tbuckley/cabot-search huggingface dataset:
SubcloneSeeker: a computational framework for reconstructing tumor clone structure for cancer variant interpretation and prioritization
Authors: Yi Qiao, Aaron R Quinlan, Amir A Jazaeri, Roeland GW Verhaak, David A Wheeler, Gabor T Marth
Journal: Genome biology (2014)

Abstract Many tumors are composed of genetically divergent cell subpopulations. We report SubcloneSeeker, a package capable of exhaustive identification of subclone structures and evolutionary histories with bulk somatic variant allele frequency measurements from tumor biopsies. We present a statistical framework to elucidate whether specific sets of mutations are present within the same subclones, and the order in which they occur. We demonstrate how subclone reconstruction provides crucial information about tumorigenesis and relapse mechanisms; guides functional study by variant prioritization, and has the potential as a rational basis for informed therapeutic strategies for the patient. SubcloneSeeker is available at: https://github.com/yiq/SubcloneSeeker .
Relationship Between Pacemaker Dependency and the Effect of Pacing Mode on Cardiovascular Outcomes
Authors: Anthony S.L. Tang, Robin S. Roberts, Charles Kerr, Anne M. Gillis, Martin S. Green, Mario Talajic, Salim Yusuf, Hoshiar Abdollah, Michael Gent, Stuart J. Connolly
Journal: Circulation (2001)

A recently completed trial, the Canadian Trial of Physiological Pacing (CTOPP), showed that physiological pacing did not significantly reduce mortality, stroke, or heart failure hospitalization, but it did show that atrial fibrillation occurred less frequently in patients with physiological pacing. Many pacemaker patients experience only transient bradyarrhythmias with an adequate unpaced heart rate (UHR) and are not pacemaker-dependent. The purpose of the present analysis was to determine if pacemaker-dependent patients have an increased benefit from physiological pacing compared with non-pacemaker-dependent patients.Of 2568 patients included in the CTOPP trial, 2244 patients had a pacemaker dependency test performed at the first follow-up visit. The yearly event rate of cardiovascular death or stroke steadily increased with decreasing UHR in the ventricular pacing group, but it remained constant in the physiological pacing group. When the patients were subdivided to UHR </=60 bpm or >60 bpm, there was an interaction between pacing mode treatment and UHR subgroup. The Kaplan-Meier plot confirmed a physiological pacing advantage only in the UHR </=60 bpm subgroup. This differential effect was also present for the outcomes of cardiovascular death and total mortality.This study demonstrated that UHR at first follow-up has an important influence on how pacing mode selection affects cardiovascular death and total mortality. Pacemaker-dependent patients with low UHR will probably be paced frequently and will likely benefit from physiological pacing. In contrast, non-pacemaker-dependent patients will likely be paced infrequently and may not benefit from physiological pacing.
On Removal of the Cancerous Uterus by the Abdominal Route
Authors: T. H. Pounds
Journal: BMJ (1900)

EXCISION of the uterus, historically considered, is of ancient date.Soranos of Ephesus, in his book on Diseases of Women, ipublished a century before Christ, mentions the operation, but there can be no doubt that it was subsequently forgotten.-Coming to the present century, Langenbeck in 1813 success- fully removed the whole uterus (by the abdomen) for cancer: followed by Sauter, of Constance, who in I822 had the first .successfulvaginal extirpation for cancer.In the following
Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice
Authors: Ruchi Bansal, Jai Prakash, Eduard Post, Leonie Beljaars, Detlef Schuppan, Klaas Poelstra
Journal: Hepatology (2011)

Liver fibrogenesis is a process tightly controlled by endogenous anti- and pro-fibrogenic factors. Interferon gamma (IFNγ) is a potent antifibrogenic cytokine in vitro and might therefore represent a powerful therapeutic entity. However, its poor pharmacokinetics and adverse effects, due to the presence of IFNγ receptors on nearly all cells, prevented its clinical application so far. We hypothesized that delivery of IFNγ specifically to the disease-inducing cells and concurrently avoiding its binding to nontarget cells might increase therapeutic efficacy and avoid side effects. We conjugated IFNγ to a cyclic peptide recognizing the platelet-derived growth factor beta receptor (PDGFβR) which is strongly up-regulated on activated hepatic stellate cells (HSC), the key effector cells responsible for hepatic fibrogenesis. The IFNγ conjugates were analyzed in vitro for PDGFβR-specific binding and biological effects and in vivo in acute (early) and chronic (progressive and established) carbon-tetrachloride-induced liver fibrosis in mice. The targeted-IFNγ construct showed PDGFβR-specific binding to fibroblasts and HSC and inhibited their activation in vitro . In vivo , the targeted-IFNγ construct attenuated local HSC activation in an acute liver injury model. In the established liver fibrosis model, it not only strongly inhibited fibrogenesis but also induced fibrolysis. In contrast, nontargeted IFNγ was ineffective in both models. Moreover, in contrast to unmodified IFNγ, our engineered targeted-IFNγ did not induce IFNγ-related side effects such as systemic inflammation, hyperthermia, elevated plasma triglyceride levels, and neurotropic effects. Conclusion: This study presents a novel HSC-targeted engineered-IFNγ, which in contrast to systemic IFNγ, blocked liver fibrogenesis and is devoid of side effects, by specifically acting on the key pathogenic cells within the liver. (Hepatology 2011;)
Nfil3-independent lineage maintenance and antiviral response of natural killer cells
Authors: Matthew A. Firth, Sharline Madera, Aimee M. Beaulieu, Georg Gasteiger, Eliseo F. Castillo, Kimberly S. Schluns, Masato Kubo, Paul B. Rothman, Eric Vivier, Joseph C. Sun
Journal: The Journal of Experimental Medicine (2013)

Development of the natural killer (NK) cell lineage is dependent on the transcription factor Nfil3 (or E4BP4), which is thought to act downstream of IL-15 signaling. Nfil3-deficient mice lack NK cells, whereas other lymphocyte lineages (B, T, and NKT cells) remain largely intact. We report the appearance of Ly49H-expressing NK cells in Nfil3−/− mice infected with mouse cytomegalovirus (MCMV) or recombinant viruses expressing the viral m157 glycoprotein. Nfil3−/− NK cells at the peak of antigen-driven expansion were functionally similar to NK cells from infected wild-type mice with respect to IFN-γ production and cytotoxicity, and could comparably produce long-lived memory NK cells that persisted in lymphoid and nonlymphoid tissues for &amp;gt;60 d. We demonstrate that generation and maintenance of NK cell memory is an Nfil3-independent but IL-15–dependent process. Furthermore, specific ablation of Nfil3 in either immature NK cells in the bone marrow or mature peripheral NK cells had no observable effect on NK cell lineage maintenance or homeostasis. Thus, expression of Nfil3 is crucial only early in the development of NK cells, and signals through activating receptors and proinflammatory cytokines during viral infection can bypass the requirement for Nfil3, promoting the proliferation and long-term survival of virus-specific NK cells.
The BODE index as a tool to predict survival in COPD lung transplant candidates
Authors: E. Marchand
Journal: European Respiratory Journal (2010)

To the Editors:

Lahzami et al. 1 state that lung transplantation conferred a significant survival benefit in their cohort of patients undergoing the procedure for chronic obstructive pulmonary disease (COPD). They came to this conclusion by comparing observed post-transplant survival with predicted survival derived from the body mass index, airflow obstruction, …
Real-time <i>In vivo</i> Dual-color Imaging of Intracapillary Cancer Cell and Nucleus Deformation and Migration
Authors: Kensuke Yamauchi, Meng Yang, Ping Jiang, Norio Yamamoto, Mingxu Xu, Yasuyuki Amoh, Kazuhiko Tsuji, Michael Bouvet, Hiroyuki Tsuchiya, Katsuro Tomita, A.R. Moossa, Robert M. Hoffman
Journal: Cancer Research (2005)

The mechanism of cancer cell deformation and migration in narrow vessels is incompletely understood. In order to visualize the cytoplasmic and nuclear dynamics of cells migrating in capillaries, red fluorescent protein was expressed in the cytoplasm, and green fluorescent protein, linked to histone H2B, was expressed in the nucleus of cancer cells. Immediately after the cells were injected in the heart of nude mice, a skin flap on the abdomen was made. With a color CCD camera, we could observe highly elongated cancer cells and nuclei in capillaries in the skin flap in living mice. The migration velocities of the cancer cells in the capillaries were measured by capturing images of the dual-color fluorescent cells over time. The cells and nuclei in the capillaries elongated to fit the width of these vessels. The average length of the major axis of the cancer cells in the capillaries increased to approximately four times their normal length. The nuclei increased their length 1.6 times in the capillaries. Cancer cells in capillaries over 8 microm in diameter could migrate up to 48.3 microm/hour. The data suggests that the minimum diameter of capillaries where cancer cells are able to migrate is approximately 8 microm. The use of the dual-color cancer cells differentially labeled in the cytoplasm and nucleus and associated fluorescent imaging provide a powerful tool to understand the mechanism of cancer cell migration and deformation in small vessels.
Indium-Tin Oxide Does Not Induce GM-CSF Autoantibodies
Authors: Hironori Masuko, Nobuyuki Hizawa, Tatsuya Chonan, Atsuko Amata, Kazuyuki Omae, Makiko Nakano, Koh Nakata, Akira Hebisawa
Journal: American Journal of Respiratory and Critical Care Medicine (2011)
Enhancement of Cisplatin Sensitivity of Cisplatin-Resistant Human Cervical Carcinoma Cells by Bryostatin 1
Authors: Sanghamitra Mohanty, Jie Huang, Alakananda Basu
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Bryostatin 1, a unique protein kinase C (PKC) activator, is already in the clinical trials. An understanding of complex regulation of PKC by bryostatin 1 is essential for effective use of bryostatin 1 in the clinic. We have previously shown that the ability of bryostatin 1 to enhance cisplatin sensitivity correlated with its ability to down-regulate PKCδ in HeLa cells. We have investigated how bryostatin 1 influences PKCδ regulation in cisplatin-resistant HeLa (HeLa/CP) cells, and if bryostatin 1 could be used to reverse cisplatin resistance. Experimental Design: Phorbol 12,13-dibutyrate (PDBu), bryostatin 1, and small interfering RNA were used to manipulate PKC level/activation status. Cell death was monitored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Annexin V dye-binding assay, and analysis of hypodiploid peak in a flow cytometer. Results: Bryostatin 1 elicited a biphasic concentration response on PKCδ down-regulation and cisplatin-induced cell death in HeLa/CP cells; the maximum effect was achieved with 1 nmol/L bryostatin 1. Down-regulation of PKCα increased with increasing concentrations of bryostatin 1. PDBu induced down-regulation of PKCα in HeLa and HeLa/CP cells but it had little effect on PKCδ down-regulation in HeLa/CP cells. However, both PDBu and bryostatin 1 enhanced the sensitivity of HeLa/CP cells to cisplatin. Knockdown of PKCδ by small interfering RNA inhibited cisplatin-induced apoptosis but knockdown of PKCα enhanced cisplatin-induced cell death. Conclusions: These results suggest that although PKCδ acts as a proapoptotic protein, full-length PKCδ may inhibit cisplatin-induced cell death. Thus, persistent activation/down-regulation of PKCδ by bryostatin 1 was associated with cisplatin sensitization. Furthermore, PKCα acts as an antiapoptotic protein and down-regulation of PKCα by PDBu was associated with cellular sensitization to cisplatin.
Activator Protein Accelerates Dihydropyrimidine Dehydrogenase Gene Transcription in Cancer Cells
Authors: Kei Ukon, Keiji Tanimoto, Tatsushi Shimokuni, Takuya Noguchi, Keiko Hiyama, Hiroaki Tsujimoto, Masakazu Fukushima, Tetsuya Toge, Masahiko Nishiyama
Journal: Cancer Research (2005)

Abstract Dihydropyrimidine dehydrogenase is the most extensively investigated predictive marker for individual response to 5-fluorouracil. Clinical responses to the anticancer agent, along with various reports, have clearly shown that dihydropyrimidine dehydrogenase activity is closely correlated to its mRNA levels, but the regulatory mechanisms of its expression have remained unclear. We attempted to clarify the mechanisms and found that activator protein (AP-1) is probably one of the key factors in the transcriptional regulation of DPYD in cancer cells, and that phorbol 12-myristate 13-acetate (PMA) plus ionomycin treatment enhances transcription of DPYD via AP-1 activation. In this study, we characterized our previously subcloned 5′ region of human DPYD, an ∼3.0-kb fragment (accession no. AB162145). Luciferase reporter assay showed that the clone showed strong promoter activities in 293T and HSC42 cells, and comparative analysis using 5′ deletion mutants suggested the existence of several positive and negative regulatory regions, including putative binding sites for AP-1, SP-1, and nuclear factor-κB. PMA/ionomycin treatment increased the mRNA level of DPYD in HSC42 cells, and electrophoretic gel mobility shift assay showed that the complex on the putative AP-1 binding site was drastically induced by PMA/ionomycin treatment. The complexes formed were competed out by preincubation with the cold-consensus AP-1 binding site, and the DNA binding complex formed on the site contained c-Jun and c-Fos, which are components of AP-1 transcription factor. We further identified the functional AP-1 binding site (nucleotide positions from −290 to −280), whose nucleotide mutations abolished PMA/ionomycin-induced DPYD promoter activation.
Inappropriate admission of young people with mental disorder to adult psychiatric wards and paediatric wards: cross sectional study of six months' activity
Authors: Adrian Worrall, Anne O'Herlihy, Sube Banerjee, Tony Jaffa, Paul Lelliott, Peter Hill, Angela Scott, Helen Brook
Journal: BMJ (2004)

Child and adolescent psychiatric inpatient wards were established because young people with mental illness are often poorly served by admission to general psychiatric wards owing to needs that differ from those adults, different skills needed by staff, and difficulty ensuring young people's safety. 1 The admission of young people with mental illness to paediatric wards also raises concerns about safety and the skills of staff.We estimated the number of inappropriate admissions of young people with mental disorder to adult psychiatric wards and paediatric wards.
Novel poly (ADP-ribose) polymerase 1 binding motif in hepatitis B virus core promoter impairs DNA damage repair
Authors: Hui-Ling Ko, Ee-Chee Ren
Journal: Hepatology (2011)

It is well-established that hepatitis B virus (HBV) infection is associated with the development of hepatocellular carcinoma (HCC), but patients with high viral DNA load have significantly higher risk. As host factors are required for efficient viral replication and may, therefore, contribute to high viral DNA load, we screened for host factors that can transcriptionally activate the HBV core promoter (HBVCP). We report here that poly (ADP-ribose) polymerase 1 (PARP1), which is known for its DNA repair activity, binds prominently to an octamer motif in the HBVCP and increases transcriptional efficiency. By utilizing a series of single base substitutions at each nucleotide position of the octamer, the PARP1 binding motif can be defined as “RNNWCAAA.” Intriguingly, introduction of a vector construct bearing tandem repeats of the octamer motif was able to impair the DNA repair function of PARP1. This finding suggests that HBV viral DNA contains specific sequence motifs that may play a role in disrupting the DNA repair pathways of infected hepatocytes. Conclusion: This study has identified a novel octamer motif in the HBVCP that binds PARP1, and this interaction increases the replication efficiency of HBV. The presence of this octamer motif in hepatocytes was shown to inhibit the DNA repair capacity of PARP1, potentially contributing to the development of HCC. (Hepatology 2011;)
Cell Coupling Between Ventricular Myocyte Pairs From Connexin43-Deficient Murine Hearts
Authors: Jian-An Yao, David E. Gutstein, Fangyu Liu, Glenn I. Fishman, Andrew L. Wit
Journal: Circulation Research (2003)

Mice with cardiac-restricted inactivation of the connexin43 gene (CKO mice) have moderate slowing of ventricular conduction and lethal arrhythmias. Mechanisms through which propagation is maintained in the absence of Cx43 are unknown. We evaluated gap junctional conductance in CKO ventricular pairs using dual patch clamp methods. Junctional coupling was reduced to 4+/-2 nS (side-to-side) and 11+/-2 nS (end-to-end), including 21% of cell-pairs with no detectable coupling, compared with 588+/-104 nS (side-to-side) and 558+/-92 nS (end-to-end) in control cell-pairs. Voltage dependence of control gap junctions was characteristic of Cx43. CKO conductance showed increased voltage dependence, suggesting low-level expression of other connexin isoforms. From theoretical models, this degree of CKO coupling is not expected to support levels of conduction persisting in vivo, suggesting the possibility that there are additional mechanisms for maintained propagation when gap junctional conductance is severely reduced.
Epidemic Lung Cancer in Women
Authors: J. Wister Meigs
Journal: JAMA (1977)

Only 40 years ago, the cause of lung cancer was completely unknown except in a few cases of occupational exposure.<sup>1</sup>As our recognition grew that smoking is the predominant cause of lung cancer in men, we unfortunately accepted the concurrent rarity of lung cancer among women as evidence that they were resistant to the disease. Our society remains ambivalent about smoking. A cigarette advertisement encourages women to seek "liberation" by smoking. It shows a young, glamorous woman with a long cigarette and says: "You've come a long way, baby." As recently as 1930, only 2% of women 18 years of age and older were smokers, when nearly 30 times as many men had the habit.<sup>2</sup>Times have changed. A 1975 survey showed that teenage girls and young women smoked nearly as much as their male counterparts.<sup>3</sup>An epidemic of lung cancer among women was predicted five years
The influenza A (H1N1-2009) experience at the inaugural Asian Youth Games Singapore 2009: mass gathering during a developing pandemic
Authors: Hoon Chin Lim, Jeffery Cutter, Weng Kee Lim, Adrian Ee, Yoong Cheong Wong, Boon Keng Tay
Journal: British Journal of Sports Medicine (2010)

From 29 June to 7 July 2009, Singapore hosted the inaugural Asian Youth Games (AYG), which brought 1210 athletes and 810 officials from 43 participating countries. On 11 June, just 1 week before the Games Village Medical Centre started operations, the World Health Organization officially declared a global H1N1 2009 pandemic. Working in close partnership with the Olympic Council of Asia Medical Commission, Singapore AYG Organising Committee and other government agencies, the AYG Medical Services Committee was successful in preventing the local transmission of H1N1, which would have been a threat to the games, as it could have led to the cancellation of these games. This article describes the experience and valuable lessons learnt from managing a sports-related mass gathering during the developing pandemic.
Uncertainty over reorganisation is destabilising primary care
Authors: Adrian O'Dowd
Journal: BMJ (2005)

Primary care staff are leaving their jobs or are becoming increasingly distracted from their day to day work because of uncertainty caused by government plans to reorganise primary care, MPs have been told.

The reconfiguration of primary care organisations is taking its toll, witnesses said at last week's hearing of the House of Commons health select committee's inquiry into changes to primary care trusts.

The finance director at one primary care trust, giving evidence to the committee, said some staff were already “voting with their feet” and leaving to go and work in the acute sector—which is seen as more stable—because of the uncertainties in primary care.

Phillip Barrett, director of finance at High Peak and …
Genetically Determined Differences in Sodium Current Characteristics Modulate Conduction Disease Severity in Mice With Cardiac Sodium Channelopathy
Authors: Carol Ann Remme, Brendon P. Scicluna, Arie O. Verkerk, Ahmad S. Amin, Sandra van Brunschot, Leander Beekman, Vera H.M. Deneer, Catherine Chevalier, Fumitaka Oyama, Haruko Miyazaki, Nobuyuki Nukina, Ronald Wilders, Denis Escande, Rémi Houlgatte, Arthur A.M. Wilde, Hanno L. Tan, Marieke W. Veldkamp, Jacques M.T. de Bakker, Connie R. Bezzina
Journal: Circulation Research (2009)

Conduction slowing of the electric impulse that drives the heartbeat may evoke lethal cardiac arrhythmias. Mutations in SCN5A, which encodes the pore-forming cardiac sodium channel alpha subunit, are associated with familial arrhythmia syndromes based on conduction slowing. However, disease severity among mutation carriers is highly variable. We hypothesized that genetic modifiers underlie the variability in conduction slowing and disease severity. With the aim of identifying such modifiers, we studied the Scn5a(1798insD/+) mutation in 2 distinct mouse strains, FVB/N and 129P2. In 129P2 mice, the mutation resulted in more severe conduction slowing particularly in the right ventricle (RV) compared to FVB/N. Pan-genomic mRNA expression profiling in the 2 mouse strains uncovered a drastic reduction in mRNA encoding the sodium channel auxiliary subunit beta4 (Scn4b) in 129P2 mice compared to FVB/N. This corresponded to low to undetectable beta4 protein levels in 129P2 ventricular tissue, whereas abundant beta4 protein was detected in FVB/N. Sodium current measurements in isolated myocytes from the 2 mouse strains indicated that sodium channel activation in myocytes from 129P2 mice occurred at more positive potentials compared to FVB/N. Using computer simulations, this difference in activation kinetics was predicted to explain the observed differences in conduction disease severity between the 2 strains. In conclusion, genetically determined differences in sodium current characteristics on the myocyte level modulate disease severity in cardiac sodium channelopathies. In particular, the sodium channel subunit beta4 (SCN4B) may constitute a potential genetic modifier of conduction and cardiac sodium channel disease.
Management of Heatstroke
Authors: Wilmot B. Boone
Journal: JAMA (1983)

<h3>To the Editor.—</h3> The development of new treatment for pilgrims to Mecca who experience heatstroke and related articles inThe Journal(1982; 247:3332) prompted me to relate a treatment often used in tropical areas. Applicable anywhere, particularly for a febrile child whose hot, dry skin recoils from the usual frightening and chilling regimen of ice and/or alcohol sponging (which increases the physiological thermal blanket with thickened gooseflesh as the shivering muscles respond to raise the temperature), this effective and comforting treatment is by the application of large, warm, sopping-wet towels up to the chin of the stripped body lying on a plastic sheet or old blankets; the wet warmth provides relaxation to the vasoconstricted skin; when the wet towels are removed after a few seconds, the "pseudosweat," in a normal evaporative fashion, cools pleasantly; as drying or recurring goosebumps are noted, the warm, wet application is repeated as long as