentage of patients who benefited by at least 1 point in pain intensity. We also assessed the percentage of attacks that required rescue medication and pain-free rates stratified by pain intensity at treatment initiation. Results: A significantly higher percentage of patients who used acute nVNS treatment (n = 120) vs sham (n = 123) reported a ≥ 1-point decrease in pain intensity at 30 min (nVNS, 32.2%; sham, 18.5%; P = 0.020), 60 min (nVNS, 38.8%; sham, 24.0%; P = 0.017), and 120 min (nVNS, 46.8%; sham, 26.2%; P = 0.002) after the first attack. Similar significant results were seen when assessing the benefit in all attacks. The proportion of patients who did not require rescue medication was significantly higher with nVNS than with sham for the first attack (nVNS, 59.3%; sham, 41.9%; P = 0.013) and all attacks (nVNS, 52.3%; sham, 37.3%; P = 0.008). When initial pain intensity was mild, the percentage of patients with no pain after treatment was significantly higher with nVNS than with sham at 60 min (all attacks: nVNS, 37.0%; sham, 21.2%; P = 0.025) and 120 min (first attack: nVNS, 50.0%; sham, 25.0%; P = 0.018; all attacks: nVNS, 46.7%; sham, 30.1%; P = 0.037). Conclusions: This post hoc analysis demonstrated that acute nVNS treatment quickly and consistently reduced pain intensity while decreasing rescue medication use. These clinical benefits provide guidance in the optimal use of nVNS in everyday practice, which can potentially reduce use of acute pharmacologic medications and their associated adverse events. Trial registration: ClinicalTrials.gov identifier: NCT02686034

Combined search for the standard model Higgs boson decaying to a bb pair using the full CDF data set

We combine the results of searches for the standard model Higgs boson based on the full CDF Run II data set obtained from sqrt(s) = 1.96 TeV p-pbar collisions at the Fermilab Tevatron corresponding to an integrated luminosity of 9.45/fb. The searches are conducted for Higgs bosons that are produced in association with a W or Z boson, have masses in the range 90-150 GeV/c^2, and decay into bb pairs. An excess of data is present that is inconsistent with the background prediction at the level of 2.5 standard deviations (the most significant local excess is 2.7 standard deviations).Comment: To be published in Phys. Rev. Lett (v2 contains minor updates based on comments from PRL

Impact of social determinants on antiretroviral therapy access and outcomes entering the era of universal treatment for people living with HIV in Italy

Background: Social determinants are known to be a driving force of health inequalities, even in high income countries. Aim of our study was to determine if these factors can limit antiretroviral therapy (ART) access, outcome and retention in care of people living with HIV (PLHIV) in Italy. Methods: All ART naïve HIV+ patients (pts) of Italian nationality enrolled in the ICONA Cohort from 2002 to 2016 were included. The association of socio-demographic characteristics (age, sex, risk factor for HIV infection, educational level, occupational status and residency area) with time to: ART initiation (from the first positive anti-HIV test), ART regimen discontinuation, and first HIV-RNA < 50 cp/mL, were evaluated by Cox regression analysis, Kaplan Meier method and log-rank test. Results: A total of 8023 HIV+ pts (82% males, median age at first pos anti-HIV test 36 years, IQR: 29-44) were included: 6214 (77.5%) started ART during the study period. Women, people who inject drugs (PWID) and residents in Southern Italy presented the lowest levels of education and the highest rate of unemployment compared to other groups. Females, pts aged > 50 yrs., unemployed vs employed, and people with lower educational levels presented the lowest CD4 count at ART initiation compared to other groups. The overall median time to ART initiation was 0.6 years (yrs) (IQR 0.1-3.7), with a significant decrease over time [2002-2006 = 3.3 yrs. (0.2-9.4); 2007-2011 = 1.0 yrs. (0.1-3.9); 2012-2016 = 0.2 yrs. (0.1-2.1), p < 0.001]. By multivariate analysis, females (p < 0.01) and PWID (p < 0.001), presented a longer time to ART initiation, while older people (p < 0.001), people with higher educational levels (p < 0.001), unemployed (p = 0.02) and students (p < 0.001) were more likely to initiate ART. Moreover, PWID, unemployed vs stable employed, and pts. with lower educational levels showed a lower 1-year probability of achieving HIV-RNA suppression, while females, older patients, men who have sex with men (MSM), unemployed had higher 1-year risk of first-line ART discontinuation. Conclusions: Despite median time to ART start decreased from 2002 to 2016, socio-demographic factors still contribute to disparities in ART initiation, outcome and durability

Precise measurements of the properties of the B-1(5721)(0,+) and B-2*(5747)(0,+) states and observation of B-+,B-0 pi(-,+) mass structures

Invariant mass distributions of B+π− and B0π+ combinations are investigated in order to study excited B mesons. The analysis is based on a data sample corresponding to 3.0 fb−1 of pp collision data, recorded by the LHCb detector at centre-of-mass energies of 7 and 8 TeV. Precise measurements of the masses and widths of the B1(5721)0,+ and B2(5747)0,+ states are reported. Clear enhancements, particularly prominent at high pion transverse momentum, are seen over background in the mass range 5850-6000 MeV in both B+π− and B0π+ combinations. The structures are consistent with the presence of four excited B mesons, labelled BJ (5840)0,+ and BJ (5960)0,+, whose masses and widths are obtained under different hypotheses for their quantum numbers

X-Linked Parkinsonism: phenotypic and genetic heterogeneity

X-linked parkinsonism encompasses rare heterogeneous disorders mainly inherited as a recessive trait, therefore being more prevalent in males. Recent developments have revealed a complex underlying panorama, including a spectrum of disorders in which parkinsonism is variably associated with additional neurological and non-neurological signs. In particular, a childhood-onset encephalopathy with epilepsy and/or cognitive disability is the most common feature. Their genetic basis is also heterogeneous, with many causative genes and different mutation types ranging from "classical" coding variants to intronic repeat expansions. In this review, we provide an updated overview of the phenotypic and genetic spectrum of the most relevant X-linked parkinsonian syndromes, namely X-linked dystonia-parkinsonism (XDP, Lubag disease), fragile X-associated tremor/ataxia syndrome (FXTAS), beta-propeller protein-associated neurodegeneration (BPAN, NBIA/PARK-WDR45), Fabry disease, Waisman syndrome, methyl CpG-binding protein 2 (MeCP2) spectrum disorder, phosphoglycerate kinase-1 deficiency syndrome (PGK1) and X-linked parkinsonism and spasticity (XPDS). All clinical and radiological features reported in the literature have been reviewed. Epilepsy occasionally represents the symptom of onset, predating parkinsonism even by a few years; action tremor is another common feature along with akinetic-rigid parkinsonism. A focus on the genetic background and its pathophysiological implications is provided. The pathogenesis of these disorders ranges from well-defined metabolic alterations (PGK1) to non-specific lysosomal dysfunctions (XPDS) and vesicular trafficking alterations (Waisman syndrome). However, in other cases it still remains poorly defined. Recognition of the phenotypic and genetic heterogeneity of X-linked parkinsonism has important implications for diagnosis, management, and genetic counseling. \ua9 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

現地観測に基づく河川流の乱流特性に関する研究

博士（工学）神戸大