tbuckley/cabot-search huggingface dataset:
Maximum Likelihood Estimation of Frequencies of Known Haplotypes from Pooled Sequence Data
Authors: D. Kessner, T. L. Turner, J. Novembre
Journal: Molecular Biology and Evolution (2013)

DNA samples are often pooled, either by experimental design or because the sample itself is a mixture. For example, when population allele frequencies are of primary interest, individual samples may be pooled together to lower the cost of sequencing. Alternatively, the sample itself may be a mixture of multiple species or strains (e.g., bacterial species comprising a microbiome or pathogen strains in a blood sample). We present an expectation-maximization algorithm for estimating haplotype frequencies in a pooled sample directly from mapped sequence reads, in the case where the possible haplotypes are known. This method is relevant to the analysis of pooled sequencing data from selection experiments, as well as the calculation of proportions of different species within a metagenomics sample. Our method outperforms existing methods based on single-site allele frequencies, as well as simple approaches using sequence read data. We have implemented the method in a freely available open-source software tool.
Preamble to Post-war Food Education
Authors: F. L. G. Clark
Journal: BMJ (1944)

We have made during the war a far more systematic attempt than ever before to influence the public in the choice and preparation of their food.The scope and plan of the wartime campaign'will be briefly examined below.The question that naturally arises at the present stage in our affairs is this: What are our prospects of continuing this wholesome work in more normal times, and what are the conditions for its success?
Uracil residues dependent on the deaminase AID in immunoglobulin gene variable and switch regions
Authors: Robert W Maul, Huseyin Saribasak, Stella A Martomo, Rhonda L McClure, William Yang, Alexandra Vaisman, Hillary S Gramlich, David G Schatz, Roger Woodgate, David M Wilson, Patricia J Gearhart
Journal: Nature Immunology (2010)
Aurora kinase A in gastrointestinal cancers: time to target
Authors: Ahmed Katsha, Abbes Belkhiri, Laura Goff, Wael El-Rifai
Journal: Molecular Cancer (2015)

Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. During the last two decades, several studies have shown amplification and overexpression of Aurora kinase A (AURKA) in several GI malignancies. These studies demonstrated that AURKA not only plays a role in regulating cell cycle and mitosis, but also regulates a number of key oncogenic signaling pathways. Although AURKA inhibitors have moved to phase III clinical trials in lymphomas, there has been slower progress in GI cancers and solid tumors. Ongoing clinical trials testing AURKA inhibitors as a single agent or in combination with conventional chemotherapies are expected to provide important clinical information for targeting AURKA in GI cancers. It is, therefore, imperative to consider investigations of molecular determinants of response and resistance to this class of inhibitors. This will improve evaluation of the efficacy of these drugs and establish biomarker based strategies for enrollment into clinical trials, which hold the future direction for personalized cancer therapy. In this review, we will discuss the available data on AURKA in GI cancers. We will also summarize the major AURKA inhibitors that have been developed and tested in pre-clinical and clinical settings.
Post-mortem examination of human fetuses: a comparison of whole-body high-field MRI at 9·4 T with conventional MRI and invasive autopsy
Authors: Sudhin Thayyil, Jon O Cleary, Neil J Sebire, Rosemary J Scott, Kling Chong, Roxanna Gunny, Catherine M Owens, Oystein E Olsen, Amaka C Offiah, Harold G Parks, Lyn S Chitty, Anthony N Price, Tarek A Yousry, Nicola J Robertson, Mark F Lythgoe, Andrew M Taylor
Journal: The Lancet (2009)
Therapeutic Efficacy of Replication-Competent Retrovirus Vector–Mediated Suicide Gene Therapy in a Multifocal Colorectal Cancer Metastasis Model
Authors: Kei Hiraoka, Takahiro Kimura, Christopher R. Logg, Chien-Kuo Tai, Kazunori Haga, Gregory W. Lawson, Noriyuki Kasahara
Journal: Cancer Research (2007)

Abstract Replication-competent retrovirus (RCR) vectors are intrinsically incapable of infecting quiescent cells and have been shown to achieve highly efficient and tumor-restricted replicative spread and gene transfer in vivo after direct intratumoral injection in a variety of primary cancer models. However, i.v. delivery of RCR vectors expressing therapeutic genes has never previously been tested, particularly in an immunocompetent tumor model. Therefore, in the present study, we sought to test the therapeutic effect of an RCR vector (ACE-CD) carrying the yeast cytosine deaminase (CD) gene, which converts the nontoxic prodrug 5-fluorocytosine (5FC) into the chemotoxin 5-fluorouracil, after delivery by infusion into the locoregional circulation in a multifocal hepatic metastasis model of colon cancer. After confirmation of suicide gene cytotoxicity in vitro, multifocal hepatic tumors were established in syngeneic mice with murine CT26 colorectal cancer cells expressing firefly luciferase (CT26-Luc), and the ACE-CD vector was infused via intrasplenic injection into the portal circulation. Fourteen days after locoregional infusion, systemic administration of 5FC resulted in significant inhibition of bioluminescent signals in mice whose tumors had been infected with RCR but not in control mice. Notably, there was no detectable RCR vector spread to normal liver or bone marrow by quantitative PCR analysis. Our results thus show that locoregional delivery of a suicide gene by RCR vectors infused into the portal circulation results in progressive transduction of multiple tumor foci in the liver, without evidence of spread to adjacent normal parenchyma or extrahepatic tissues, and can achieve significant tumor growth inhibition. [Cancer Res 2007;67(11):5345–53]
Development of Biologic Markers of Response and Assessment of Antiangiogenic Activity in a Clinical Trial of Human Recombinant Endostatin
Authors: Roy S. Herbst, Nizar A. Mullani, Darren W. Davis, Kenneth R. Hess, David J. McConkey, Chusilp Charnsangavej, Michael S. O’Reilly, Hyung-Woo Kim, Cheryl Baker, Jennifer Roach, Lee M. Ellis, Asif Rashid, James Pluda, Corazon Bucana, Timothy L. Madden, Hai T. Tran, James L. Abbruzzese
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Angiogenesis is a target for the treatment of cancer and other diseases, and its complex biology suggests that establishing the appropriate dose and schedule for antiangiogenic treatment will require extensive study. We present the initial results of a dose-finding clinical trial of recombinant human endostatin (rh-Endo) that examined potential surrogates for response to antiangiogenic therapy. PATIENTS AND METHODS: Twenty-five patients were treated with escalating doses of rh-Endo. Positron emission tomography (PET) was used to assess tumor blood flow (with [ 15 O]H 2 O) and metabolism (with [ 18 F]fluorodeoxyglucose) before the start of therapy and then every 4 weeks. To directly assess the effects of rh-Endo on endothelial cells within the tumors, biopsy specimens of tumor tissue were obtained before therapy and again at 8 weeks and evaluated for endothelial cell and tumor cell apoptosis. RESULTS: Tumor blood flow and metabolism as measured by PET scans generally decreased with increasing doses of rh-Endo; however, the effects were complex and in some analyses nonlinear. Tumor biopsy analysis revealed a significant increase in tumor cell apoptosis (P = .027) and endothelial cell apoptosis (P = .027) after 8 weeks of therapy. However, there was no statistically significant relationship between rh-Endo dose and induction of tumor cell or endothelial cell apoptosis. CONCLUSION: These initial data suggest that rh-Endo has measurable effects on tumor blood flow and metabolism and induces endothelial and tumor cell apoptosis even in the absence of demonstrable anticancer effects. Further study and validation of these biomarkers in the context of antiangiogenic therapy will be required.
Epithelial to Mesenchymal Transition and Peritoneal Membrane Failure in Peritoneal Dialysis Patients
Authors: Luiz S. Aroeira, Abelardo Aguilera, José A. Sánchez-Tomero, M. Auxiliadora Bajo, Gloria del Peso, José A. Jiménez-Heffernan, Rafael Selgas, Manuel López-Cabrera
Journal: Journal of the American Society of Nephrology (2007)

Peritoneal dialysis (PD) is a form of renal replacement and is based on the use of the peritoneum as a semipermeable membrane across which ultrafiltration and diffusion take place. Nevertheless, continuous exposure to bioincompatible PD solutions and episodes of peritonitis or hemoperitoneum cause acute and chronic inflammation and injury to the peritoneal membrane, which progressively undergoes fibrosis and angiogenesis and, ultimately, ultrafiltration failure. The pathophysiologic mechanisms that are involved in peritoneal functional impairment have remained elusive. Resident fibroblasts and infiltrating inflammatory cells have been considered the main entities that are responsible for structural and functional alterations of the peritoneum. Recent findings, however, demonstrated that new fibroblastic cells may arise from local conversion of mesothelial cells (MC) by epithelial-to-mesenchymal transition (EMT) during the inflammatory and repair responses that are induced by PD and pointed to MC as protagonists of peritoneal membrane deterioration. Submesothelial myofibroblasts, which participate in inflammatory responses, extracellular matrix accumulation, and angiogenesis, can originate from activated resident fibroblasts and from MC through EMT. This heterogeneous origin of myofibroblasts reveals new pathogenic mechanisms and offers novel therapeutic possibilities. This article provides a comprehensive review of recent advances on understanding the mechanisms that are implicated in peritoneal structural alterations, which have allowed the identification of the EMT of MC as a potential therapeutic target of membrane failure.
Reply to S.M. Sorscher et al
Authors: David H. Henry, Luis Costa, Francois Goldwasser, Vera Hirsh, Vania Hungria, Jana Prausova, Giorgio Vittorio Scagliotti, Harm Sleeboom, Andrew Spencer, Saroj Vadhan-Raj, Roger von Moos, Wolfgang Willenbacher, Jianming Wang, Qi Jiang, Susie Jun, Roger Dansey, Howard Yeh
Journal: Journal of Clinical Oncology (2011)

The hypothesis put forward by Sorscher et al 1 to explain survival differences in the subgroup of patients with multiple myeloma (MM) who were described in our article 2 bears consideration, and the potential effect of zoledronic acid on survival in patients with MM and Ras mutation will require additional study.However, an alternative hypothesis is that the survival findings in our study are spurious.As noted in our article, 2 differences in prognostic variables at study entry and differences in on-study antineoplastic treatments in the small cohort of patients with MM may confound the interpretation of survival in our study, which was primarily designed to evaluate complications of bone metastases.This alternative hypothesis is also supported when comparing the trial results with other recently published data on survival in MM.In the well-conducted Myeloma IX study, 3 which forms the clinical basis for the hypothesis proposed by Sorscher et al, 1 a survival benefit for zoledronic acid in comparison with clodronate was claimed.The 1-year survival rate of patients who were treated in this study was 80% for zoledronic acid, a rate nearly identical to the 1-year survival rate of 83% for patients with MM who were treated with denosumab in our study.However, the 1-year survival rate for patients with MM who were treated with zoledronic acid in our study was 96%-a rate substantially higher than the 80% survival rate with zoledronic acid in the Myeloma IX study.In addition, the 1-year survival rate for patients with MM who were treated with denosumab is consistent with published reports of similar patients from large epidemiologic and population-based database studies (72% to 83%) and from controlled clinical studies that have used either pamidronate or a placebo (78%). [4]5][6][7] Given these comparisons, it is reasonable to hypothesize that the survival difference seen in our study is an artifact.On the basis of multiple preclinical findings 8-10 that indicate a significant role for the receptor activator of nuclear factor kappa-B ligand pathway in the pathogenesis of myeloma bone disease and the need to continue to improve the lives of patients with MM, an adequately powered, phase III denosumab study is being initiated.The study compares denosumab with zoledronic acid in a fashion similar to that described in our article 2 and includes appropriate stratification of key MM baseline prognostic factors for survival and of antimyeloma treatments as well as skeletal-related events.The study will additionally inform on the efficacy and safety of denosumab in this patient population.
Treating Multidrug-Resistant Tuberculosis: Compliance and Side Effects
Authors: C. Patrick Chaulk, Richard E. Chaisson, John N. Lewis, Rosetta T. Rizzo
Journal: JAMA (1994)

<h3>To the Editor.</h3> —The recent article by Mahmoudi and Iseman<sup>1</sup>highlights avoidable pitfalls in the care of patients with<i>Mycobacterium tuberculosis</i>. In particular, we would like to underscore their recommendation for greater commitment to TB control programs such as those involving directly observed therapy (DOT). The authors recommend, among other things, that "directly observed therapy should be provided in situations when noncompliance is demonstrated or deemed likely." However, since many studies suggest that predicting a patient's potential for compliance with therapy is itself fraught with difficulties, and since DOT is a proven strategy for TB management,<sup>2</sup>we recommend implementing DOT more broadly throughout the community. The impact of such a strategy can be demonstrated in the city of Baltimore, Md. Between 1965 and 1978, Baltimore consistently ranked among the first three major US cities in the incidence of TB. In 1978, Baltimore began a clinic-based DOT program for
Ligand-independent Signaling Functions for the B Lymphocyte Antigen Receptor and Their Role in Positive Selection during B Lymphopoiesis
Authors: Gregory Bannish, Ezequiel M. Fuentes-Pananá, John C. Cambier, Warren S. Pear, John G. Monroe
Journal: The Journal of Experimental Medicine (2001)

Signal transduction through the B cell antigen receptor (BCR) is determined by a balance of positive and negative regulators. This balance is shifted by aggregation that results from binding to extracellular ligand. Aggregation of the BCR is necessary for eliciting negative selection or activation by BCR-expressing B cells. However, ligand-independent signaling through intermediate and mature forms of the BCR has been postulated to regulate B cell development and peripheral homeostasis. To address the importance of ligand-independent BCR signaling functions and their regulation during B cell development, we have designed a model that allows us to isolate the basal signaling functions of immunoglobulin (Ig)α/Igβ-containing BCR complexes from those that are dependent upon ligand-mediated aggregation. In vivo, we find that basal signaling is sufficient to facilitate pro-B → pre-B cell transition and to generate immature/mature peripheral B cells. The ability to generate basal signals and to drive developmental progression were both dependent on plasma membrane association of Igα/Igβ complexes and intact immunoregulatory tyrosine activation motifs (ITAM), thereby establishing a correlation between these processes. We believe that these studies are the first to directly demonstrate biologically relevant basal signaling through the BCR where the ability to interact with both conventional as well as nonconventional extracellular ligands is eliminated.
Rapid diagnostic tests for neurological infections in central Africa
Authors: Cedric P Yansouni, Emmanuel Bottieau, Pascal Lutumba, Andrea S Winkler, Lut Lynen, Philippe Büscher, Jan Jacobs, Philippe Gillet, Veerle Lejon, Emilie Alirol, Katja Polman, Jürg Utzinger, Michael A Miles, Rosanna W Peeling, Jean-Jacques Muyembe, François Chappuis, Marleen Boelaert
Journal: The Lancet Infectious Diseases (2013)
Sarcoidosis is associated with a truncating splice site mutation in BTNL2
Authors: Ruta Valentonyte, Jochen Hampe, Klaus Huse, Philip Rosenstiel, Mario Albrecht, Annette Stenzel, Marion Nagy, Karoline I Gaede, Andre Franke, Robert Haesler, Andreas Koch, Thomas Lengauer, Dirk Seegert, Norbert Reiling, Stefan Ehlers, Eberhard Schwinger, Matthias Platzer, Michael Krawczak, Joachim Müller-Quernheim, Manfred Schürmann, Stefan Schreiber
Journal: Nature Genetics (2005)
Allergen‐dependent CD14 modulation and apoptosis in monocytes from allergic patients
Authors: J. Monteseirín, I. Bonilla, P. Chacón, A. Vega, M. J. Camacho, P. Guardia, J. Conde, F. Sobrino
Journal: Allergy (2003)

Background: CD14 is a most important monocyte surface molecule. Recently, it has been reported that there is an important relationship between CD14 and immunoglobulin E, and that regulation of CD14 expression is an effector mechanism mediating apoptosis of monocytes. Objective: The present study was designed to determine whether specific allergens were able to modulate CD14 expression and apoptosis by monocytes from allergic patients or whether specific immunotherapy (IT) might affect these processes. Methods: One group of adult allergic asthmatic patients had received IT for the previous 3 years. Another similar group was not treated with IT. We challenged peripheral blood monocytes from both groups of asthmatic patients in vitro with the specific allergen that produced clinical symptoms in asthmatic patients. The cells were also challenged with allergen to which the patients were not sensitive. Monocytes from normal subjects were also challenged with allergens. Expression of CD14 on the monocyte surface was analyzed by flow cytometry, and soluble CD14 (sCD14) in culture supernatant by enzyme‐linked immunosorbent assay. The three groups of subjects were challenged with allergens, and apoptosis was analyzed by flow cytometry. Results: When monocytes from non‐IT‐treated asthmatic patients were cultivated with the allergens to which the patients were sensitive, a significant up‐regulation on the monocyte surface was observed compared with results from the healthy group ( P &lt; 0.003) and from the IT asthmatic group ( P &lt; 0.003). A significantly higher sCD14 level was observed in the culture supernatant of the monocytes from the IT asthmatic group were observed compared with those from the healthy group ( P &lt; 0.001) and those from the non‐IT asthmatic group ( P &lt; 0.001). A significantly higher apoptosis level was observed in monocytes from the IT asthmatic group compared with those from the healthy group ( P &lt; 0.001) and those from the non‐IT asthmatic group (&lt;0.001). Conclusions: We present evidence that the expression of CD14 on the surface of monocytes and the apoptosis of the same cells can be modulated by an allergen‐dependent mechanism. These processes can be affected by IT.
Pivotal Study of Iodine-131–Labeled Chimeric Tumor Necrosis Treatment Radioimmunotherapy in Patients With Advanced Lung Cancer
Authors: Shaoliang Chen, Like Yu, Changying Jiang, Yan Zhao, Da Sun, Shenyu Li, Guoqing Liao, Yangchun Chen, Qing Fu, Qun Tao, Dan Ye, Peisheng Hu, Leslie A. Khawli, Clive R. Taylor, Alan L. Epstein, Dian Wen Ju
Journal: Journal of Clinical Oncology (2005)

Tumor necrosis treatment (TNT) uses degenerating tumor cells and necrotic regions of tumors as targets for radioimmunotherapy. Previous studies in animal tumor models and clinical trials have demonstrated that when linked to the therapeutic radionuclide iodine-131, recombinant chimeric TNT antibody ((131)I-chTNT) can deliver therapeutic doses to tumors regardless of the location or type of malignancy. Therapeutic efficacy and toxicity of (131)I-chTNT in advanced lung cancer patients were studied in this pivotal registration trial.Patients with advanced lung cancer were treated with systemic or intratumoral injection of (131)I-chTNT in eight oncology centers in China. The objective response rate (ORR) was assessed as the primary end point.All 107 patients who were entered onto the study and completed therapy had experienced treatment failure after prior radiotherapy or chemotherapy a mean of three times. The results showed an ORR of 34.6% (complete response, 3.7%; partial response, 30.8%; no change, 55.1%; and progressive disease, 10.3%) in all patients and 33% in 97 non-small-cell lung cancer patients. A biodistribution study demonstrated excellent localization of the radioactivity in tumors in both systemically and intratumorally injected patients. The most obvious adverse side effect was mild and reversible bone marrow suppression.Radioimmunotherapy with (131)I-chTNT was well tolerated and can be used systemically or locally to treat refractory tumors of the lung.
Repopulation of the fibrotic/cirrhotic rat liver by transplanted hepatic stem/progenitor cells and mature hepatocytes
Authors: Mladen I. Yovchev, Yuhua Xue, David A. Shafritz, Joseph Locker, Michael Oertel
Journal: Hepatology (2013)

Considerable progress has been made in developing antifibrotic agents and other strategies to treat liver fibrosis; however, significant long-term restoration of functional liver mass has not yet been achieved. Therefore, we investigated whether transplanted hepatic stem/progenitor cells can effectively repopulate the liver with advanced fibrosis/cirrhosis. Stem/progenitor cells derived from fetal livers or mature hepatocytes from DPPIV(+) F344 rats were transplanted into DPPIV(-) rats with thioacetamide (TAA)-induced fibrosis/cirrhosis; rats were sacrificed 1, 2, or 4 months later. Liver tissues were analyzed by histochemistry, hydroxyproline determination, reverse-transcription polymerase chain reaction (RT-PCR), and immunohistochemistry. After chronic TAA administration, DPPIV(-) F344 rats exhibited progressive fibrosis, cirrhosis, and severe hepatocyte damage. Besides stellate cell activation, increased numbers of stem/progenitor cells (Dlk-1(+), AFP(+), CD133(+), Sox-9(+), FoxJ1(+)) were observed. In conjunction with partial hepatectomy (PH), transplanted stem/progenitor cells engrafted, proliferated competitively compared to host hepatocytes, differentiated into hepatocytic and biliary epithelial cells, and generated new liver mass with extensive long-term liver repopulation (40.8 ± 10.3%). Remarkably, more than 20% liver repopulation was achieved in the absence of PH, associated with reduced fibrogenic activity (e.g., expression of alpha smooth muscle actin, platelet-derived growth factor receptor β, desmin, vimentin, tissue inhibitor of metalloproteinase-1) and fibrosis (reduced collagen). Furthermore, hepatocytes can also replace liver mass with advanced fibrosis/cirrhosis, but to a lesser extent than fetal liver stem/progenitor cells.This study is a proof of principle demonstration that transplanted epithelial stem/progenitor cells can restore injured parenchyma in a liver environment with advanced fibrosis/cirrhosis and exhibit antifibrotic effects.