tbuckley/cabot-search huggingface dataset:
Fortnightly review: Lyme disease in the United Kingdom
Authors: S. O'Connell
Journal: BMJ (1995)

<h3>Abstract</h3> For precision medicine to reach its full potential for treatment of cancer and other diseases, protein variant effect prediction tools are needed that characterize variants of unknown significance (VUS) in a patient’s genome with respect to their likelihood to influence treatment response and outcomes. However, the performance of most variant prediction tools is limited by the difficulty of acquiring sufficient training and validation data. To overcome these limitations, we applied an iterative active learning approach starting from available biochemical, evolutionary, and functional annotations. The potential of active learning to improve variant interpretation was first demonstrated by applying it to synthetic and deep mutational scanning (DMS) datasets for four cancer-relevant proteins. We then probed its utility to guide interpretation and functional validation of tumor VUS in a potential biomarker for cancer therapy sensitivity, the nucleotide excision repair (NER) protein Xeroderma Pigmentosum Complementation Group A (XPA). A quantitative high-throughput cell-based NER activity assay, fluorescence-based multiplex flow-cytometric host cell reactivation (FM-HCR), was used to validate XPA VUS selected by the active learning strategy. In all cases, selecting VUS for validation by active learning yielded an improvement in performance over traditional learning. These analyses suggest that active learning is well-suited to significantly improve interpretation of VUS and cancer patient genomes.
SPEED, ROAD INJURY, AND PUBLIC HEALTH
Authors: Elihu D. Richter, Tamar Berman, Lee Friedman, Gerald Ben-David
Journal: Annual Review of Public Health (2006)

▪ Abstract We review milestones in the history of increases in speed limits and travel speeds (“speed creep”) and risks for road deaths and injury. Reduced speed limits, speed-camera networks, and speed calming substantially reduce these tolls in absolute numbers—a trend that is apparent in the United Kingdom, Australia, France, and other countries, but not in the United States, which has raised speed limits and does not have speed-camera networks. Newtonian relationships between the fourth power of small increases or reductions in speed and large increases or reductions in deaths state the case for speed control. Speed adaptation and the interaction between speed and other determinants of injury risks, including congestion and countermeasures, enter into these relationships. Speed-camera networks and speed calming lead to large, sustainable, and highly cost-effective drops in road deaths and injuries and should target entire populations, not merely high-risk subgroups or situations. Yet, there are major barriers to preventive strategies based on the discovery that speed kills. Modal shifts from speed on roads to speed on rail, lower maximum vehicle speeds, and speed-camera networks are required for progress toward Vision Zero—the goal of no road deaths—through Killing Speed. The human cost of the delay in killing speed in the United States may be as high as 20,000 lives lost per year.
FDA Perspective on Companion Diagnostics: An Evolving Paradigm
Authors: Elizabeth A. Mansfield
Journal: Clinical Cancer Research (2014)

Abstract Therapeutic products are now being developed that target particular molecular lesions found in various types of cancers. The ability to correctly identify patients whose cancers have targetable lesions generally depends on a well-validated diagnostic test. Development and use of diagnostic tests together with therapies in clinical trials yields the information necessary to make a regulatory determination that both products are safe and effective, likely have clinical utility when used together, and reach the market for patient benefit. This model, called co-development, has been developed relatively recently, and is being put to use in numerous cancer therapeutic development programs. The U.S. Food and Drug Administration (FDA) has articulated a policy that requires the coapproval of a diagnostic with a therapeutic product when the diagnostic is essential to the safe and effective use of the therapeutic product. At the same time, FDA has implemented a number of processes to manage the model without slowing the approval of the co-developed products. New diagnostic technologies, together with a rapid uptick in interest in targeted drugs, will challenge the still-evolving regulatory paradigm, but will likely result in some simplified approaches presenting new challenges in determining safety and effectiveness, but all with the promise of greater benefit to patients with cancer. See all articles in this CCR Focus section, “The Precision Medicine Conundrum: Approaches to Companion Diagnostic Co-development.” Clin Cancer Res; 20(6); 1453–7. ©2014 AACR.
Relative Densities of Muscarinic Cholinergic and β-Adrenergic Receptors in the Canine Sinoatrial Node and Their Relation to Sites of Pacemaker Activity
Authors: Scott L. Beau, Dwight E. Hand, Richard B. Schuessler, Burt I. Bromberg, Brian Kwon, John P. Boineau, Jeffrey E. Saffitz
Journal: Circulation Research (1995)

The site of earliest extracellular electrical activation in the sinoatrial node (SAN) is known to shift in response to autonomic stimuli, but the mechanisms underlying this phenomenon and the determinants of the location of dominant pacemaker activity have not been elucidated. The present study was designed to characterize the spatial distribution of muscarinic cholinergic and beta-adrenergic receptors in the canine SAN and to determine whether a consistent relationship exists between autonomic receptor densities and the site of dominant pacemaker activity. We used quantitative light-microscopic autoradiography of radioligand binding sites to characterize the spatial distribution of muscarinic cholinergic and beta-adrenergic receptor subtypes in tissue sections containing the SAN and adjacent right atrial muscle from 18 canine hearts. Muscarinic receptor density was 5.4 times greater in SAN cells than in atrial myocytes (P < .01). Total beta-adrenergic receptor density was more than 3 times greater in SAN cells than in atrial myocytes (P < .0001), due entirely to the significantly greater number of beta 1-adrenergic receptors in the SAN. The region of dominant pacemaker activity, localized in 4 hearts with in vitro mapping, consistently exhibited greater densities of muscarinic and beta 1-adrenergic receptors than other SAN regions. Muscarinic receptor density in the dominant pacemaker region was 18 +/- 2% and 29 +/- 7% higher than in adjacent superior and inferior regions, respectively. beta 1-Receptor density in the dominant site was 53 +/- 5% and 26 +/- 4% higher than in adjacent superior and inferior SAN regions, respectively. Thus, the SAN is richly endowed with both muscarinic cholinergic and beta 1-adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
The behavior of skin grafts incompatible with respect to skin alloantigens on mice rendered tolerant at birth with lymphoid cells.
Authors: W K Silvers, S S Wachtel, T W Poole
Journal: The Journal of Experimental Medicine (1976)

It has been reported that lethally irradiated adult B6 mice restored with (A X B6) hemopoietic cells subsequently reject adult A-strain skin grafts because they are not tolerant of A-strain skin-specific (Sk) antigens. This thesis has been confirmed by a series of experiments conducted on neonatally treated animals. Thus sublethally irradiated neonatal B6 mice, inoculated with (A X B6) lymphoid cells, permanently accept these cells while subsequently rejecting adult strain A skin grafts. Further evidence that the destruction of these grafts results from the reaction of the host to Sk antigens, is provided by the fact that similarly treated recipients often permanently accept neonatal A-strain skin. Such grafts usually induce tolerance of adult A-strain skin grafts.
Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up
Authors: Thorsten Zenz, Alexander Kröber, Katrin Scherer, Sonja Häbe, Andreas Bühler, Axel Benner, Tina Denzel, Dirk Winkler, Jennifer Edelmann, Carsten Schwänen, Hartmut Döhner, Stephan Stilgenbauer
Journal: Blood (2008)
The search for the<i>perfect animal model</i>discloses the importance of biological targets for the treatment of systemic sclerosis
Authors: Francesco Del Galdo, Marco Matucci-Cerinic
Journal: Annals of the Rheumatic Diseases (2013)

The pathogenesis of systemic sclerosis (SSc) has been intensely investigated, and the scientific community is unravelling a detailed dissection of the molecular pathways leading to the fibrotic process. Additionally, a wealth of brilliant in vivo studies on several animal models has shown the capacity of several drugs to temper the fibrotic process. However, to date, the translation of these data in the clinic with interventional studies failed to demonstrate any consistent efficacy in ameliorating tissue fibrosis or modifying the evolution of SSc. The discrepancy between the extremely promising in vitro and in vivo results, and the otherwise disappointing results of clinical studies is striking, and it is now inevitably dampening the enthusiasm on the potentially direct translation of research into clinical progress. Moreover, it is pushing the community to raise an increasing number of doubts on the use of the current preclinical models.

The studies on the use of tyrosine kinase inhibitors (TKI) nilotinib and imatinib for skin fibrosis are a clear example of the contrast between extremely promising in vitro and in vivo data, and the poor data obtained in the clinical setting.

Indeed, in vitro data on TGF-β and PDGF signalling have built a strong rationale for the use of TKI as antifibrotic agents in SSc.1 ,2 Furthermore, extensive in vivo studies on bleomycin-treated mice and TSK mice, widely used animal models of SSc, showed brilliant results of nilotinib and imatinib in preventing skin fibrosis and improving fibrosis in different organs.3 Unfortunately, both TKIs failed to demonstrate consistent clinical results in SSc patients in open label and controlled trials.4 ,5

An interesting manuscript from Maurer et al , published in the December issue of Ann Rheum Dis , describes the effort to understand the reasons of this discrepancy …
Progression to Impaired Glucose Regulation and Diabetes in the Population-Based Inter99 Study
Authors: Susanne Engberg, Dorte Vistisen, Cathrine Lau, Charlotte Glümer, Torben Jørgensen, Oluf Pedersen, Knut Borch-Johnsen
Journal: Diabetes Care (2008)

OBJECTIVE The purpose of this study was to estimate the progression rates to impaired glucose regulation (impaired fasting glucose or impaired glucose tolerance) and diabetes in the Danish population–based Inter99 study and in a high-risk subpopulation, separately. RESEARCH DESIGN AND METHODS From a population-based primary prevention study, the Inter99 study, 4,615 individuals without diabetes at baseline and with relevant follow-up data were divided into a low- and a high-risk group based on a risk estimate of ischemic heart disease or the presence of risk factors (smoking, hypertension, hypercholesterolemia, obesity, or impaired glucose tolerance). High-risk individuals (57.1%) were examined with an oral glucose tolerance test at 1 and 3 years, and all of the participants were reexamined at the 5-year follow-up. Person-years at risk were calculated. Progression rates to impaired glucose regulation and diabetes were estimated directly from baseline to the 5-year follow-up for all the participants and from baseline through the 1- and 3- to 5-year follow-up examinations for the high-risk individuals, separately. RESULTS In the combined low- and high-risk group, 2.1 individuals per 100 person-years progressed from normal glucose tolerance (NGT) to impaired glucose regulation or diabetes. Among high-risk individuals, 5.8 per 100 person-years with NGT progressed to impaired glucose regulation or diabetes, and 4.9 per 100 person-years progressed from impaired glucose regulation to diabetes. CONCLUSIONS Progression rates to impaired glucose regulation using the current World Health Organization classification criteria were calculated for the first time in a large European population-based study. The progression rates to diabetes show the same pattern as seen in the few similar European studies.
Antitumor drug sends new signals
Authors: Hema Bashyam
Journal: The Journal of Experimental Medicine (2007)

Drugs that collapse the tumor vasculature by increasing the leakiness of tumor blood vessels are a new breed of chemotherapeutic agents, but how they worked was unknown. Now, Roberts et al. (page [1559][1]) have determined the pathway and targets of one such vasculature-disrupting agent (VDA). They
The effect of encapsulated VEGF-secreting cells on brain amyloid load and behavioral impairment in a mouse model of Alzheimer’s disease
Authors: Carlos Spuch, Desiree Antequera, Aitziber Portero, Gorka Orive, Rosa Ma Hernández, Jose A. Molina, Felix Bermejo-Pareja, José L. Pedraz, Eva Carro
Journal: Biomaterials (2010)
I<scp>NSIGHTS INTO THE</scp> P<scp>ATHOGENESIS OF</scp> G<scp>ALACTOSEMIA</scp>
Authors: Nancy D. Leslie
Journal: Annual Review of Nutrition (2003)

▪ Abstract In humans, the absence of galactose-1-phosphate uridyltransferase (GALT) leads to significant neonatal morbidity and mortality which are dependent on galactose ingestion, as well as long-term complications of primary ovarian failure and cognitive dysfunction, which are diet independent. The creation of a knockout mouse model for GALT deficiency was aimed at providing an organism in which metabolic challenges and gene manipulation could address the enigmatic pathophysiologic questions raised by humans with galactosemia. Instead, the mouse represents a biochemical phenotype without evidence of clinical morbidity. The similarities and differences between mice and humans with galactosemia are explored from metabolite, enzyme, and process points of view. The mouse both produces and oxidizes galactose in a manner similar to humans. It differs in brain accumulation of galactitol. Future directions for exploration of this enigmatic condition are discussed.
The Role of Targeted Agents in Adjuvant Therapy for Non–Small Cell Lung Cancer
Authors: Karen Kelly
Journal: Clinical Cancer Research (2005)

Abstract The recent survival benefit of adjuvant chemotherapy in early stage non–small cell lung cancer provides optimism for the future success of targeted therapy in this setting. It is important that we begin to explore molecularly targeted agents in the adjuvant arena, but how best to accomplish this in the face of these new findings presents a challenge. Criteria for selecting promising targeted therapies and optimal trial designs to evaluate them expeditiously in the adjuvant setting are clearly needed.
Efficacy and Safety of Mipomersen, an Antisense Inhibitor of Apolipoprotein B, in Hypercholesterolemic Subjects Receiving Stable Statin Therapy
Authors: Fatima Akdim, Erik S.G. Stroes, Eric J.G. Sijbrands, Diane L. Tribble, Mieke D. Trip, J. Wouter Jukema, JoAnn D. Flaim, John Su, Rosie Yu, Brenda F. Baker, Mark K. Wedel, John J.P. Kastelein
Journal: Journal of the American College of Cardiology (2010)
PSYCHIATRIC SYMPTOMS ASSOCIATED WITH INTRACRANIAL NEOPLASMS
Authors: T. L. L. SONIAT
Journal: American Journal of Psychiatry (1951)

The presence of psychiatric symptoms in patients with intracranial neoplasms often increases the difficulty of recognizing the true nature of the patient's trouble. Such symptoms are frequently associated with brain tumors. A review of the records of 128 patients with proved intracranial neoplasms seen at the Ochsner Clinic revealed that approximately half exhibited on admission symptoms that could be considered "psychiatric." Alert suspicion during history-taking and examination is the best means of appreciably minimizing diagnostic errors, since there is usually apparent a symptom or sign that should serve to cause the examiner to exercise diagnostic caution. In this series there existed a similarity in incidence of psychiatric symptoms exhibited by patients with tumors of the frontal and temporal lobes. Some psychiatric symptoms stem from the cerebral damage incident to the tumor and are fairly definite, whereas others are vague and seem to be part of the patient's previous personality, perhaps accentuated by his total reaction to his illness. Cases illustrating this point are cited.
Conserved sequence motifs, alignment, and secondary structure for the third domain of animal 12S rRNA
Authors: R. E. Hickson, C. Simon, A. Cooper, G. S. Spicer, J. Sullivan, D. Penny
Journal: Molecular Biology and Evolution (1996)

Secondary structure models are an important step for aligning sequences, understanding probabilities of nucleotide substitutions, and evaluating the reliability of phylogenetic reconstructions. A set of conserved sequence motifs is derived from comparative sequence analysis of 184 invertebrate and vertebrate taxa (including many taxa from the same genera, families, and orders) with reference to a secondary structure model for domain III of animal mitochondrial small subunit (12S) ribosomal RNA. A template is presented to assist with secondary structure drawing. Our model is similar to previous models but is more specific to mitochondrial DNA, fitting both invertebrate and vertebrate groups, including taxa with markedly different nucleotide compositions. The second half of the domain III sequence can be difficult to align precisely, even when secondary structure information is considered. This is especially true for comparisons of anciently diverged taxa, but well-conserved motifs assist in determining biologically meaningful alignments. Patterns of conservation and variability in both paired and unpaired regions make differential phylogenetic weighting in terms of "stems" and "loops" unsatisfactory. We emphasize looking carefully at the sequence data before and during analyses, and advocate the use of conserved motifs and other secondary structure information for assessing sequencing fidelity.
Autocrine Induction of Invasive and Metastatic Phenotypes by the MIF-CXCR4 Axis in Drug-Resistant Human Colon Cancer Cells
Authors: Anne-Frédérique Dessein, Laurence Stechly, Nicolas Jonckheere, Patrick Dumont, Didier Monté, Emmanuelle Leteurtre, Stéphanie Truant, François-René Pruvot, Martin Figeac, Mohamed Hebbar, Charles-Henri Lecellier, Thécla Lesuffleur, Rodrigue Dessein, Georges Grard, Marie-José Dejonghe, Yvan de Launoit, Yasuhiro Furuichi, Grégoire Prévost, Nicole Porchet, Christian Gespach, Guillemette Huet
Journal: Cancer Research (2010)

Abstract Metastasis and drug resistance are major problems in cancer chemotherapy. The purpose of this work was to analyze the molecular mechanisms underlying the invasive potential of drug-resistant colon carcinoma cells. Cellular models included the parental HT-29 cell line and its drug-resistant derivatives selected after chronic treatment with either 5-fluorouracil, methotrexate, doxorubicin, or oxaliplatin. Drug-resistant invasive cells were compared with noninvasive cells using cDNA microarray, quantitative reverse transcription-PCR, flow cytometry, immunoblots, and ELISA. Functional and cellular signaling analyses were undertaken using pharmacologic inhibitors, function-blocking antibodies, and silencing by retrovirus-mediated RNA interference. 5-Fluorouracil– and methotrexate-resistant HT-29 cells expressing an invasive phenotype in collagen type I and a metastatic behavior in immunodeficient mice exhibited high expression of the chemokine receptor CXCR4. Macrophage migration-inhibitory factor (MIF) was identified as the critical autocrine CXCR4 ligand promoting invasion in drug-resistant colon carcinoma HT-29 cells. Silencing of CXCR4 and impairing the MIF-CXCR4 signaling pathways by ISO-1, pAb FL-115, AMD-3100, monoclonal antibody 12G5, and BIM-46187 abolished this aggressive phenotype. Induction of CXCR4 was associated with the upregulation of two genes encoding transcription factors previously shown to control CXCR4 expression (HIF-2α and ASCL2) and maintenance of intestinal stem cells (ASCL2). Enhanced CXCR4 expression was detected in liver metastases resected from patients with colon cancer treated by the standard FOLFOX regimen. Combination therapies targeting the CXCR4-MIF axis could potentially counteract the emergence of the invasive metastatic behavior in clonal derivatives of drug-resistant colon cancer cells. Cancer Res; 70(11); 4644–54. ©2010 AACR.
Tube feeding in advanced dementia: the metabolic perspective
Authors: L John Hoffer
Journal: BMJ (2006)

Problems with the procedure do not fully explain its ineffectiveness

Questions about tube feeding in advanced dementia continue to bedevil doctors, surrogate decision makers, and administrators and stimulate research, topic reviews, and position papers.1 2 3 4 5 This article shows that the dilemma of whether or not to tube feed an incompetent, demented patient can always be clarified, and often resolved, by applying the principles of nutritional physiology. The concepts described in this article have not previously appeared in the literature dealing with the artificial feeding of incompetent patients.⇓ 



Elderly demented patients often eat enough for their diminished energy requirements 



Reduced food intake and weight loss are normal features of advancing old age.6 7 Food intake by elderly people may also be pathologically curtailed by factors such as ill fitting dentures, functional disability, depression, isolation, and poverty. There is increasing evidence that non-demented, elderly malnourished people benefit from nutritional supplements.8 To my knowledge, no randomised clinical trials have been carried out in tube fed, severely demented patients,9 but observational data and the results of trials of tube feeding in other conditions have led to a consensus of expert opinion that tube feeding patients with advanced dementia neither prolongs their life nor improves its quality.1 3 4 5 9 10 11 12 Why would this be so? 

Tube feeding shortens the life of some patients, and it is often inefficient at delivering food.4 5 9 10 12 13 But problems with the procedure do not fully explain its ineffectiveness. Severely demented patients usually fail to benefit …
Eph Receptors and Ephrins: Therapeutic Opportunities
Authors: Antonio Barquilla, Elena B. Pasquale
Journal: The Annual Review of Pharmacology and Toxicology (2014)

The erythropoietin-producing hepatocellular carcinoma (Eph) receptor tyrosine kinase family plays important roles in developmental processes, adult tissue homeostasis, and various diseases. Interaction with Eph receptor-interacting protein (ephrin) ligands on the surface of neighboring cells triggers Eph receptor kinase-dependent signaling. The ephrins can also transmit signals, leading to bidirectional cell contact-dependent communication. Moreover, Eph receptors and ephrins can function independently of each other through interplay with other signaling systems. Given their involvement in many pathological conditions ranging from neurological disorders to cancer and viral infections, Eph receptors and ephrins are increasingly recognized as attractive therapeutic targets, and various strategies are being explored to modulate their expression and function. Eph receptor/ephrin upregulation in cancer cells, the angiogenic vasculature, and injured or diseased tissues also offer opportunities for Eph/ephrin-based targeted drug delivery and imaging. Thus, despite the challenges presented by the complex biology of the Eph receptor/ephrin system, exciting possibilities exist for therapies exploiting these molecules.