tbuckley/cabot-search huggingface dataset:
Comparative Proteomics Reveals a Significant Bias Toward Alternative Protein Isoforms with Conserved Structure and Function
Authors: I. Ezkurdia, A. del Pozo, A. Frankish, J. M. Rodriguez, J. Harrow, K. Ashman, A. Valencia, M. L. Tress
Journal: Molecular Biology and Evolution (2012)

Advances in high-throughput mass spectrometry are making proteomics an increasingly important tool in genome annotation projects. Peptides detected in mass spectrometry experiments can be used to validate gene models and verify the translation of putative coding sequences (CDSs). Here, we have identified peptides that cover 35% of the genes annotated by the GENCODE consortium for the human genome as part of a comprehensive analysis of experimental spectra from two large publicly available mass spectrometry databases. We detected the translation to protein of "novel" and "putative" protein-coding transcripts as well as transcripts annotated as pseudogenes and nonsense-mediated decay targets. We provide a detailed overview of the population of alternatively spliced protein isoforms that are detectable by peptide identification methods. We found that 150 genes expressed multiple alternative protein isoforms. This constitutes the largest set of reliably confirmed alternatively spliced proteins yet discovered. Three groups of genes were highly overrepresented. We detected alternative isoforms for 10 of the 25 possible heterogeneous nuclear ribonucleoproteins, proteins with a key role in the splicing process. Alternative isoforms generated from interchangeable homologous exons and from short indels were also significantly enriched, both in human experiments and in parallel analyses of mouse and Drosophila proteomics experiments. Our results show that a surprisingly high proportion (almost 25%) of the detected alternative isoforms are only subtly different from their constitutive counterparts. Many of the alternative splicing events that give rise to these alternative isoforms are conserved in mouse. It was striking that very few of these conserved splicing events broke Pfam functional domains or would damage globular protein structures. This evidence of a strong bias toward subtle differences in CDS and likely conserved cellular function and structure is remarkable and strongly suggests that the translation of alternative transcripts may be subject to selective constraints.
Behavior of genes directly injected into the rat heart in vivo.
Authors: P M Buttrick, A Kass, R N Kitsis, M L Kaplan, L A Leinwand
Journal: Circulation Research (1992)

Gene transfer can be achieved in the adult rat heart in vivo by direct injection of plasmid DNA. In this report we define the spatial and temporal limits of reporter gene expression after a single intracardiac injection. pRSVCAT (100 micrograms), in which the Rous sarcoma virus long terminal repeat is fused to the chloramphenicol acetyltransferase reporter gene, and p alpha MHCluc (100 micrograms), in which the alpha-cardiac myosin heavy chain promoter is fused to the firefly luciferase gene, were injected into hearts, and reporter gene activities were assayed at various times. Both chloramphenicol acetyltransferase and luciferase were detectable in 100% of the rats from 1 to 7 days, in 60% of the rats from 17 to 23 days, and in 30% of the rats from 38 to 60 days after injection. Reporter gene activity was largely limited to a 1-2-mm region of the ventricle surrounding the injection site. Closed circular DNA was far more effective than linear DNA in transfecting cells in vivo. The relative strengths of three different promoters, Rous sarcoma virus long terminal repeat, alpha-myosin heavy chain, and alpha 1-antitrypsin, all fused to the luciferase reporter gene were determined. The constitutive viral promoter was approximately 20-fold more active than the cardiac-specific cellular promoter, and the liver-specific cellular promoter was not active at all in the cardiac environment. Thus, direct injection of genes into the heart offers a simple and powerful tool with which to assess the behavior of genes in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
O3.04 * COGNITIVE AND STRUCTURAL BRAIN CHANGES ASSOCIATED WITH PROPHYLACTIC CRANIAL IRRADIATION IN LONG TERM SMALL CELL LUNG CANCER SURVIVORS
Authors: M. Simo, L. Vaquero, P. Ripolles, J. Jove, R. Fuentes, F. Cardenal, A. Rodriguez-Fornells, J. Bruna
Journal: Neuro-Oncology (2014)

PURPOSE: The long-term toxic effects of prophylactic cranial irradiation (PCI) on cognition in small cell lung cancer (SCLC) patients have not yet been well-established. The aim of our study was to examine the changes in neuropsychological variables and brain structure in a group of long-term SCLC survivors treated with PCI. PATIENTS AND METHODS: Eleven long-term SCLC patients, who underwent PCI at least two years before were compared to an age and education matched healthy control group. Both groups were evaluated using a neuropsychological battery and multimodal structural magnetic resonance imaging (MRI: T1-weigthed and diffusion-weighted imaging, DTI). Voxel-based morphometry (T1-VBM) and Tract-based Spatial Statistics (DTI-TBSS) were used to analyze gray matter (GM) and white matter (WM) integrity, respectively. RESULTS: Nearly half (45%, n = 5) of the SCLC patients met criteria for cognitive impairment in relation to verbal abilities, processing speed and visual memory. In addition, SCLC patients showed significant decreases of GM in subcortical regions such are the basal ganglia bilaterally (including the putamen and caudate), bilateral thalamus and right insula, together with lower WM integrity of the entire corpus callosum. CONCLUSION: This is the first study to demonstrate neuropsychological deficits together with brain-specific structural differences of both GM and WM in long-term SCLC survivors. Our results suggest that PCI therapy is associated with the development of permanent long-term cognitive and structural brain effects in a SCLC population.
Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial
Authors: EGJ Vermeulen, CDA Stehouwer, JWR Twisk, M van den Berg, SC de Jong, AJC Mackaay, CMC van Campen, FC Visser, CAJM Jakobs, EJ Bulterijs, JA Rauwerda
Journal: The Lancet (2000)
Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data
Authors: N Chaturvedi
Journal: Annals of Internal Medicine (2001)

Purpose: To determine whether response of albumin excretion rate, to angiotensin-converting enzyme (ACE) inhibitors has a threshold in patients with type 1 diabetes mellitus and microalbuminuria an ...
Predicting drug susceptibility of non–small cell lung cancers based on genetic lesions
Authors: Martin L. Sos, Kathrin Michel, Thomas Zander, Jonathan Weiss, Peter Frommolt, Martin Peifer, Danan Li, Roland Ullrich, Mirjam Koker, Florian Fischer, Takeshi Shimamura, Daniel Rauh, Craig Mermel, Stefanie Fischer, Isabel Stückrath, Stefanie Heynck, Rameen Beroukhim, William Lin, Wendy Winckler, Kinjal Shah, Thomas LaFramboise, Whei F. Moriarty, Megan Hanna, Laura Tolosi, Jörg Rahnenführer, Roel Verhaak, Derek Chiang, Gad Getz, Martin Hellmich, Jürgen Wolf, Luc Girard, Michael Peyton, Barbara A. Weir, Tzu-Hsiu Chen, Heidi Greulich, Jordi Barretina, Geoffrey I. Shapiro, Levi A. Garraway, Adi F. Gazdar, John D. Minna, Matthew Meyerson, Kwok-Kin Wong, Roman K. Thomas
Journal: Journal of Clinical Investigation (2009)

Somatic genetic alterations in cancers have been linked with response to targeted therapeutics by creation of specific dependency on activated oncogenic signaling pathways. However, no tools currently exist to systematically connect such genetic lesions to therapeutic vulnerability. We have therefore developed a genomics approach to identify lesions associated with therapeutically relevant oncogene dependency. Using integrated genomic profiling, we have demonstrated that the genomes of a large panel of human non-small cell lung cancer (NSCLC) cell lines are highly representative of those of primary NSCLC tumors. Using cell-based compound screening coupled with diverse computational approaches to integrate orthogonal genomic and biochemical data sets, we identified molecular and genomic predictors of therapeutic response to clinically relevant compounds. Using this approach, we showed that v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations confer enhanced Hsp90 dependency and validated this finding in mice with KRAS-driven lung adenocarcinoma, as these mice exhibited dramatic tumor regression when treated with an Hsp90 inhibitor. In addition, we found that cells with copy number enhancement of v-abl Abelson murine leukemia viral oncogene homolog 2 (ABL2) and ephrin receptor kinase and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (SRC) kinase family genes were exquisitely sensitive to treatment with the SRC/ABL inhibitor dasatinib, both in vitro and when it xenografted into mice. Thus, genomically annotated cell-line collections may help translate cancer genomics information into clinical practice by defining critical pathway dependencies amenable to therapeutic inhibition.
Precapillary Oxygenation Contributes Relevantly to Gas Exchange in the Intact Lung
Authors: Arata Tabuchi, Beata Styp-Rekowska, Arthur S. Slutsky, Peter D. Wagner, Axel R. Pries, Wolfgang M. Kuebler
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Rationale: Oxygen uptake is the elemental function of the lung. However, current understanding of this process has largely been derived from theoretical considerations and measurements of global pulmonary gas exchange.Objectives: To report the direct visualization of pulmonary oxygen uptake in vivo and its use for the analysis of temporal and spatial oxygenation profiles along individual arteriovenous pathways in lungs of healthy and chronic hypoxic mice.Methods: A murine model for intravital microscopy of the breathing lung under sealed thorax conditions was combined with multispectral oximetry for two-dimensional oxygen saturation mapping. This combination allowed for visualization of the blood oxygenation process from pulmonary arterioles to capillaries and venules in two-dimensional oxygen saturation maps.Measurements and Main Results: Temporal and spatial oxygenation profiles revealed that oxygenation occurs within 100 milliseconds over a distance of approximately 130 μm in the pulmonary microvasculature of the anesthetized mouse. About 50% of total oxygen uptake takes place in precapillary arterioles of less than 30 μm in diameter before the blood enters the alveolar capillary bed. In chronic hypoxic mice, precapillary oxygenation was significantly attenuated as a result of the widened transarteriolar diffusion distance.Conclusions: Oxygen saturation mapping in the intact lung yields unique insights into the temporal and spatial characteristics of pulmonary gas exchange in intact and diseased lungs. Precapillary gas exchange contributes importantly to blood oxygenation at rest, but is attenuated in remodeled lung arterioles, which may be of relevance in pulmonary hypertension.
Rapid T cell–based identification of human tumor tissue antigens by automated two-dimensional protein fractionation
Authors: Philipp Beckhove, Rolf Warta, Britt Lemke, Diana Stoycheva, Frank Momburg, Martina Schnölzer, Uwe Warnken, Hubertus Schmitz-Winnenthal, Rezvan Ahmadi, Gerhard Dyckhoff, Mariana Bucur, Simone Jünger, Thomas Schueler, Volker Lennerz, Thomas Woelfel, Andreas Unterberg, Christel Herold-Mende
Journal: Journal of Clinical Investigation (2010)

Identifying the antigens that have the potential to trigger endogenous antitumor responses in an individual cancer patient is likely to enhance the efficacy of cancer immunotherapy, but current methodologies do not efficiently identify such antigens. This study describes what we believe to be a new method of comprehensively identifying candidate tissue antigens that spontaneously cause T cell responses in disease situations. We used the newly developed automated, two-dimensional chromatography system PF2D to fractionate the proteome of human tumor tissues and tested protein fractions for recognition by preexisting tumor-specific CD4+ Th cells and CTLs. Applying this method using mice transgenic for a TCR that recognizes an OVA peptide presented by MHC class I, we demonstrated efficient separation, processing, and cross-presentation to CD8+ T cells by DCs of OVA expressed by the OVA-transfected mouse lymphoma RMA-OVA. Applying this method to human tumor tissues, we identified MUC1 and EGFR as tumor-associated antigens selectively recognized by T cells in patients with head and neck cancer. Finally, in an exemplary patient with a malignant brain tumor, we detected CD4+ and CD8+ T cell responses against two novel antigens, transthyretin and calgranulin B/S100A9, which were expressed in tumor and endothelial cells. The immunogenicity of these antigens was confirmed in 4 of 10 other brain tumor patients. This fast and inexpensive method therefore appears suitable for identifying candidate T cell antigens in various disease situations, such as autoimmune and malignant diseases, without being restricted to expression by a certain cell type or HLA allele.
Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus.
Authors: F Folli, M J Saad, J M Backer, C R Kahn
Journal: Journal of Clinical Investigation (1993)

Insulin stimulates tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), which in turn binds to and activates phosphatidylinositol 3-kinase (PI 3-kinase). In the present study, we have examined these processes in animal models of insulin-resistant and insulin-deficient diabetes mellitus. After in vivo insulin stimulation, there was a 60-80% decrease in IRS-1 phosphorylation in liver and muscle of the ob/ob mouse. There was no insulin stimulation of PI 3-kinase (85 kD subunit) association with IRS-1, and IRS-1-associated PI 3-kinase activity was reduced 90%. Insulin-stimulated total PI 3-kinase activity was also absent in both tissues of the ob/ob mouse. By contrast, in the streptozotocin diabetic rat, IRS-1 phosphorylation increased 50% in muscle, IRS-1-associated PI 3-kinase activity was increased two- to threefold in liver and muscle, and there was a 50% increase in the p85 associated with IRS-1 after insulin stimulation in muscle. In conclusion, (a) IRS-1-associated PI 3-kinase activity is differentially regulated in hyperinsulinemic and hypoinsulinemic diabetic states; (b) PI 3-kinase activation closely correlates with IRS-1 phosphorylation; and (c) reduced PI 3-kinase activity may play a role in the pathophysiology of insulin resistant diabetic states, such as that seen in the ob/ob mouse.
Differential Th1/Th2 cytokine patterns in chronic arthritis: interferon gamma is highly expressed in synovium of rheumatoid arthritis compared with seronegative spondyloarthropathies
Authors: J. D Canete
Journal: Annals of the Rheumatic Diseases (2000)

To investigate possible differences in Th1 and Th2 cytokine mRNA expression in the synovial tissue (ST) of patients with rheumatoid arthritis (RA) and seronegative spondyloarthropathies (SpA) with diagnostic and/or pathogenic interest.Eleven RA patients and 14 SpA patients (10 with undifferentiated spondyloarthropathy (USpA), two with ankylosing spondylitis (AS) and two with psoriatic arthritis (PsA)) were included. Th1 (interferon gamma, interleukin 2) and Th2 (interleukin 4, interleukin 5 and interleukin 10) cytokine mRNA levels from arthritic knee ST were quantified by using an optimised polymerase chain reaction method with a computerised analysis system. Protein levels of proinflammatory cytokines (interleukin 1, tumour necrosis factor alpha and interleukin 6) in synovial fluid were quantified with a specific ELISA test.Th1 cytokines were detected in all of RA ST samples in contrast with 58% (interferon gamma) and 71% (interleukin 2) of SpA samples. Th2 cytokines were expressed in 90% of RA ST samples, but the findings in SpA were interleukin 10 in 90%, interleukin 4 in 60% and interleukin 5 in 40% of ST samples. However, when the mRNA levels of each cytokine were quantified and corrected for T cell mRNA levels, only interferon gamma levels were significantly higher in RA than in SpA (p<0.003). Thus, the Th1/Th2 cytokine ratio in RA was fivefold that of SpA. Synovial fluid interleukin 1beta concentrations were higher in RA than in SpA (p<0. 05); there were also higher synovial fluid levels of tumour necrosis factor alpha in RA than in SpA, but without statistical significance.This study has detected both Th1 and Th2 cytokine gene expression in ST from RA and SpA patients. Synovium interferon gamma mRNA levels and SF interleukin 1beta protein levels were significantly higher in RA than in SpA, so reflecting the known proinflammatory activity of interferon gamma through macrophage activation. Thus, the Th1 (interferon gamma)/Th2 (interleukin 4) ratio is significantly higher in RA than in SpA ST. These data confirm previous studies on ST Th1/Th2 balance in RA and extend previous work in comparing ST RA with subgroups of SpA distinct of ReA.
Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia
Authors: Axel Freischmidt, Thomas Wieland, Benjamin Richter, Wolfgang Ruf, Veronique Schaeffer, Kathrin Müller, Nicolai Marroquin, Frida Nordin, Annemarie Hübers, Patrick Weydt, Susana Pinto, Rayomond Press, Stéphanie Millecamps, Nicolas Molko, Emilien Bernard, Claude Desnuelle, Marie-Hélène Soriani, Johannes Dorst, Elisabeth Graf, Ulrika Nordström, Marisa S Feiler, Stefan Putz, Tobias M Boeckers, Thomas Meyer, Andrea S Winkler, Juliane Winkelman, Mamede de Carvalho, Dietmar R Thal, Markus Otto, Thomas Brännström, Alexander E Volk, Petri Kursula, Karin M Danzer, Peter Lichtner, Ivan Dikic, Thomas Meitinger, Albert C Ludolph, Tim M Strom, Peter M Andersen, Jochen H Weishaupt
Journal: Nature Neuroscience (2015)
Chemosensory Receptor Specificity and Regulation
Authors: Ryan P. Dalton, Stavros Lomvardas
Journal: Annual Review of Neuroscience (2015)

The senses provide a means by which data on the physical and chemical properties of the environment may be collected and meaningfully interpreted. Sensation begins at the periphery, where a multitude of different sensory cell types are activated by environmental stimuli as different as photons and odorant molecules. Stimulus sensitivity is due to expression of different cell surface sensory receptors, and therefore the receptive field of each sense is defined by the aggregate of expressed receptors in each sensory tissue. Here, we review current understanding on patterns of expression and modes of regulation of sensory receptors.
Changing of the guard
Authors: L. VAN DE PUTTE
Journal: Annals of the Rheumatic Diseases (1999)

<i>Objectives</i>—To establish whether injury surveillance based on sampling strategies is as valid as total patient surveillance. <i>Methods</i>—Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP) data for 1996 were retrospectively analysed using five sampling frames. Proportions for key variables were calculated for each sample, then compared with the proportions for the total population of patients. <i>Results</i>—Two of the five sampling frames produced statistically significant differences from the total population, which can be explained by seasonal variations. However, no significant differences were observed between the remaining three samples and the total population. <i>Conclusions</i>—A well planned and executed sampling strategy can generate as valid data as total patient surveillance, obviating the need for data collection on every patient presenting with an injury or poisoning. In practice, however, systematic sampling can be difficult to implement and sustain, counterbalancing the economic advantages.
The management of Hodgkin's disease: Half a century of change
Authors: S.A. Rosenberg
Journal: Annals of Oncology (1996)

The results of treating more than 2600 patients with Hodgkin's disease at Stanford over a 35-year period are summarized.It is now a reality that Hodgkin's disease can be cured with initial treatment programs in virtually all patients, except the elderly.Histologic factors, staging methods, and prognostic groups are becoming less and less relevant.The current protocols used at Stanford and elsewhere will be reviewed to emphasize that combined modality is really the key to improving the cure rate and minimizing late complications.
Drosophila P Transposons in the Human Genome?
Authors: Sylvia Hagemann, Wilhelm Pinsker
Journal: Molecular Biology and Evolution (2001)

P elements are DNA transposons that were first discovered to be the causative agent of hybrid dysgenesis in Drosophila melanogaster (Kidwell, Kidwell, and Sved 1977) but were later found to occur in many drosophilid species. The interspecific distribution of P-element sequences, as well as their sequence relationships, is not in accordance with the phylogeny of their host species. Therefore, P elements are not merely vertically inherited but can also be transmitted horizontally between sexually isolated taxa. The most striking example is the rather recent transfer from Drosophila willistoni to D. melanogaster (Daniels et al. 1990), which must have occurred in the last century and was followed by a rapid spread of P elements through the natural populations of this new host (Anxolabehere, Kidwell, and Periquet 1988). Additional cases of horizontal transmission show that P elements have repeatedly crossed species barriers and have even invaded species of the related genera Scaptomyza and Lordiphosa (Hagemann, Haring, and Pinsker 1996a; Clark and Kidwell 1997; Haring, Hagemann, and Pinsker 2000; Silva and Kidwell 2000). However, due to the fact that their mode of transposition requires host-encoded proteins (Rio and Rubin 1988), the distribution of active P elements seemed to be restricted to fruit flies of the drosophilid family. Thanks to the data provided by the human genome project, we are able to show that a homolog of the P element coding sequence exists as a stationary single-copy sequence in the human genome. The molecular structure of actively transposing Drosophila P elements consists of four exons (designated 0–3) flanked by terminal inverted repeats (O’Hare and Rubin 1983). The exons code for two different proteins produced by differential splicing of the primary transcript (Misra and Rio 1990). The transposase contains the information of all four exons and mediates transposition in germ line cells. A second protein, which is translated from an mRNA that retains the third intron, acts as a repressor of P-element transposition in somatic cells. Besides these full-sized P elements, terminally truncated P element homologs have been detected in two different Drosophila lineages (Miller et al. 1992; Nouaud and Anxolabehere 1997). In both cases, the terminal inverted repeats are missing and the coding region lacks the transposase-specific exon 3. It is assumed that these truncated P homologs are derivatives of previously active transposons that were primarily maintained in