Pediatric T-Cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemia is identified in 10-25% of all newly diagnosed acute lymphoblastic leukemia's in children...e disease results from cytogenetic and molecular abnormalities which disrupt key oncogenic, tumor suppressor, and developmental pathways which control normal thymocyte development. Disruption of key pathways alter normal control of cell growth and proliferation, along with survival and differentiation. This paper provides an update on the cytogenetic and molecular ba

t(14;20)(q32;q12) IGH/MAFB in Plasma Cell Myeloma

Plasma cell myeloma (PCM) is a complex and genetically heterogenous hematological malignancy involving clonal proliferation of plasma cells in bone marrow. It is the third most common hematolymphoid malignancy in the United States and primarily affects elderly people with a median onset age of 69 years and a survival duration ranging from a few months to more than 10 years. Standard karyotype and fluorescence in situ hybridization (FISH) evaluation of bone marrow is required in the initial diagnostic workup to risk stratify patients based on their cytogenetic status. Primary cytogenetic events are classified as either hyperdiploid or non-hyperdiploid. Common in non-hyperdiploid cases is rearrangement of the IGH gene on chromosome 14q32.33, most commonly with the CCND1 gene at 11q13.3, and to a lesser extent FGFR3/MMSET genes at 4p16.3 or the MAF gene at 16q23.2. The rarest of these IGH translocations involves the MAFB gene at 20q12, which is the subject of this review

Release of MicroRNAs into body fluids from ten organs of mice exposed to cigarette smoke

Purpose: MicroRNAs are small non-coding RNAs that regulate gene expression, thereby playing a role in a variety of physiological and pathophysiological states. Exposure to cigarette smoke extensively downregulates microRNA expression in pulmonary cells of mice, rats, and humans. Cellular microRNAs are released into body fluids, but a poor parallelism was previously observed between lung microRNAs and circulating microRNAs. The purpose of the present study was to validate the application of this epigenetic biomarker by using less invasive collection procedures. Experimental design: Using microarray analyses, we measured 1135 microRNAs in 10 organs and 3 body fluids of mice that were either unexposed or exposed to mainstream cigarette smoke for up to 8 weeks. The results obtained with selected miRNAs were validated by qPCR. Results: The lung was the main target affected by smoke (190 dysregulated miRNAs), followed by skeletal muscle (180), liver (138), blood serum (109), kidney (96), spleen (89), stomach (36), heart (33), bronchoalveolar lavage fluid (32), urine (27), urinary bladder (12), colon (5), and brain (0). Skeletal muscle, kidney, and lung were the most important sources of smoke-altered microRNAs in blood serum, urine, and bronchoalveolar lavage fluid, respectively. Conclusions: microRNA expression analysis was able to identify target organs after just 8 weeks of exposure to smoke, well before the occurrence of any detectable histopathological alteration. The present translational study validates the use of body fluid microRNAs as biomarkers applicable to human biomonitoring for mechanistic studies, diagnostic purposes, preventive medicine, and therapeutic strategies

Next-generation carrier screening

Purpose: Carrier screening for recessive Mendelian disorders traditionally employs focused genotyping to interrogate limited sets of mutations most prevalent in specific ethnic groups. We sought to develop a next-generation DNA sequencing–based workflow to enable analysis of a more comprehensive set of disease-causing mutations. Methods: We utilized molecular inversion probes to capture the protein-coding regions of 15 genes from genomic DNA isolated from whole blood and sequenced those regions using the Illumina HiSeq 2000 (Illumina, San Diego, CA). To assess the quality of the resulting data, we measured both the fraction of the targeted region yielding high-quality genotype calls, and the sensitivity and specificity of those calls by comparison with conventional Sanger sequencing across hundreds of samples. Finally, to improve the overall accuracy for detecting insertions and deletions, we introduce a novel assembly-based approach that substantially increases sensitivity without reducing specificity. Results: We generated high-quality sequence for at least 99.8% of targeted base pairs in samples derived from blood and achieved high concordance with Sanger sequencing (sensitivity >99.9%, specificity >99.999%). Our novel algorithm is capable of detecting insertions and deletions inaccessible by current methods. Conclusion: Our next-generation DNA sequencing–based approach yields the accuracy and completeness necessary for a carrier screening test

Priority questions in multidisciplinary drought research

Addressing timely and relevant questions across a multitude of spatio-temporal scales, state-of-the-art interdisciplinary drought research will likely increase in importance under projected climate change. Given the complexity of the various direct and indirect causes and consequences of a drier world, scientific tasks need to be coordinated efficiently. Drought-related research endeavors ranging from individual projects to global initiatives therefore require prioritization. Here, we present 60 priority questions for optimizing future drought research. This topical catalogue reflects the experience of 65 scholars from 21 countries and almost 20 fields of research in both natural sciences and the humanities. The set of drought-related questions primarily covers drought monitoring, impacts, forecasting, climatology, adaptation, as well as planning and policy. The questions highlight the increasingly important role of remote sensing techniques in drought monitoring, importance of drought forecasting and understanding the relationships between drought parameters and drought impacts, but also challenges of drought adaptation and preparedness policies

Capsaicin-Induced Changes in LTP in the Lateral Amygdala Are Mediated by TRPV1

The transient receptor potential vanilloid type 1 (TRPV1) channel is a well recognized polymodal signal detector that is activated by painful stimuli such as capsaicin. Here, we show that TRPV1 is expressed in the lateral nucleus of the amygdala (LA). Despite the fact that the central amygdala displays the highest neuronal density, the highest density of TRPV1 labeled neurons was found within the nuclei of the basolateral complex of the amygdala. Capsaicin specifically changed the magnitude of long-term potentiation (LTP) in the LA in brain slices of mice depending on the anesthetic (ether, isoflurane) used before euthanasia. After ether anesthesia, capsaicin had a suppressive effect on LA-LTP both in patch clamp and in extracellular recordings. The capsaicin-induced reduction of LTP was completely blocked by the nitric oxide synthase (NOS) inhibitor L-NAME and was absent in neuronal NOS as well as in TRPV1 deficient mice. The specific antagonist of cannabinoid receptor type 1 (CB1), AM 251, was also able to reduce the inhibitory effect of capsaicin on LA-LTP, suggesting that stimulation of TRPV1 provokes the generation of anandamide in the brain which seems to inhibit NO synthesis. After isoflurane anesthesia before euthanasia capsaicin caused a TRPV1-mediated increase in the magnitude of LA-LTP. Therefore, our results also indicate that the appropriate choice of the anesthetics used is an important consideration when brain plasticity and the action of endovanilloids will be evaluated. In summary, our results demonstrate that TRPV1 may be involved in the amygdala control of learning mechanisms

Enlightenment, Passion, Modernity: Historical Essays in European Thought and Culture

During the 1970s and 1980s, the study of intellectual and cultural history was often denigrated for its alleged elitist and canonical nature. Today, the situation has changed dramatically. Enriched by the methods and insights of such neighboring areas of inquiry as social history, the history of mentalités, linguistics, anthropology, literary theory, and art history, intellectual and cultural history is experiencing a renewed vitality. The far-ranging essays in this volume, by an internationally distinguished group of scholars, represent a generous sampling of these new studies. The book is in five parts: The Enlightenment and Its Heritages; Mind and Culture in the Victorian Middle Classes; European Cultural Modernism; Culture, Politics, and Society in Twentieth-Century Germany; and Freud and the History of Psychoanalysis. Striking for its interdisciplinarity, the volume includes essays in political theory, historical philosophy, cultural criticism, theology, literature, medicine, and psychoanalysis. Among the topics are Thomas Hobbes\u27s civil science, Enlightenment philosophies of history, ancien régime pornography, German modernist architecture, T. S. Eliot\u27s social criticism, the history of cultural censorship in Germany, German-Jewish women during the Nazi persecution, and Freud\u27s attitudes toward death and dying. The essays have been written in honor of Peter Gay, one of the most provocative and influential historians of the twentieth century and one of the leading American scholars of European thought and culture today; the essays reflect themes and issues running through his work. The contributors are W. F. Bynum, David Cannadine, Stefan Collini, Robert Darnton, Robert L. Dietle, Ilse Grubrich-Simitis, Judith Hughes, Martin Jay, Peter Jelavich, Marion A. Kaplan, Thomas A. Kohut, Peter Loewenberg, Mark S. Micale, Harry C. Payne, Quentin Skinner, John Toews, R. K. Webb, Dora B. Weiner, and Jay Winter.https://digitalcommons.wku.edu/history_book/1014/thumbnail.jp