MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours.

Wilms tumour is an embryonal tumour of childhood that closely resembles the developing kidney. Genomic changes responsible for the development of the majority of Wilms tumours remain largely unknown. Here we identify recurrent mutations within Wilms tumours that involve the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Moreover, MLLT1-mutant tumours show an increase in MYC gene expression and HOX dysregulation. Patients with MLLT1-mutant tumours present at a younger age and have a high prevalence of precursor intralobar nephrogenic rests. These data support a model whereby activating MLLT1 mutations early in renal development result in the development of Wilms tumour

Decrease of Markers Related to Bone Erosion in Serum of Patients with Musculoskeletal Disorders after Serial Low-Dose Radon Spa Therapy

Musculoskeletal disorders (MSDs) are the most frequent cause of disability in Europe. Reduced mobility and quality of life of the patients are often associated with pain due to chronic inflammation. The inflammatory process, accompanied by a destruction of the cartilage and bone tissue, is discussed as a result of (A) the infiltration of immune cells into the joints, (B) an altered homeostasis of the joint cavity (synovium) with a critical role of bone remodeling cells, and (C) release of inflammatory factors including adipokines in the arthritic joint. In addition to the classical medication, low-dose radiation therapy using photons or radon spa treatments has shown to reduce pain and improve the mobility of the patients. However, the cellular and molecular mechanisms of anti-inflammatory effects of radon are yet poorly understood. We analyzed blood and serum samples from 32 patients, suffering from MSDs, who had been treated in the radon spa in Bad Steben (Germany). Before and after therapy, we measured the levels of markers related to bone metabolism (collagen fragments type-1, cartilage oligomeric matrix protein, receptor activator of NFκB ligand, and osteoprotegerin) in the serum of patients. In addition, adipokines related to inflammation (visfatin, leptin, resistin, and adiponectin) were analyzed. Some of these factors are known to correlate with disease activity. Since T cells play an important role in the progression of the disease, we further analyzed in blood samples the frequency of pro- and anti-inflammatory T cell subpopulations (CD4⁺IL17⁺ T cells and CD4⁺FoxP3⁺ regulatory T cells). Overall, we found a decrease of collagen fragments (CTX-I), indicating decreased bone resorption, presumably by osteoclasts, in the serum of MSD patients. We also observed reduced levels of visfatin and a consistent trend toward an increase of regulatory T cells in the peripheral blood, both indicating attenuation of inflammation. However, key proteins of bone metabolism were unchanged on a systemic level, suggesting that these factors act locally after radon spa therapy of patients with MSDs

Pharmacological Modulation of the Psychiatric Risk Factor FKBP51 Alters Efficiency of Common Antidepressant Drugs

Despite a growing body of research over the last few decades, mental disorders, including anxiety disorders or depression, are still one of the most prevalent and hardest to treat health burdens worldwide. Since pharmacological treatment with a single drug is often rather ineffective, approaches such as co-medication with functionally diverse antidepressants (ADs) have been discussed and tried more recently. Besides classical ADs, there is a growing number of candidate targets identified as potential starting points for new treatment methods. One of these candidates, the FK506 binding protein 51 (FKBP51) is linked to a number of psychiatric disorders in humans. In this study, we used SAFit2-a newly developed modulator of FKBP51, which has shown promising results in rodent models for stress-related disorders delivered in a depot formulation. We combined SAFit2 with the commonly prescribed selective serotonin reuptake inhibitor (SSRI) escitalopram and performed basic behavioral characterization in a mouse model. Remarkably, co-application of SAFit2 lowered the efficacy of escitalopram in anxiety-related tests but improved stress coping behavior. Given the fact that mental diseases such as anxiety disorders or depression can be divided into different sub-categories, some of which more or less prone to stress, SAFit2 could indeed be a highly beneficial co-medication in very specific cases. This study could be a first, promising step towards the use of FKBP51 modulators as potent and specific enhancers of AD efficiency for subclasses of patients in the future

Study Protocol for an Online Questionnaire Survey on Symptoms/Signs, Protective Measures, Level of Awareness and Perception Regarding COVID-19 Outbreak among Dentists. A Global Survey

The Centres for Disease Control and Prevention and the World Health Organization have developed preparedness and prevention checklists for healthcare professionals regarding the containment of COVID-19. The aim of the present protocol is to evaluate the impact of the COVID-19 outbreak among dentists in different countries where various prevalence of the epidemic has been reported. Several research groups around the world were contacted by the central management team. The online anonymous survey will be conducted on a convenience sample of dentists working both in national health systems and in private or public clinics. In each country/area, a high (~5–20%) proportion of dentists working there will be invited to participate. The questionnaire, developed and standardized previously in Italy, has four domains: (1) personal data; (2) symptoms/signs relative to COVID-19; (3) working conditions and PPE (personal protective equipment) adopted after the infection’s outbreak; (4) knowledge and self-perceived risk of infection. The methodology of this international survey will include translation, pilot testing, and semantic adjustment of the questionnaire. The data will be entered on an Excel spreadsheet and quality checked. Completely anonymous data analyses will be performed by the central management team. This survey will give an insight into the dental profession during COVID-19 pandemic globally

Feasibility of Azacitidine Added to Standard Chemotherapy in Older Patients with Acute Myeloid Leukemia — A Randomised SAL Pilot Study

Introduction: Older patients with acute myeloid leukemia (AML) experience short survival despite intensive chemotherapy. Azacitidine has promising activity in patients with low proliferating AML. The aim of this dose-finding part of this trial was to evaluate feasibility and safety of azacitidine combined with a cytarabine- and daunorubicin-based chemotherapy in older patients with AML. Trial Design: Prospective, randomised, open, phase II trial with parallel group design and fixed sample size. Patients and Methods: Patients aged 61 years or older, with untreated acute myeloid leukemia with a leukocyte count of ,20,000/ml at the time of study entry and adequate organ function were eligible. Patients were randomised to receive azacitidine either 37.5 (dose level 1) or 75 mg/sqm (dose level 2) for five days before each cycle of induction (7+3 cytarabine plus daunorubicine) and consolidation (intermediate-dose cytarabine) therapy. Dose-limiting toxicity was the primary endpoint. Results: Six patients each were randomised into each dose level and evaluable for analysis. No dose-limiting toxicity occurred in either dose level. Nine serious adverse events occurred in five patients (three in the 37.5 mg, two in the 75 mg arm) with two fatal outcomes. Two patients at the 37.5 mg/sqm dose level and four patients at the 75 mg/sqm level achieved a complete remission after induction therapy. Median overall survival was 266 days and median event-free survival 215 days after a median follow up of 616 days. Conclusions: The combination of azacitidine 75 mg/sqm with standard induction therapy is feasible in older patients with AML and was selected as an investigational arm in the randomised controlled part of this phase-II study, which is currently halted due to an increased cardiac toxicity observed in the experimental arm. Trial Registration: This trial is registered at clinical trials.gov (identifier: NCT00915252)

Somatic sequence alterations in twenty-one genes selected by expression profile analysis of breast carcinomas

Abstract Introduction Genomic alterations have been observed in breast carcinomas that affect the capacity of cells to regulate proliferation, signaling, and metastasis. Re-sequence studies have investigated candidate genes based on prior genetic observations (changes in copy number or regions of genetic instability) or other laboratory observations and have defined critical somatic mutations in genes such as TP53 and PIK3CA. Methods We have extended the paradigm and analyzed 21 genes primarily identified by expression profiling studies, which are useful for breast cancer subtyping and prognosis. This study conducted a bidirectional re-sequence analysis of all exons and 5', 3', and evolutionarily conserved regions (spanning more than 16 megabases) in 91 breast tumor samples. Results Eighty-seven unique somatic alterations were identified in 16 genes. Seventy-eight were single base pair alterations, of which 23 were missense mutations; 55 were distributed across conserved intronic regions or the 5' and 3' regions. There were nine insertion/deletions. Because there is no a priori way to predict whether any one of the identified synonymous and noncoding somatic alterations disrupt function, analysis unique to each gene will be required to establish whether it is a tumor suppressor gene or whether there is no effect. In five genes, no somatic alterations were observed. Conclusion The study confirms the value of re-sequence analysis in cancer gene discovery and underscores the importance of characterizing somatic alterations across genes that are related not only by function, or functional pathways, but also based upon expression patterns

A community challenge for a pancancer drug mechanism of action inference from perturbational profile data

The Columbia Cancer Target Discovery and Development (CTD2) Center is developing PANACEA, a resource comprising dose-responses and RNA sequencing (RNA-seq) profiles of 25 cell lines perturbed with similar to 400 clinical oncology drugs, to study a tumor-specific drug mechanism of action. Here, this resource serves as the basis for a DREAM Challenge assessing the accuracy and sensitivity of computational algorithms for de novo drug polypharmacology predictions. Dose-response and perturbational profiles for 32 kinase inhibitors are provided to 21 teams who are blind to the identity of the compounds. The teams are asked to predict high-affinity binding targets of each compound among similar to 1,300 targets cataloged in DrugBank. The best performing methods leverage gene expression profile similarity analysis as well as deep-learning methodologies trained on individual datasets. This study lays the foundation for future integrative analyses of pharmacogenomic data, reconciliation of polypharmacology effects in different tumor contexts, and insights into network-based assessments of drug mechanisms of action.Peer reviewe

LongSAGE profiling of nine human embryonic stem cell lines

Analysis of a 2.6 million longSAGE sequence tag resource generated from nine human embryonic stem cell lines reveals an enrichment of RNA binding proteins and novel ES-specific transcripts