Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells

Treatment failure in pediatric acute lymphoblastic leukemia (ALL) is related to cellular resistance to glucocorticoids (eg, prednisolone). Recently, we demonstrated that genes associated with glucose metabolism are differentially expressed between prednisolone-sensitive and prednisolone-resistant precursor B-lineage leukemic patients. Here, we show that prednisolone resistance is associated with increased glucose consumption and that inhibition of glycolysis sensitizes prednisolone-resistant ALL cell lines to glucocorticoids. Treatment of prednisolone-resistant Jurkat and Molt4 cells with 2-deoxy-D-glucose (2-DG), lonidamine (LND), or3-bromopyruvate (3-BrPA) increased the in vitro sensitivity to glucocorticoids, while treatment of the prednisolone-sensitive cell lines Tom-1 and RS4; 11 did not influence drug cyto-toxicity. This sensitizing effect of the glycolysis inhibitors in glucocorticoid-resistant ALL cells was not found for other classes of antileukemic drugs (ie, vincris-tine and daunorubicin). Moreover, down-regulation of the expression of GAPDH by RNA interference also sensitized to prednisolone, comparable with treatment with glycolytic inhibitors. Importantly, the ability of 2-DG to reverse glucocorticoid resistance was not limited to cell lines, but was also observed in isolated primary ALL cells from patients. Together, these findings indicate the importance of the glycolytic pathway in glucocorticoid resistance in ALL and suggest that targeting glycolysis is a viable strategy for modulating prednisolone resistance in ALL

The Diabetes Pearl: Diabetes biobanking in The Netherlands

Contains fulltext : 109720.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Type 2 diabetes is associated with considerable comorbidity and severe complications, which reduce quality of life of the patients and require high levels of healthcare. The Diabetes Pearl is a large cohort of patients diagnosed with type 2 diabetes, covering different geographical areas in the Netherlands. The aim of the study is to create a research infrastructure that will allow the study of risk factors, including biomarkers and genetic determinants for severe diabetes complications. METHODS/DESIGN: Baseline examinations began November 2009 and will continue through 2012. By the end of 2012, it is expected that 7000 patients with type 2 diabetes will be included in the Diabetes Pearl cohort. To ensure quality of the data collected, standard operation procedures were developed and used in all 8 recruitment centers. From all patients who provide informed consent, the following information is collected: personal information, medication use, physical examination (antropometry, blood pressure, electrocardiography (ECG), retina photographs, ankle-brachial index, peripheral vibration perception), self-report questionnaire (socio-economic status, lifestyle, (family) history of disease, and psychosocial well-being), laboratory measurements (glucose, A1c, lipid profile, kidney function), biobank material (storage of urine and blood samples and isolated DNA). All gathered clinical data and biobank information is uploaded to a database for storage on a national level. Biobanks are maintained locally at all recruitment centers. DISCUSSION: The Diabetes Pearl is large-scale cohort of type 2 diabetes patients in the Netherlands aiming to study risk factors, including biomarkers and genetic markers, for disease deterioration and the development of severe diabetes complications. As a result of the well-designed research design and the national coverage, the Diabetes Pearl data can be of great value to national and international researchers with an interest in diabetes related research

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present

An incremental training method with automated, extendable maze for training spatial behavioral tasks in rodents

Contains fulltext : 214958.pdf (publisher's version ) (Open Access

The Diagnostic Value of Language Screening in Primary Progressive Aphasia: Validation and Application of the Sydney Language Battery

Purpose: The three variants of primary progressive aphasia (PPA) differ in clinical presentation, underlying brain pathology, and clinical course, which stresses the need for early differentiation. However, brief cognitive tests that validly distinguish between all PPA variants are lacking. The Sydney Language Battery (SYDBAT) is a promising screening instrument that can be used as a first step in a comprehensive neuropsychological assessment to distinguish PPA subtypes, but evidence on its validity and reliability is to date limited. In the current study, the validation and diagnostic value of the SYDBAT are described for discriminating PPA subtypes as well as distinguishing PPA from mild cognitive impairment (MCI) or Alzheimer’s dementia (AD). Method: Forty-five patients with PPA (13 with semantic PPA, 20 with logopenic PPA, and 12 with nonfluent/agrammatic PPA), 25 MCI patients, 13 AD patients, and 50 cognitively unimpaired controls were included in this study. Both patients and controls completed the SYDBAT-NL (Dutch version). Performance on and predictive ability of the four subtests (i.e., Naming, Word Comprehension, Repetition, and Semantic Association) were assessed. In addition, construct validity and internal consistency were examined. Results: Different SYDBAT performance patterns were found across PPA and non-PPA patient groups. While a discriminant function analysis based on SYDBAT subtest scores could predict PPA subtype with 78% accuracy, it was more difficult to disentangle PPA from non-PPA patients based on SYDBAT scores alone. For assisting in clinical interpretation, simple rules were set up and translated into a diagnostic decision tree for subtyping PPA, which was capable of diagnosing a large proportion of the cases. Satisfying validity and reliability measures were found. Conclusions: The SYDBAT is an easy-to-use and promising screen for assessing single-word language processes, which may contribute to the differential diagnostic process of PPA and the assessment of language impairment in MCI and AD. It can be easily implemented for initial screening of patients in a memory clinic

The Diabetes Pearl: Diabetes biobanking in The Netherlands

Background: Type 2 diabetes is associated with considerable comorbidity and severe complications, which reduce quality of life of the patients and require high levels of healthcare. The Diabetes Pearl is a large cohort of patients diagnosed with type 2 diabetes, covering different geographical areas in the Netherlands. The aim of the study is to create a research infrastructure that will allow the study of risk factors, including biomarkers and genetic determinants for severe diabetes complications. Methods/design: Baseline examinations began November 2009 and will continue through 2012. By the end of 2012, it is expected that 7000 patients with type 2 diabetes will be included in the Diabetes Pearl cohort. To ensure quality of the data collected, standard operation procedures were developed and used in all 8 recruitment centers. From all patients who provide informed consent, the following information is collected: personal information, medication use, physical examination (antropometry, blood pressure, electrocardiography (ECG), retina photographs, ankle-brachial index, peripheral vibration perception), self-report questionnaire (socio-economic status, lifestyle, (family) history of disease, and psychosocial well-being), laboratory measurements (glucose, A1c, lipid profile, kidney function), biobank material (storage of urine and blood samples and isolated DNA). All gathered clinical data and biobank information is uploaded to a database for storage on a national level. Biobanks are maintained locally at all recruitment centers. Discussion: The Diabetes Pearl is large-scale cohort of type 2 diabetes patients in the Netherlands aiming to study risk factors, including biomarkers and genetic markers, for disease deterioration and the development of severe diabetes complications. As a result of the well-designed research design and the national coverage, the Diabetes Pearl data can be of great value to national and international researchers with an interest in diabetes related research

The Power of Flash Mob Research Conducting a Nationwide Observational Clinical Study on Capillary Refill Time in a Single Day

BACKGROUND: Capillary refill time (CRT) is a clinical test used to evaluate the circulatory status of patients; various methods are available to assess CRT. Conventional clinical research often demands large numbers of patients, making it costly, labor-intensive, and time-consuming. We studied the interobserver agreement on CRT in a nationwide study by using a novel method of research called flash mob research (FMR). METHODS: Physicians in the Netherlands were recruited by using word-of-mouth referrals, conventional media, and social media to participate in a nationwide, single-day, "nineto-five," multicenter, cross-sectional, observational study to evaluate CRT. Patients aged >= 18 years presenting to the ED or who were hospitalized were eligible for inclusion. CRT was measured independently (by two investigators) at the patient's sternum and distal phalanx after application of pressure for 5 s (5s) and 15 s (15s). RESULTS: On October 29, 2014, a total of 458 investigators in 38 Dutch hospitals enrolled 1,734 patients. The mean CRT measured at the distal phalanx were 2.3 s (5s, SD1.1) and 2.4 s (15s, SD1.3). The mean CRT measured at the sternum was 2.6 s (5s, SD1.1) and 2.7 s (15s, SD1.1). Interobserver agreement was higher for the distal phalanx (k value, 0.40) than for the sternum (k value, 0.30). CONCLUSIONS: Interobserver agreement on CRT is, at best, moderate. CRT measured at the distal phalanx yielded higher interobserver agreement compared with sternal CRT measurements. FMR proved a valuable instrument to investigate a relatively simple clinical question in an inexpensive, quick, and reliable manner