tbuckley/cabot-search huggingface dataset:
Massively Parallel Tumor Multigene Sequencing to Evaluate Response to Panitumumab in a Randomized Phase III Study of Metastatic Colorectal Cancer
Authors: Marc Peeters, Kelly S. Oliner, Alex Parker, Salvatore Siena, Eric Van Cutsem, Jing Huang, Yves Humblet, Jean-Luc Van Laethem, Thierry André, Jeffrey Wiezorek, David Reese, Scott D. Patterson
Journal: Clinical Cancer Research (2013)

To investigate whether EGF receptor (EGFR) pathway mutations predicted response to monotherapy with panitumumab, an anti-EGFR monoclonal antibody, in a randomized phase III study of metastatic colorectal cancer.Using massively parallel multigene sequencing, we analyzed 320 samples for 9 genes, with multigene sequence data from 288 (90%) samples.Mutation rates were: KRAS (45%), NRAS (5%), BRAF (7%), PIK3CA (9%), PTEN (6%), TP53 (60%), EGFR (1%), AKT1 (<1%), and CTNNB1 (2%). In the randomized study and open-label extension, 22 of 138 (16%) wild-type KRAS (codons 12/13/61) patients versus 0 of 103 mutant KRAS (codons 12/13) patients had objective responses. Of 6 mutant KRAS (codon 61) patients, 1 with a Q61H mutation achieved partial response during the extension. Among wild-type KRAS (codons 12/13/61) patients, 0 of 9 patients with NRAS mutations, 0 of 13 with BRAF mutations, 2 of 10 with PIK3CA mutations, 1 of 9 with PTEN mutations, and 1 of 2 with CTNNB1 mutations responded to panitumumab. No patients responded to best supportive care alone. Panitumumab treatment was associated with longer progression-free survival (PFS) among wild-type KRAS (codons 12/13/61) patients [HR, 0.39; 95% confidence interval (CI), 0.28-0.56]. Among wild-type KRAS patients, a treatment effect for PFS favoring panitumumab occurred in patients with wild-type NRAS (HR, 0.39; 95% CI, 0.27-0.56) and wild-type BRAF (HR, 0.37; 95% CI, 0.24-0.55) but not mutant NRAS (HR, 1.94; 95% CI, 0.44-8.44).These results show the feasibility and potential clinical use of next-generation sequencing for evaluating predictive biomarkers.
Role of interleukin 12 and costimulators in T cell anergy in vivo
Authors: L Van Parijs, V L Perez, A Biuckians, R G Maki, C A London, A K Abbas
Journal: The Journal of Experimental Medicine (2009)

The induction of T cell anergy in vivo is thought to result from antigen recognition in the absence of co-stimulation and inflammation, and is associated with a block in T cell proliferation and Th1 differentiation. Here we have examined the role of interleukin (IL)-12, a potent inducer of Th1 responses, in regulating this process. T cell tolerance was induced by the administration of protein antigen without adjuvant in normal mice, and in recipients of adoptively transferred T cells from T cell receptor transgenic mice. The administration of IL-12 at the time of tolerance induction stimulates Th1 differentiation, but does not promote antigen-specific T cell proliferation. Conversely, inhibiting CTLA-4 engagement during anergy induction reverses the block in T cell proliferation, but does not promote full Th1 differentiation. T cells exposed to tolerogenic antigen in the presence of both IL-12 and anti-CTLA-4 antibody are not anergized, and behave identically to T cells which have encountered immunogenic antigen. These results suggest that two processes contribute to the induction of anergy in vivo; CTLA-4 engagement, which leads to a block in the ability of T cells to proliferate to antigen, and the absence of a prototypic inflammatory cytokine, IL-12, which prevents the differentiation of T cells into Th1 effector cells. The combination of IL-12 and anti-CTLA-4 antibody is sufficient to convert a normally tolerogenic stimulus to an immunogenic one.
microRNA-29a induces aberrant self-renewal capacity in hematopoietic progenitors, biased myeloid development, and acute myeloid leukemia
Authors: Yoon-Chi Han, Christopher Y. Park, Govind Bhagat, Jinping Zhang, Yulei Wang, Jian-Bing Fan, Mofang Liu, Yongrui Zou, Irving L. Weissman, Hua Gu
Journal: The Journal of Experimental Medicine (2010)

The function of microRNAs (miRNAs) in hematopoietic stem cells (HSCs), committed progenitors, and leukemia stem cells (LSCs) is poorly understood. We show that miR-29a is highly expressed in HSC and down-regulated in hematopoietic progenitors. Ectopic expression of miR-29a in mouse HSC/progenitors results in acquisition of self-renewal capacity by myeloid progenitors, biased myeloid differentiation, and the development of a myeloproliferative disorder that progresses to acute myeloid leukemia (AML). miR-29a promotes progenitor proliferation by expediting G1 to S/G2 cell cycle transitions. miR-29a is overexpressed in human AML and, like human LSC, miR-29a-expressing myeloid progenitors serially transplant AML. Our data indicate that miR-29a regulates early hematopoiesis and suggest that miR-29a initiates AML by converting myeloid progenitors into self-renewing LSC.
BatMeth: improved mapper for bisulfite sequencing reads on DNA methylation
Authors: Jing-Quan Lim, Chandana Tennakoon, Guoliang Li, Eleanor Wong, Yijun Ruan, Chia-Lin Wei, Wing-Kin Sung
Journal: Genome biology (2012)

DNA methylation plays a crucial role in higher organisms. Coupling bisulfite treatment with next generation sequencing enables the interrogation of 5-methylcytosine sites in the genome. However, bisulfite conversion introduces mismatches between the reads and the reference genome, which makes mapping of Illumina and SOLiD reads slow and inaccurate. BatMeth is an algorithm that integrates novel Mismatch Counting, List Filtering, Mismatch Stage Filtering and Fast Mapping onto Two Indexes components to improve unique mapping rate, speed and precision. Experimental results show that BatMeth is faster and more accurate than existing tools. BatMeth is freely available at http://code.google.com/p/batmeth/.
TIM-3/Gal-9 interaction induces IFNγ-dependent IDO1 expression in acute myeloid leukemia blast cells
Authors: Valentina Folgiero, Loredana Cifaldi, Giuseppina Li Pira, Bianca Maria Goffredo, Luciana Vinti, Franco Locatelli
Journal: Journal of Hematology & Oncology (2015)

NK cells expressing TIM-3 show a marked increase in IFNγ production in response to acute myeloid leukemia (AML) blast cells that endogenously express Gal-9. Herein, we demonstrate that NK cell-mediated production of IFNγ, induced by TIM-3/Gal-9 interaction and released in bone marrow microenvironment, is responsible for IDO1 expression in AML blasts. IDO1-expressing AML blasts consequently down-regulate NK cell degranulation activity, by sustaining leukemia immune escape. Furthermore, the blocking of TIM-3/Gal-9 interaction strongly down-regulates IFNγ-dependent IDO1 activity. Thus, the inhibition of TIM-3/Gal-9 immune check point, which affects NK cell-dependent IFNγ production and the consequent IDO1 activation, could usefully integrate current chemotherapeutic approaches.
Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13–induced inflammation and remodeling
Authors: Sophie Lanone, Tao Zheng, Zhou Zhu, Wei Liu, Chun Geun Lee, Bing Ma, Qingsheng Chen, Robert J. Homer, Jingming Wang, Lesley A. Rabach, Morgan E. Rabach, J. Michael Shipley, Steven D. Shapiro, Robert M. Senior, Jack A. Elias
Journal: Journal of Clinical Investigation (2002)

IL-13 potently stimulates eosinophilic and lymphocytic inflammation and alveolar remodeling in the lung, effects that depend on the induction of various matrix metalloproteinases (MMPs). Here, we compared the remodeling and inflammatory effects of an IL-13 transgene in lungs of wild-type, MMP-9-deficient, or MMP-12-deficient mice. IL-13-induced alveolar enlargement, lung enlargement, compliance alterations, and respiratory failure and death were markedly decreased in the absence of MMP-9 or MMP-12. Moreover, IL-13 potently induced MMPs-2, -12, -13, and -14 in the absence of MMP-9, while induction of MMPs-2, -9, -13, and -14 by IL-13 was diminished in the absence of MMP-12. A deficiency in MMP-9 did not alter eosinophil, macrophage, or lymphocyte recovery, but increased the recovery of total leukocytes and neutrophils in bronchoalveolar lavage (BAL) fluids from IL-13 transgenic mice. In contrast, a deficiency in MMP-12 decreased the recovery of leukocytes, eosinophils, and macrophages, but not lymphocytes or neutrophils. These studies demonstrate that IL-13 acts via MMPs-9 and -12 to induce alveolar remodeling, respiratory failure, and death and that IL-13 induction of MMPs-2, -9, -13, and -14 is mediated at least partially by an MMP-12-dependent pathway. The also demonstrate that MMPs-9 and -12 play different roles in the generation of IL-13-induced inflammation, with MMP-9 inhibiting neutrophil accumulation and MMP-12 contributing to the accumulation of eosinophils and macrophages.
Developing and Validating Continuous Genomic Signatures in Randomized Clinical Trials for Predictive Medicine
Authors: Shigeyuki Matsui, Richard Simon, Pingping Qu, John D. Shaughnessy, Bart Barlogie, John Crowley
Journal: Clinical Cancer Research (2012)

It is highly challenging to develop reliable diagnostic tests to predict patients' responsiveness to anticancer treatments on clinical endpoints before commencing the definitive phase III randomized trial. Development and validation of genomic signatures in the randomized trial can be a promising solution. Such signatures are required to predict quantitatively the underlying heterogeneity in the magnitude of treatment effects.We propose a framework for developing and validating genomic signatures in randomized trials. Codevelopment of predictive and prognostic signatures can allow prediction of patient-level survival curves as basic diagnostic tools for treating individual patients.We applied our framework to gene-expression microarray data from a large-scale randomized trial to determine whether the addition of thalidomide improves survival for patients with multiple myeloma. The results indicated that approximately half of the patients were responsive to thalidomide, and the average improvement in survival for the responsive patients was statistically significant. Cross-validated patient-level survival curves were developed to predict survival distributions of individual future patients as a function of whether or not they are treated with thalidomide and with regard to their baseline prognostic and predictive signature indices.The proposed framework represents an important step toward reliable predictive medicine. It provides an internally validated mechanism for using randomized clinical trials to assess treatment efficacy for a patient population in a manner that takes into consideration the heterogeneity in patients' responsiveness to treatment. It also provides cross-validated patient-level survival curves that can be used for selecting treatments for future patients.
Skeletal muscle metabolism during exercise and recovery in patients with respiratory failure.
Authors: C H Thompson, R J Davies, G J Kemp, D J Taylor, G K Radda, B Rajagopalan
Journal: Thorax (1993)

BACKGROUND--Patients with respiratory failure have early fatiguability which may be due to limitation of oxygen supply for oxidative (mitochondrial) ATP synthesis. Skeletal muscle in exercise and recovery was studied to examine the effect of chronic hypoxia on mitochondrial activity in vivo. METHODS--The skeletal muscle of five patients with respiratory failure (PaO2 &lt; 9 kPa) was studied by phosphorus-31 magnetic resonance spectroscopy and compared with 10 age and sex matched controls. Patients lay in a 1.9 Tesla superconducting magnet with the gastrocnemius muscle overlying a six cm surface coil. Spectra were acquired at rest, during plantar flexion exercise, and during recovery from exercise. Relative concentrations of inorganic phosphate (Pi), phosphocreatine (PCr) and ATP were measured from peak areas, and pH and free ADP concentration were calculated. For the start of exercise, the rates of PCr depletion and estimated lactic acid production were calculated. For the post exercise recovery period, the initial rate of PCr recovery (a quantitative measure of mitochondrial ATP synthesis), the apparent Vmax for mitochondrial ATP synthesis (calculated from initial PCr resynthesis and the end exercise ADP concentration which drives this process), and the recovery half times of PCr, Pi, and ADP (also measures of mitochondrial function) were determined. RESULTS--Considerably greater and faster PCr depletion and intracellular acidosis were found during exercise. This is consistent with limitation of oxygen supply to the muscle and might explain the early fatiguability of these patients. There was no abnormality in recovery from exercise, however, suggesting that mitochondria function normally after exercise. CONCLUSIONS--These results are consistent with one or more of the following: (a) decreased level of activity of these patients; (b) changes in the fibre type of the muscle; (c) decreased oxygen supply to the muscle during exercise but not during recovery. They are not consistent with an intrinsic defect of mitochondrial ATP synthesis in skeletal muscle in respiratory failure.
Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice
Authors: Paritha I. Arumugam, Eric S. Mullins, Shiva Kumar Shanmukhappa, Brett P. Monia, Anastacia Loberg, Maureen A. Shaw, Tilat Rizvi, Janaka Wansapura, Jay L. Degen, Punam Malik
Journal: Blood (2015)
CD49d Is the Strongest Flow Cytometry–Based Predictor of Overall Survival in Chronic Lymphocytic Leukemia
Authors: Pietro Bulian, Tait D. Shanafelt, Chris Fegan, Antonella Zucchetto, Lilla Cro, Holger Nückel, Luca Baldini, Antonina V. Kurtova, Alessandra Ferrajoli, Jan A. Burger, Gianluca Gaidano, Giovanni Del Poeta, Chris Pepper, Davide Rossi, Valter Gattei
Journal: Journal of Clinical Oncology (2014)

Although CD49d is an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL), definitive validation evidence is lacking. A worldwide multicenter analysis was performed using published and unpublished CLL series to evaluate the impact of CD49d as an overall (OS) and treatment-free survival (TFS) predictor.A training/validation strategy was chosen to find the optimal CD49d cutoff. The hazard ratio (HR) for death and treatment imposed by CD49d was estimated by pooled analysis of 2,972 CLLs; Cox analysis stratified by center and stage was used to adjust for confounding variables. The importance of CD49d over other flow cytometry-based prognosticators (eg, CD38, ZAP-70) was ranked by recursive partitioning.Patients with ≥ 30% of neoplastic cells expressing CD49d were considered CD49d+. Decrease in OS at 5 and 10 years among CD49d+ patients was 7% and 23% (decrease in TFS, 26% and 25%, respectively). Pooled HR of CD49d for OS was 2.5 (2.3 for TFS) in univariate analysis. This HR remained significant and of similar magnitude (HR, 2.0) in a Cox model adjusted for clinical and biologic prognosticators. Hierarchic trees including all patients or restricted to those with early-stage disease or those age ≤ 65 years always selected CD49d as the most important flow cytometry-based biomarker, with negligible additional prognostic information added by CD38 or ZAP-70. Consistently, by bivariate analysis, CD49d reliably identified patient subsets with poorer outcome independent of CD38 and ZAP-70.In this analysis of approximately 3,000 patients, CD49d emerged as the strongest flow cytometry-based predictor of OS and TFS in CLL.
Overcoming Fas-Mediated Apoptosis Accelerates <i>Helicobacter</i>-Induced Gastric Cancer in Mice
Authors: Xun Cai, Calin Stoicov, Hanchen Li, Jane Carlson, Mark Whary, James G. Fox, JeanMarie Houghton
Journal: Cancer Research (2005)

The initiating molecular events in Helicobacter-induced gastric carcinogenesis are not known. Early in infection, Fas antigen-mediated apoptosis depletes parietal and chief cell populations, leading to architectural distortion. As infection progresses, metaplastic and dysplastic glands appear, which are resistant to Fas-mediated apoptosis. These abnormal lineages precede, and are thought to be the precursor lesions of, gastric cancer. Acquisition of an antiapoptotic phenotype before transformation of cells suggests that loss of Fas sensitivity may be an early required trait for gastric cancer. We reasoned that forced Fas-apoptosis resistance would result in earlier and more aggressive gastric cancer in our mouse model. Fas antigen-deficient (lpr) mice or C57BL/6 wild-type mice were irradiated and reconstituted with C57BL/6 marrow forming partial lpr/wt chimera or wt/wt control mice, extending the life span of the lpr and ensuring a competent immune response to Helicobacter felis infection. Infected lpr/wt mice developed gastric cancer as early as 7 months after infection (compared with 15 months in wt/wt mice). At 10 months (90%) and 15 months (100%), mice developed aggressive invasive lesions. This earlier onset and more aggressive histology strongly argues that Fas-apoptosis resistance is an early and important feature of gastric cancer formation.
Clinical highlights from the 2013 ERS Congress in Barcelona
Authors: Martijn A. Spruit, Maurizio Marvisi, Johan Coolen, Venerino Poletti, Stefano Gasparini, Björn Ställberg, Felix J.F. Herth, Enrico M. Clini
Journal: European Respiratory Journal (2014)

This article reviews a selection of scientific presentations in the area of clinical problems, which were presented at the 2013 European Respiratory Society Annual Congress in Barcelona, Spain. This article discusses the most relevant topics of interest in the field of clinical respiratory medicine, including breakthrough reports and studies of particular interest to the healthcare professionals. Topics are presented and discussed in the context of the most up-to-date literature, including basic science and translational research. In particular, the reviewed topics deal with the areas of complex chronic obstructive pulmonary disease and asthma (even in the primary care setting), idiopathic pulmonary fibrosis (pathogenesis and therapy), advances in functional chest imaging, interventional pulmonology, pulmonary rehabilitation and chronic care.
THE TRANSFER OF LYMPH NODE CELLS IN THE STUDY OF THE IMMUNE RESPONSE TO FOREIGN PROTEINS
Authors: James C. Roberts, Frank J. Dixon
Journal: The Journal of Experimental Medicine (1955)

A secondary immune response to the soluble foreign protein antigens I*BSA and I*BGG has been demonstrated when lymph node cells, largely lymphocytes with a few reticulo-endothelial and plasma cells, from previously immunized rabbits were transferred to x-radiated recipient rabbits, and the recipients then challenged with antigen. The total specific antibody synthesized by the transferred cells during the first 8 days of the secondary response amounted to approximately (2/3) of the wet weight of the transferred cells. In an attempt to elicit a primary response, lymph node cells were obtained from normal, non-immunized donors, and transferred to x-radiated recipients. No immune response was observed upon antigenic stimulation. When normal or previously immunized lymph node cells were incubated with antigen for periods up to 1 hour, washed and injected into recipients, no antibody production was observed.
T cell receptor transgenic lymphocytes infiltrating murine tumors are not induced to express foxp3
Authors: Jon G Quatromoni, Lilah F Morris, Timothy R Donahue, Yue Wang, William McBride, Talal Chatila, James S Economou
Journal: Journal of Hematology & Oncology (2011)

Regulatory T cells (Treg) that express the transcription factor Foxp3 are enriched within a broad range of murine and human solid tumors. The ontogeny of these Foxp3 Tregs - selective accumulation or proliferation of natural thymus-derived Treg (nTreg) or induced Treg (iTreg) converted in the periphery from naïve T cells - is not known. We used several strains of mice in which Foxp3 and EGFP are coordinately expressed to address this issue. We confirmed that Foxp3-positive CD4 T cells are enriched among tumor-infiltrating lymphocytes (TIL) and splenocytes (SPL) in B16 murine melanoma-bearing C57BL/6 Foxp3(EGFP) mice. OT-II Foxp3(EGFP) mice are essentially devoid of nTreg, having transgenic CD4 T cells that recognize a class II-restricted epitope derived from ovalbumin; Foxp3 expression could not be detected in TIL or SPL in these mice when implanted with ovalbumin-transfected B16 tumor (B16-OVA). Likewise, TIL isolated from B16 tumors implanted in Pmel-1 Foxp3(EGFP) mice, whose CD8 T cells recognize a class I-restricted gp100 epitope, were not induced to express Foxp3. All of these T cell populations - wild-type CD4, pmel CD8 and OTII CD4 - could be induced in vitro to express Foxp3 by engagement of their T cell receptor (TCR) and exposure to transforming growth factor β (TGFβ). B16 melanoma produces TGFβ and both pmel CD8 and OTII CD4 express TCR that should be engaged within B16 and B16-OVA respectively. Thus, CD8 and CD4 transgenic T cells in these animal models failed to undergo peripheral induction of Foxp3 in a tumor microenvironment.
Microsatellites as Targets of Natural Selection
Authors: R. J. Haasl, B. A. Payseur
Journal: Molecular Biology and Evolution (2012)

The ability to survey polymorphism on a genomic scale has enabled genome-wide scans for the targets of natural selection. Theory that connects patterns of genetic variation to evidence of natural selection most often assumes a diallelic locus and no recurrent mutation. Although these assumptions are suitable to selection that targets single nucleotide variants, fundamentally different types of mutation generate abundant polymorphism in genomes. Moreover, recent empirical results suggest that mutationally complex, multiallelic loci including microsatellites and copy number variants are sometimes targeted by natural selection. Given their abundance, the lack of inference methods tailored to the mutational peculiarities of these types of loci represents a notable gap in our ability to interrogate genomes for signatures of natural selection. Previous theoretical investigations of mutation-selection balance at multiallelic loci include assumptions that limit their application to inference from empirical data. Focusing on microsatellites, we assess the dynamics and population-level consequences of selection targeting mutationally complex variants. We develop general models of a multiallelic fitness surface, a realistic model of microsatellite mutation, and an efficient simulation algorithm. Using these tools, we explore mutation-selection-drift equilibrium at microsatellites and investigate the mutational history and selective regime of the microsatellite that causes Friedreich's ataxia. We characterize microsatellite selective events by their duration and cost, note similarities to sweeps from standing point variation, and conclude that it is premature to label microsatellites as ubiquitous agents of efficient adaptive change. Together, our models and simulation algorithm provide a powerful framework for statistical inference, which can be used to test the neutrality of microsatellites and other multiallelic variants.