β-Catenin Activation in Hepatocellular Cancer: Implications in Biology and Therapy

Hepatocellular cancer (HCC), the most common primary liver tumor, has been gradually growing in incidence globally. The whole-genome and whole-exome sequencing of HCC has led to an improved understanding of the molecular drivers of this tumor type. Activation of the Wnt signaling pathway, mostly due to stabilizing missense mutations in its downstream effector β-catenin (encoded by CTNNB1) or loss-of-function mutations in AXIN1 (the gene which encodes for Axin-1, an essential protein for β-catenin degradation), are seen in a major subset of HCC. Because of the important role of β-catenin in liver pathobiology, its role in HCC has been extensively investigated. In fact, CTNNB1 mutations have been shown to have a trunk role. β-Catenin has been shown to play an important role in regulating tumor cell proliferation and survival and in tumor angiogenesis, due to a host of target genes regulated by the β-catenin transactivation of its transcriptional factor TCF. Proof-of-concept preclinical studies have shown β-catenin to be a highly relevant therapeutic target in CTNNB1-mutated HCCs. More recently, studies have revealed a unique role of β-catenin activation in regulating both tumor metabolism as well as the tumor immune microenvironment. Both these roles have notable implications for the development of novel therapies for HCC. Thus, β-catenin has a pertinent role in driving HCC development and maintenance of this tumor-type, and could be a highly relevant therapeutic target in a subset of HCC cases

Field validation of a farmer supplied data approach to close soybean yield gaps in the US North Central region

CONTEXT: Producer-reported data can be used to identify suites of management practices that lead to higher yield and profit. However, a rigorous validation of the approach in relation to its potential impact on farmer yield and profit is lacking. OBJECTIVE: This study aimed to validate a producer-data approach on its capability to guide on-farm evaluation of management practices with greatest potential for increasing producer yield and profit. We show proof of concept using soybean in the North Central US region as a case study. METHODS: We used a combination of regression tree analysis and a spatial framework to determine practices with highest influence on yield for specific climate domains across the region. These practices were used as a basis for designing an ‘improved’ management package for each domain. The impact associated with adoption of the ‘improved’ management package on producer yield, seed constituents, and profit was evaluated against a ‘reference’ treatment that follows farmer management via replicated on-farm trials across 100 sites over two crop seasons. RESULTS AND CONCLUSIONS: Average yield was 278 kg ha-1 higher in the improved versus reference management, equivalent to a closure of the current exploitable yield gap by 40%. In turn, adoption of the improved management led to an average increase of $76 ha-1 in net profit. Sensitivity analysis showed that adoption of the improved management packages should increase farmer profit across a wide range of grain price scenarios, with very small downside risk. Seed protein concentration was negatively associated with the positive yield advantage of the improved management, whereas seed oil concentration tended to increase. SIGNIFICANCE: Analysis of producer data can accelerate discovery, evaluation, and adoption of suites of management practices that consistently lead to higher farmer yield and profit, which, in turn, would help speed up current rates of yield gain

Does 3-Day Course of Oral Amoxycillin Benefit Children of Non-Severe Pneumonia with Wheeze: A Multicentric Randomised Controlled Trial

WHO-defined pneumonias, treated with antibiotics, are responsible for a significant proportion of childhood morbidity and mortality in the developing countries. Since substantial proportion pneumonias have a viral etiology, where children are more likely to present with wheeze, there is a concern that currently antibiotics are being over-prescribed for it. Hence the current trial was conducted with the objective to show the therapeutic equivalence of two treatments (placebo and amoxycillin) for children presenting with non-severe pneumonia with wheeze, who have persistent fast breathing after nebulisation with salbutamol, and have normal chest radiograph.This multi-centric, randomised placebo controlled double blind clinical trial intended to investigate equivalent efficacy of placebo and amoxicillin and was conducted in ambulatory care settings in eight government hospitals in India. Participants were children aged 2-59 months of age, who received either oral amoxycillin (31-54 mg/Kg/day, in three divided doses for three days) or placebo, and standard bronchodilator therapy. Primary outcome was clinical failure on or before day- 4.We randomized 836 cases in placebo and 835 in amoxycillin group. Clinical failures occurred in 201 (24.0%) on placebo and 166 (19.9%) on amoxycillin (risk difference 4.2% in favour of antibiotic, 95% CI: 0.2 to 8.1). Adherence for both placebo and amoxycillin was >96% and 98.9% subjects were followed up on day- 4. Clinical failure was associated with (i) placebo treatment (adjusted OR = 1.28, 95% CI: 1.01 to1.62), (ii) excess respiratory rate of >10 breaths per minute (adjusted OR = 1.51, 95% CI: 1.19, 1.92), (iii) vomiting at enrolment (adjusted OR = 1.49, 95% CI: 1.13, 1.96), (iv) history of use of broncho-dilators (adjusted OR = 1.71, 95% CI: 1.30, 2.24) and (v) non-adherence (adjusted OR = 8.06, 95% CI: 4.36, 14.92).Treating children with non-severe pneumonia and wheeze with a placebo is not equivalent to treatment with oral amoxycillin.ClinicalTrials.gov NCT00407394

High rate, fast timing Glass RPC for the high {\eta} CMS muon detectors

The HL-LHC phase is designed to increase by an order of magnitude the amount of data to be collected by the LHC experiments. To achieve this goal in a reasonable time scale the instantaneous luminosity would also increase by an order of magnitude up to $6.10^{34} cm^{-2} s^{-1}$ . The region of the forward muon spectrometer ($|{\eta}| > 1.6$) is not equipped with RPC stations. The increase of the expected particles rate up to $2 kHz/cm^{2}$ (including a safety factor 3) motivates the installation of RPC chambers to guarantee redundancy with the CSC chambers already present. The actual RPC technology of CMS cannot sustain the expected background level. The new technology that will be chosen should have a high rate capability and provides a good spatial and timing resolution. A new generation of Glass-RPC (GRPC) using low-resistivity (LR) glass is proposed to equip at least the two most far away of the four high ${\eta}$ muon stations of CMS. First the design of small size prototypes and studies of their performance in high-rate particles flux is presented. Then the proposed designs for large size chambers and their fast-timing electronic readout are examined and preliminary results are provided.Comment: 14 pages, 11 figures, Conference proceeding for the 2016 Resistive Plate Chambers and Related Detector

Signs and symptoms in children with a serious infection: a qualitative study

BACKGROUND: Early diagnosis of serious infections in children is difficult in general practice, as incidence is low, patients present themselves at an early stage of the disease and diagnostic tools are limited to signs and symptoms from observation, clinical history and physical examination. Little is known which signs and symptoms are important in general practice. With this qualitative study, we aimed to identify possible new important diagnostic variables. METHODS: Semi-structured interviews with parents and physicians of children with a serious infection. We investigated all signs and symptoms that were related to or preceded the diagnosis. The analysis was done according to the grounded theory approach. Participants were recruited in general practice and at the hospital. RESULTS: 18 children who were hospitalised because of a serious infection were included. On average, parents and paediatricians were interviewed 3 days after admittance of the child to hospital, general practitioners between 5 and 8 days after the initial contact. The most prominent diagnostic signs in seriously ill children were changed behaviour, crying characteristics and the parents' opinion. Children either behaved drowsy or irritable and cried differently, either moaning or an inconsolable, loud crying. The parents found this illness different from previous illnesses, because of the seriousness or duration of the symptoms, or the occurrence of a critical incident. Classical signs, like high fever, petechiae or abnormalities at auscultation were helpful for the diagnosis when they were present, but not helpful when they were absent. CONCLUSION: behavioural signs and symptoms were very prominent in children with a serious infection. They will be further assessed for diagnostic accuracy in a subsequent, quantitative diagnostic study

Prognostic factors related to sequelae in childhood bacterial meningitis: Data from a Greek meningitis registry

<p>Abstract</p> <p>Background</p> <p>Bacterial meningitis (BM) is a life-threatening disease, often related with serious complications and sequelae. Infants and children who survive bacterial meningitis often suffer neurological and other sequelae.</p> <p>Methods</p> <p>A total of 2,477 patients aged 1 month to 14 years old hospitalized in a Children's Hospital in Greece diagnosed with acute bacterial meningitis were collected through a Meningitis Registry, from 1974 to 2005. Clinical, laboratory and other parameters (sex, age, pathogen, duration of symptoms before and after admission) were evaluated through univariate and multivariate analysis with regard to sequelae. Analysis of acute complications were also studied but not included in the final model.</p> <p>Results</p> <p>The rate of acute complications (arthritis and/or subdural effusion) was estimated at 6.8% (152 out of 2,251 patients, 95%CI 5.8-7.9) while the rate of sequelae (severe hearing loss, ventriculitis, hydrocephalus or seizure disorder) among survivors was estimated at 3.3% (73 out of 2,207 patients, 95%CI 2.6-4.2). Risk factors on admission associated with sequelae included seizures, absence of hemorrhagic rash, low CSF glucose, high CSF protein and the etiology of meningitis. A combination of significant prognostic factors including presence of seizures, low CSF glucose, high CSF protein, positive blood culture and absence of petechiae on admission presented an absolute risk of sequelae of 41.7% (95%CI 15.2-72.3).</p> <p>Conclusions</p> <p>A combination of prognostic factors of sequelae in childhood BM may be of value in selecting patients for more intensive therapy and in identifying possible candidates for new treatment strategies.</p