Hypoxia helps glioma to fight therapy

Despite major improvements in the surgical management the prognosis for patients bearing malignant gliomas is still dismal. Malignant gliomas are notoriously resistant to treatment and the survival time of patients is between 3-8 years for low-grade and anaplastic gliomas and 6 - 12 month for glioblastoma. Increasing malignancy of gliomas correlates with an increase in cellularity and a poorly organized tumour vasculature leading to insufficient blood supply, hypoxic areas and ultimately to the formation of necrosis, a characteristic of glioblastoma. Hypoxic/necrotic tumours are more resistant to chemotherapy and radiation. Hypoxia induces either directly or indirectly (through the activation of transcription factors) changes in the biology of a tumour and its microenvironment leading to increased aggressiveness and tumour resistance to chemotherapy and radiation. This review is focused on hypoxia-induced molecular changes affecting glioma biology and therapy

A Systematic Review of International Clinical Guidelines for Rehabilitation of People With Neurological Conditions: What Recommendations Are Made for Upper Limb Assessment?

Conclusions: We present a comprehensive, critical, and original summary of current recommendations. Defining a core set of measures and agreed protocols requires international consensus between experts representing the diverse and multi-disciplinary field of neurorehabilitation including clinical researchers and practitioners, rehabilitation technology researchers, and commercial developers. Current lack of guidance may hold-back progress in understanding function and recovery. Together with a Delphi consensus study and an overview of systematic reviews of outcome measures it will contribute to the development of international guidelines for upper limb assessment in neurological conditions.This review formed part of the COST Action TD 1006A European Network on Robotics for Neurorehabilitation. It was an interdisciplinary EU-funded research network concentrating on the coordination of European research in the area of rehabilitation robotics

Symmetrical Dimethylarginine as a Diagnostic Parameter in Hermann's Tortoises (Testudo hermanni)

BackgroundDespite improvements in habitational conditions, kidney disease is relatively common in tortoises. ObjectivesPurpose of this study was the establishment of Symmetrical dimethylarginine (SDMA) reference values for clinically healthy Hermann's Tortoises. AnimalsClinically healthy Hermann's Tortoises (n = 131) were included in the period from October 2017 to September 2019. MethodsCreatinine and other biomarkers were tested at IDEXX Laboratories, Germany using residual blood samples from Hermann's tortoises. SDMA was measured with the IDEXX test and verified by liquid chromatography-mass spectrometry at IDEXX Laboratories, USA. ResultsSDMA values ranged from 1 to 21 mu g/dl (n = 131) for the IDEXX SDMA Test and SDMA values ranged from 1 to 17 mu g/dl (n = 82) for LC-MS. For the comparison of the two measuring systems, the following results were obtained R-2 = 0.75 (p < 0.001). Conclusion and Clinical ImportanceSDMA can be measured in Hermann's Tortoises and the reference values range in clinically healthy animals is comparable to that of dogs and cats

European evidence-based recommendations for clinical assessment of upper limb in neurorehabilitation (CAULIN): data synthesis from systematic reviews, clinical practice guidelines and expert consensus

Background: Technology-supported rehabilitation can help alleviate the increasing need for cost-effective rehabilitation of neurological conditions, but use in clinical practice remains limited. Agreement on a core set of reliable, valid and accessible outcome measures to assess rehabilitation outcomes is needed to generate strong evidence about effectiveness of rehabilitation approaches, including technologies. This paper collates and synthesizes a core set from multiple sources; combining existing evidence, clinical practice guidelines and expert consensus into European recommendations for Clinical Assessment of Upper Limb In Neurorehabilitation (CAULIN). Methods: Data from systematic reviews, clinical practice guidelines and expert consensus (Delphi methodology) were systematically extracted and synthesized using strength of evidence rating criteria, in addition to recommendations on assessment procedures. Three sets were defined: a core set: strong evidence for validity, reliability, responsiveness and clinical utility AND recommended by at least two sources; an extended set: strong evidence OR recommended by at least two sources and a supplementary set: some evidence OR recommended by at least one of the sources. Results: In total, 12 measures (with primary focus on stroke) were included, encompassing body function and activity level of the International Classification of Functioning and Health. The core set recommended for clinical practice and research: Fugl-Meyer Assessment of Upper Extremity (FMA-UE) and Action Research Arm Test (ARAT); the extended set recommended for clinical practice and/or clinical research: kinematic measures, Box and Block Test (BBT), Chedoke Arm Hand Activity Inventory (CAHAI), Wolf Motor Function Test (WMFT), Nine Hole Peg Test (NHPT) and ABILHAND; the supplementary set recommended for research or specific occasions: Motricity Index (MI); Chedoke-McMaster Stroke Assessment (CMSA), Stroke Rehabilitation Assessment Movement (STREAM), Frenchay Arm Test (FAT), Motor Assessment Scale (MAS) and body-worn movement sensors. Assessments should be conducted at pre-defined regular intervals by trained personnel. Global measures should be applied within 24 h of hospital admission and upper limb specific measures within 1 week. Conclusions: The CAULIN recommendations for outcome measures and assessment procedures provide a clear, simple, evidence-based three-level structure for upper limb assessment in neurological rehabilitation. Widespread adoption and sustained use will improve quality of clinical practice and facilitate meta-analysis, critical for the advancement of technology-supported neurorehabilitation.The European Network on Robotics for NeuroRehabilitation (Working Group 1) developed these recommendations. Their work was funded by the European Co-Operation in Science and Technology (COST Action TD1006) programme. The funding body had no role in or infuence on the selected approach and synthesis, analysis, and interpretation of data and in writing the manuscript

Prognostic value of the 6-gene OncoMasTR test in hormone receptor–positive HER2-negative early-stage breast cancer: Comparative analysis with standard clinicopathological factors

Aim: The aim of the study was to assess the prognostic performance of a 6-gene molecular score (OncoMasTR Molecular Score [OMm]) and a composite risk score (OncoMasTR Risk Score [OM]) and to conduct a within-patient comparison against four routinely used molecular and clinicopathological risk assessment tools: Oncotype DX Recurrence Score, Ki67, Nottingham Prognostic Index and Clinical Risk Category, based on the modified Adjuvant! Online definition and three risk factors: patient age, tumour size and grade. Methods: Biospecimens and clinicopathological information for 404 Irish women also previously enrolled in the Trial Assigning Individualized Options for Treatment [Rx] were provided by 11 participating hospitals, as the primary objective of an independent translational study. Gene expression measured via RT-qPCR was used to calculate OMm and OM. The prognostic value for distant recurrence-free survival (DRFS) and invasive disease-free survival (IDFS) was assessed using Cox proportional hazards models and Kaplan-Meier analysis. All statistical tests were two-sided ones. Results: OMm and OM (both with likelihood ratio statistic [LRS] P Discussion: Both OncoMasTR scores were significantly prognostic for DRFS and IDFS and provided additional prognostic information to the molecular and clinicopathological risk factors/tools assessed. OM was also the most accurate risk classification tool for identifying DR. A concise 6-gene signature with superior risk stratification was shown to increase prognosis reliability, which may help clinicians optimise treatment decisions. Trial registration: ClinicalTrials.gov NCT02050750 NCT00310180.</p

Comparison of abdominal adiposity and overall obesity in relation to risk of small intestinal cancer in a European Prospective Cohort

Published version. Source at http://dx.doi.org/10.1007/s10552-016-0772-z Background: The etiology of small intestinal cancer (SIC) is largely unknown, and there are very few epidemiological studies published to date. No studies have investigated abdominal adiposity in relation to SIC. Methods: We investigated overall obesity and abdominal adiposity in relation to SIC in the European Prospective Investigation into Cancer and Nutrition (EPIC), a large prospective cohort of approximately half a million men and women from ten European countries. Overall obesity and abdominal obesity were assessed by body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR). Multivariate Cox proportional hazards regression modeling was performed to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). Stratified analyses were conducted by sex, BMI, and smoking status. Results: During an average of 13.9 years of follow-up, 131 incident cases of SIC (including 41 adenocarcinomas, 44 malignant carcinoid tumors, 15 sarcomas and 10 lymphomas, and 21 unknown histology) were identified. WC was positively associated with SIC in a crude model that also included BMI (HR per 5-cm increase = 1.20, 95 % CI 1.04, 1.39), but this association attenuated in the multivariable model (HR 1.18, 95 % CI 0.98, 1.42). However, the association between WC and SIC was strengthened when the analysis was restricted to adenocarcinoma of the small intestine (multivariable HR adjusted for BMI = 1.56, 95 % CI 1.11, 2.17). There were no other significant associations. Conclusion: WC, rather than BMI, may be positively associated with adenocarcinomas but not carcinoid tumors of the small intestine. Impact: Abdominal obesity is a potential risk factor for adenocarcinoma in the small intestine

MicroRNA-mediated rescue of fear extinction memory by miR-144-3p in extinction-impaired mice

Background MicroRNA (miRNA)-mediated control of gene expression suggests that miRNAs are interesting targets and/or biomarkers in the treatment of anxiety- and trauma-related disorders, where often memory-associated gene expression is adversely affected. Methods The role of miRNAs in the rescue of impaired fear extinction was assessed using the 129S1/SvlmJ (S1) mouse model of impaired fear extinction. miRNA microarray analysis, reverse transcription polymerase chain reaction, fluorescent in situ hybridization, lentiviral overexpression, and Luciferase reporter assays were used to gain insight into the mechanisms underlying miRNA-mediated normalization of deficient fear extinction. Results Rescuing impaired fear extinction via dietary zinc restriction was associated with differential expression of miRNAs in the amygdala. One candidate, miR-144-3p, robustly expressed in the basolateral amygdala, showed specific extinction-induced, but not fear-induced, increased expression in both extinction-rescued S1 mice and extinction-intact C57BL/6 (BL6) mice. miR-144-3p upregulation and effects on subsequent behavioral adaption was assessed in S1 and BL6 mice. miR-144-3p overexpression in the basolateral amygdala rescued impaired fear extinction in S1 mice, led to enhanced fear extinction acquisition in BL6 mice, and furthermore protected against fear renewal in BL6 mice. miR-144-3p targets a number of genes implicated in the control of plasticity-associated signaling cascades, including Pten, Spred1, and Notch1. In functional interaction studies, we revealed that the miR-144-3p target, PTEN, colocalized with miR-144-3p in the basolateral amygdala and showed functional downregulation following successful fear extinction in S1 mice. Conclusions These findings identify a fundamental role of miR-144-3p in the rescue of impaired fear extinction and suggest this miRNA as a viable target in developing novel treatments for posttraumatic stress disorder and related disorders

Metabolically-Defined Body Size Phenotypes and Risk of Endometrial Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Background: Obesity is a risk factor for endometrial cancer but whether metabolic dysfunction is associated with endometrial cancer independent of body size is not known. Methods: The association of metabolically defined body size phenotypes with endometrial cancer risk was investigated in a nested case-control study (817 cases/ 817 controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC). Concentrations of C-peptide were used to define metabolically healthy (MH; _1st tertile) status among the control participants. These metabolic health definitions were combined with normal weight (NW); body mass index (BMI)_25 kg/m2 or WC >_80 cm or WHR >_0. 8) status, generating four phenotype groups for each anthropometric measure: (i) MH/NW, (ii) MH/OW, (iii) MU/ NW, and (iv) MU/OW. Results: In a multivariable-adjusted conditional logistic regression model, compared with MH/NW individuals, endometrial cancer risk was higher among those classified as MU/NW [ORWC, 1.48; 95% confidence interval (CI), 1.05-2.10 and ORWHR, 1.68; 95% CI, 1.21- 2.35] and MU/OW (ORBMI, 2.38; 95% CI, 1.73-3.27; ORWC, 2.69; 95% CI, 1.92-3.77 and ORWHR, 1.83; 95% CI, 1.32-2.54). MH/OW individuals were also at increased endometrial cancer risk compared with MH/NW individuals (ORWC, 1.94; 95% CI, 1.24-3.04). Conclusions: Women with metabolic dysfunction appear to have higher risk of endometrial cancer regardless of their body size. However, OW status raises endometrial cancer risk even among women with lower insulin levels, suggesting that obesity related pathways are relevant for the development of this cancer beyond insulin. Impact: Classifying women by metabolic health may be of greater utility in identifying those at higher risk for endometrial cancer than anthropometry per se