tbuckley/cabot-search huggingface dataset:
Vertebrate gene finding from multiple-species alignments using a two-level strategy.
Authors: David Carter, Richard Durbin
Journal: Genome biology (2006)

Abstract Background One way in which the accuracy of gene structure prediction in vertebrate DNA sequences can be improved is by analyzing alignments with multiple related species, since functional regions of genes tend to be more conserved. Results We describe DOGFISH, a vertebrate gene finder consisting of a cleanly separated site classifier and structure predictor. The classifier scores potential splice sites and other features, using sequence alignments between multiple vertebrate species, while the structure predictor hypothesizes coding transcripts by combining these scores using a simple model of gene structure. This also identifies and assigns confidence scores to possible additional exons. Performance is assessed on the ENCODE regions. We predict transcripts and exons across the whole human genome, and identify over 10,000 high confidence new coding exons not in the Ensembl gene set. Conclusion We present a practical multiple species gene prediction method. Accuracy improves as additional species, up to at least eight, are introduced. The novel predictions of the whole-genome scan should support efficient experimental verification.
Phase I/II Trial of an Allogeneic Cellular Immunotherapy in Hormone-Naïve Prostate Cancer
Authors: Jonathan W. Simons, Michael A. Carducci, Bahar Mikhak, Michael Lim, Barbara Biedrzycki, Flavia Borellini, Shirley M. Clift, Kristen M. Hege, Dale G. Ando, Steven Piantadosi, Richard Mulligan, William G. Nelson
Journal: Clinical Cancer Research (2006)

Abstract Purpose: To determine the toxicity, immunologic, and clinical activity of immunotherapy with irradiated, allogeneic, prostate cancer cells expressing granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with recurrent prostate cancer. Patients and Methods: A single-institution phase I/II trial was done in hormone therapy–naïve patients with prostate-specific antigen (PSA) relapse following radical prostatectomy and absence of radiologic metastases. Treatments were administered weekly via intradermal injections of 1.2 × 108 GM-CSF gene–transduced, irradiated, cancer cells (6 × 107 LNCaP cells and 6 × 107 PC-3 cells) for 8 weeks. Results: Twenty-one patients were enrolled and treated. Toxicities included local injection-site reactions, pruritus, and flu-like symptoms. One patient had a partial PSA response of 7-month duration. At 20 weeks post first treatment, 16 of 21 (76%) patients showed a statistically significant decrease in PSA velocity (slope) compared with prevaccination (P &amp;lt; 0.001). Injection site biopsies showed intradermal infiltrates consisting of CD1a+ dendritic cells and CD68+ macrophages, similar to previous clinical trials using autologous GM-CSF-transduced cancer cells. Posttreatment, patients developed new oligoclonal antibodies reactive against at least five identified antigens present in LNCaP or PC-3 cells. A high-titer antibody response against a 250-kDa antigen expressed on normal prostate epithelial cells was induced in a patient with partial PSA remission; titers of this antibody decreased when treatment ended, and subsequent PSA relapse occurred. Conclusions: This non-patient-specific prostate cancer immunotherapy has a favorable safety profile and is immunologically active. Continued clinical investigation at higher doses and with longer boosting schedules is warranted.
Magnetic resonance imaging can accurately assess the long-term progression of knee structural changes in experimental dog osteoarthritis
Authors: C Boileau, J Martel-Pelletier, F Abram, J-P Raynauld, E Troncy, M-A D'Anjou, M Moreau, J-P Pelletier
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objectives:</h3> Osteoarthritis (OA) structural changes take place over decades in humans. MRI can provide precise and reliable information on the joint structure and changes over time. In this study, we investigated the reliability of quantitative MRI in assessing knee OA structural changes in the experimental anterior cruciate ligament (ACL) dog model of OA. <h3>Methods:</h3> OA was surgically induced by transection of the ACL of the right knee in five dogs. High resolution three dimensional MRI using a 1.5 T magnet was performed at baseline, 4, 8 and 26 weeks post surgery. Cartilage volume/thickness, cartilage defects, trochlear osteophyte formation and subchondral bone lesion (hypersignal) were assessed on MRI images. Animals were killed 26 weeks post surgery and macroscopic evaluation was performed. <h3>Results:</h3> There was a progressive and significant increase over time in the loss of knee cartilage volume, the cartilage defect and subchondral bone hypersignal. The trochlear osteophyte size also progressed over time. The greatest cartilage loss at 26 weeks was found on the tibial plateaus and in the medial compartment. There was a highly significant correlation between total knee cartilage volume loss or defect and subchondral bone hypersignal, and also a good correlation between the macroscopic and the MRI findings. <h3>Conclusion:</h3> This study demonstrated that MRI is a useful technology to provide a non-invasive and reliable assessment of the joint structural changes during the development of OA in the ACL dog model. The combination of this OA model with MRI evaluation provides a promising tool for the evaluation of new disease-modifying osteoarthritis drugs (DMOADs).
Guidelines for the management of inflammatory bowel disease in adults
Authors: M J Carter
Journal: Gut (2004)

Ulcerative colitis (UC) and Crohn’s disease (CD) (collectively termed inflammatory bowel disease (IBD)) are complex disorders reflected by wide variation in clinical practice. These guidelines, commissioned by the Clinical Services’ Committee of the British Society of Gastroenterology (BSG) for clinicians and allied professionals caring for patients with IBD in the United Kingdom, provide an evidence based document describing good clinical practice for investigation and treatment. The guidelines are intended to bring consistency, but should not necessarily be regarded as the standard of care for all patients. Individual cases must be managed on the basis of all clinical data available for that case. Patient preferences should be sought and decisions jointly made between patient and health professional.

### 1.1 Development of guidelines

A comprehensive literature search was performed using electronic databases (Medline, PubMed, and Ovid; keywords: “inflammatory bowel disease”, “ulcerative colitis”, and “Crohn’s disease”) by Dr Carter. A preliminary document was drafted by Dr Carter, Dr Lobo, and contributing authors. This was summarised by Dr Travis and revised after circulation first to the committee and then to members of the IBD section of the BSG, before submission to the Clinical Services’ Committee.

### 1.2 Grading of recommendations1

The guidelines conform to the North of England evidence based guidelines development project. The grading of each recommendation is dependent on the category of evidence supporting it:





### 1.3 Scheduled review of guidelines

The content and evidence base …
Antiretroviral Therapy for Adult HIV-lnfected Patients
Authors: Merle A. Sande, Charles C. J. Carpenter, C. Glenn Cobbs, King K. Holmes, Jay P. Sanford, Robert W. Coombs, Thomas R. Fleming, Rebecca Denison, Mitchell H. Gail, Wayne Lamar Greaves, Martin S. Hirsch, Roberta Luskin-Hawk, Donna Mildvan, Charles A. Nelson, John P. Phair, Robert Schooley, R. Gabriel Torres, Robert Vazquez, Lawrence Deyton, John Jermano, Juanita Koziol, Carla Pettinelli, Debbie Katz
Journal: JAMA (1993)

This document summarizes recommendations from a state-of-the-art conference convened to evaluate the role of nucleoside analogue reverse transcriptase inhibitors in the treatment of human immunodeficiency virus (HIV) infection. Data from controlled clinical trials of zidovudine, didanosine, and zalcitabine were reviewed by an expert panel, which then formulated guidelines to assist clinicians and HIV-infected patients in the use of these agents. Recommendations were framed in the context of clinical scenarios for patients with asymptomatic HIV infection who have not had prior antiretroviral therapy; those with signs and symptoms of HIV-related disease who have not received prior therapy; clinically stable patients who are tolerating initial zidovudine therapy; patients experiencing clinical progression while on zidovudine therapy; and those who are intolerant of antiretroviral therapy. The panel concluded that physicians need to integrate up-to-date scientific knowledge with other relevant needs to improve the care of HIV-infected patients. (<i>JAMA</i>. 1993;270:2583-2589)
Differential Activation of Mitogen-Activated Protein Kinases in Experimental Mesangioproliferative Glomerulonephritis
Authors: DIRK BOKEMEYER, TAMMO OSTENDORF, UTA KUNTER, MARION LINDEMANN, HERBERT J. KRAMER, JU[Combining Diaeresis]RGEN FLOEGE
Journal: Journal of the American Society of Nephrology (2000)

Multiple extracellular mitogens are involved in the pathogenesis of proliferative forms of glomerulonephritis (GN). In vitro studies demonstrate the pivotal role of mitogenactivated protein (MAP) kinases in the regulation of cellular proliferation. This study was conducted to examine whether these kinases, as a convergence point of mitogenic stimuli, are activated in mesangioproliferative GN in vivo. Therefore, anti-Thy1 GN was induced in rats using a monoclonal anti-Thy1.1 antibody (OX-7). Whole cortical tissue as well as isolated glomeruli were examined at different time points using kinase activity assays and Western blot analysis. A maximal increase in the number of glomerular mitotic figures (9.7-fold) was demonstrated 6 d after injection of the anti-Thy1.1 antibody. In parallel with this finding, a significant increase in cortical, and more dramatically glomerular, activity of extracellular signal-regulated kinase (ERK) was detected. Maximal activation of ERK was detectable on day 6. This activation of ERK was accompanied by an increase in the expression of MEK (MAP kinase/ERK kinase), the ERK-activating kinase. A marked induction of glomerular apoptosis at 2 h after injection of the anti-Thy1.1 antibody, which subsided subsequently, was demonstrated using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay as well as staining for single-stranded DNA. However, no significant activation of stress-activated protein kinase or p38 MAP kinase, both MAP kinases that are suggested to induce apoptosis and to inhibit cellular growth, was detectable at this early time point. Rather, on day 6 a dramatic decrease in the activity of p38 MAP kinase, which might have contributed to the overshooting glomerular cellular proliferation, was observed. Treatment of rats with heparin blunted glomerular proliferation as well as ERK activation and restored p38 MAP kinase activity. These observations point to ERK and p38 MAP kinase as putative mediators of the proliferative response in mesangioproliferative GN and suggest that upregulation of MEK is involved in the long-term regulation of ERK in vivo.
Physical Activity and Weight Management Across the Lifespan
Authors: Jennifer H. Goldberg, Abby C. King
Journal: Annual Review of Public Health (2007)

This review discusses key findings and recommendations related to the role of physical activity in weight gain prevention, weight loss, and weight-loss maintenance across the lifespan. For weight gain prevention, epidemiological and clinical studies suggest that regular physical activity is critical, with increases above the recommended 30 min daily for health (e.g., to 45 to 60 min daily) potentially desirable for curtailing weight gain. For weight loss, clinical studies suggest that physical activity interventions alone usually produce only modest results. Combining physical activity with dietary interventions increases the chance of success, especially at higher levels of physical activity (e.g., 200 to 300 min or more weekly). For weight-loss maintenance, high levels of physical activity (e.g., 40 to 90 min daily) may be necessary. To manage weight across the lifespan, a comprehensive approach to physical activity is needed supported by public policy interventions that help make physical activity a part of daily life.
A Targeted RNAi Screen of the Breast Cancer Genome Identifies <i>KIF14</i> and <i>TLN1</i> as Genes That Modulate Docetaxel Chemosensitivity in Triple-Negative Breast Cancer
Authors: Stina Mui Singel, Crystal Cornelius, Kimberly Batten, Gail Fasciani, Woodring E. Wright, Lawrence Lum, Jerry W. Shay
Journal: Clinical Cancer Research (2013)

To identify biomarkers within the breast cancer genome that may predict chemosensitivity in breast cancer.We conducted an RNA interference (RNAi) screen within the breast cancer genome for genes whose loss-of-function enhanced docetaxel chemosensitivity in an estrogen receptor-negative, progesterone receptor-negative, and Her2-negative (ER-, PR-, and Her2-, respectively) breast cancer cell line, MDA-MB-231. Top candidates were tested for their ability to modulate chemosensitivity in 8 breast cancer cell lines and to show in vivo chemosensitivity in a mouse xenograft model.From ranking chemosensitivity of 328 short hairpin RNA (shRNA) MDA-MB-231 cell lines (targeting 133 genes with known somatic mutations in breast cancer), we focused on the top two genes, kinesin family member 14 (KIF14) and talin 1 (TLN1). KIF14 and TLN1 loss-of-function significantly enhanced chemosensitivity in four triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, HCC38, HCC1937, and Hs478T) but not in three hormone receptor-positive cell lines (MCF7, T47D, and HCC1428) or normal human mammary epithelial cells (HMEC). Decreased expression of KIF14, but not TLN1, also enhanced docetaxel sensitivity in a Her2-amplified breast cancer cell line, SUM190PT. Higher KIF14 and TLN1 expressions are found in TNBCs compared with the other clinical subtypes. Mammary fat pad xenografts of KIF14- and TLN1-deficient MDA-MB-231 cells revealed reduced tumor mass compared with control MDA-MB-231 cells after chemotherapy. KIF14 expression is also prognostic of relapse-free and overall survival in representative breast cancer expression arrays.KIF14 and TLN1 are modulators of response to docetaxel and potential therapeutic targets in TNBC.
Neoadjuvant Chemotherapy Compared With Surgery Alone for Locally Advanced Cancer of the Stomach and Cardia: European Organisation for Research and Treatment of Cancer Randomized Trial 40954
Authors: Christoph Schuhmacher, Stephan Gretschel, Florian Lordick, Peter Reichardt, Werner Hohenberger, Claus F. Eisenberger, Cornelie Haag, Murielle E. Mauer, Baktiar Hasan, John Welch, Katja Ott, Arnulf Hoelscher, Paul M. Schneider, Wolf Bechstein, Hans Wilke, Manfred P. Lutz, Bernard Nordlinger, Eric Van Cutsem, Jörg R. Siewert, Peter M. Schlag
Journal: Journal of Clinical Oncology (2010)

Patients with locally advanced gastric cancer benefit from combined pre- and postoperative chemotherapy, although fewer than 50% could receive postoperative chemotherapy. We examined the value of purely preoperative chemotherapy in a phase III trial with strict preoperative staging and surgical resection guidelines.
Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis
Authors: A R Horsley, P M Gustafsson, K A Macleod, C Saunders, A P Greening, D J Porteous, J C Davies, S Cunningham, E W F W Alton, J A Innes
Journal: Thorax (2007)

<h3>Background:</h3> Lung clearance index (LCI) is a sensitive marker of early lung disease in children but has not been assessed in adults. Measurement is hindered by the complexity of the equipment required. The aims of this study were to assess performance of a novel gas analyser (Innocor) and to use it as a clinical tool for the measurement of LCI in cystic fibrosis (CF). <h3>Methods:</h3> LCI was measured in 48 healthy adults, 12 healthy school-age children and 33 adults with CF by performing an inert gas washout from 0.2% sulfur hexafluoride (SF<sub>6</sub>). SF<sub>6</sub> signal:noise ratio and 10–90% rise time of Innocor were compared with a mass spectrometer used in similar studies in children. <h3>Results:</h3> Compared with the mass spectrometer, Innocor had a superior signal:noise ratio but a slower rise time (150 ms vs 60 ms) which may limit its use in very young children. Mean (SD) LCI in healthy adults was significantly different from that in patients with CF: 6.7 (0.4) vs 13.1 (3.8), p&lt;0.001. Ten of the patients with CF had forced expiratory volume in 1 s ⩾80% predicted but only one had a normal LCI. LCI repeats were reproducible in all three groups of subjects (mean intra-visit coefficient of variation ranged from 3.6% to 5.4%). <h3>Conclusions:</h3> Innocor can be adapted to measure LCI and affords a simpler alternative to a mass spectrometer. LCI is raised in adults with CF with normal spirometry, and may prove to be a more sensitive marker of the effects of treatment in this group.
Relationship between alveolar PO2 and the rate of p-nitroanisole O-demethylation by the cytochrome P-450 pathway in isolated rabbit lungs.
Authors: A B Fisher, N Itakura, C Dodia, R G Thurman
Journal: Journal of Clinical Investigation (1979)

The relationship between alveolar PO2 and the rate of O-demethylation of p-nitroanisole, a model substrate for cytochrome P-450 -linked mixed-function oxidation, was evaluated in the isolated rabbit lung perfused with Krebs-Ringer bicarbonate buffer. The appearance of the product, p-nitrophenol, in the pulmonary perfusate was measured spectrophotometrically, The PO2 of the ventilating gas was varied with an accurate gas mixing pump and measured with an electrochemical O2 analyzer. In control lungs ventilated with 5% CO2 in air, the rate of p-nitrophenol production was approximately equal to 3.1 +/- 0.04 (mean +/- SE; n = 9) mumol/h per g dry wt. p-Nitrophenol production was unaltered when O2 in the ventilating gas was decreased to 1%, but it was depressed reversibly when alveolar O2 WAS 0.1% OR LESS AND WAS ABOLISHED DURING VENTILATION WITH 0.005% O2. The rate of the reaction was inhibited by 50% when alveolar PO2 was 0.3 mm Hg representing and intracellular [O2] OF approximately equal to muM. In the presence of metyrapone (0.1--1 mM), an inhibitor of cytochrome P-450-dependent reactions, p-nitrophenol production was 0.07--0.17 mumol/h per g dry wt. Ventilation of lungs with varying CO concentration in 20% O2 resulted in 50% inhibition of p-nitrophenol production when CO concentration was 10% (CO/O2 = 0.5). These results indicated that O-demethylation of p-nitroanisole by the lung is a cytochrome P-450-dependent reaction and that its rate is not affected until alveolar PO2 is less than 1 mm Hg.
The pulmonary physician in critical care 2: Oxygen delivery and consumption in the critically ill
Authors: R M Leach
Journal: Thorax (2002)

Early detection and correction of tissue hypoxia is essential if progressive organ dysfunction and death are to be avoided. However, hypoxia in individual tissues or organs caused by disordered regional distribution of oxygen delivery or disruption of the processes of cellular oxygen uptake and utilisation cannot be identified from global measurements. Regional oxygen transport and cellular utilisation have an important role in maintaining tissue function. When tissue hypoxia is recognised, treatment must be aimed at the primary cause. Supplemental oxygen may be life saving in some situations but cannot correct inadequate oxygen delivery caused by a low cardiac output or impaired ventilation. Recent innovations include artificial oxygen carrying proteins and "haemoglobin" molecules designed to improve tissue blood flow by reducing viscosity. Regulating cell metabolism using different substrates or drugs has so far been poorly explored but is an exciting area for further research. A minimum level of global oxygen delivery and perfusion pressure must be maintained in the critically ill patient with established "shock", but advances in the understanding and control of regional distribution and other "downstream" factors in the oxygen cascade are needed to improve outcome in these patients.
Nocturnal monitoring of home non-invasive ventilation: the contribution of simple tools such as pulse oximetry, capnography, built-in ventilator software and autonomic markers of sleep fragmentation
Authors: J.-P. Janssens, J.-C. Borel, J.-L. Pepin
Journal: Thorax (2010)

Complex respiratory events, which may have a detrimental effect on both quality of sleep and control of nocturnal hypoventilation, occur during sleep in patients treated with non-invasive ventilation (NIV). Among these events are patient-ventilator asynchrony, increases in upper airway resistance (with or without increased respiratory drive) and leaks. Detection of these events is important in order to select the most appropriate ventilator settings and interface. Simple tools can provide important information when monitoring NIV. Pulse oximetry is important to ensure that adequate oxygen saturation is provided and to detect either prolonged or short and recurrent desaturations. However, the specificity of pulse oximetry tracings during NIV is low. Transcutaneous capnography helps discriminate between hypoxaemia related to ventilation/perfusion mismatch and hypoventilation, documents correction of nocturnal hypoventilation and may detect ventilator-induced hyperventilation, a possible cause for central apnoea/hypopnoea and glottic closure. Data provided by ventilator software help the clinician by estimating ventilation, tidal volume, leaks and the rate of inspiratory or expiratory triggering by the patient, although further validation of these signals by independent studies is indicated. Finally, autonomic markers of sympathetic tone using signals such as pulse wave amplitude of the pulse oximetry signal can provide reliable information of sleep fragmentation.
Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines.
Authors: B Fisk, T L Blevins, J T Wharton, C G Ioannides
Journal: The Journal of Experimental Medicine (1995)

Synthetic peptide analogues of sequences in the HER-2 protooncogene (HER-2) were selected based on the presence of HLA-A2.1 anchor motifs to identify the epitopes on HER-2 recognized by ovarian tumor-reactive CTL. 19 synthetic peptides were evaluated for recognition by four HLA-A2 ovarian-specific cytotoxic T lymphocyte (CTL) lines obtained from leukocytes associated with ovarian tumors. The nonapeptide E75 (HER-2, 369-377:KIFGSLAFL) was efficient in sensitizing T2 cells for lysis by all four CTL lines. This peptide was specifically recognized by cloned CD8+ CTL isolated from one of the ovarian-specific CTL lines. E75-pulsed T2 cells inhibited lysis by the same CTL clone of both an HLA-A2+ HER-2high ovarian tumor and a HER-2high cloned ovarian tumor line transfected with HLA-A2, suggesting that this or a structurally similar epitope may be specifically recognized by these CTL on ovarian tumors. Several other HER-2 peptides were recognized preferentially by one or two CTL lines, suggesting that both common and private HER-2 epitopes may be immunogenic in patients with ovarian tumors. Since HER-2 is a self-antigen, these peptides may be useful for understanding mechanisms of tumor recognition by T cells, immunological tolerance to tumor, and structural characterization of tumor antigens.