tbuckley/cabot-search huggingface dataset:
Selective survival of peripheral blood lymphocytes in children with HIV-1 following delivery of an anti-HIV gene to bone marrow CD34+ cells
Authors: Greg M. Podsakoff, Barbara C. Engel, Denise A. Carbonaro, Chris Choi, Elzbieta M. Smogorzewska, Gerhard Bauer, David Selander, Susan Csik, Kathy Wilson, Michael R. Betts, Richard A. Koup, Gary J. Nabel, Keith Bishop, Steven King, Manfred Schmidt, Christof von Kalle, Joseph A. Church, Donald B. Kohn
Journal: Molecular Therapy (2005)

Two HIV-1-infected children on antiretroviral therapy were enrolled into a clinical study of retroviral-mediated transfer of a gene that inhibits replication of HIV-1, targeting bone marrow CD34+ hematopoietic stem/progenitor cells. Two retroviral vectors were used, one encoding a "humanized" dominant-negative REV protein (huM10) that is a potent inhibitor of HIV-1 replication and one encoding a nontranslated marker gene (FX) to serve as an internal control for the level of gene marking. Peripheral blood mononuclear cells (PBMC) containing the huM10 gene or FX gene were detected by quantitative PCR at frequencies of approximately 1/10,000 in both subjects for the first 1-3 months following re-infusion of the gene-transduced bone marrow, but then were at or below the limits of detection (<1/1,000,000) at most times over 2 years. In one patient, a reappearance of PBMC containing the huM10 gene, but not the FX gene, occurred concomitant with a rise in the HIV-1 viral load during a period of nonadherence to the antiretroviral regimen. Unique clones of gene-marked PBMC were detected by LAM-PCR during the time of elevated HIV-1 levels. These findings indicate that there was a selective survival advantage for PBMC containing the huM10 gene during the time of increased HIV-1 load.
Abstract LB-249: Characterization of a novel potent and selective CDK4/6 inhibitor and a resistance mechanism
Authors: Kang Dai, Cong Li, Lingming Liang, Minqing Rong, Jessica Orf, Kathy Keegan, Zhihong Li, Jiasheng Fu, Ji Ma, Tim Carlson, Larry McGee, Julio Medina, Alexander Kamb, Dineli Wickramasinghe
Journal: Cancer Research (2012)

Abstract CDK4 and CDK6 are two highly related cyclin D-dependent cell cycle regulatory kinases. CDK4/6 activity promotes G1 to S phase transition by phosphorylating the retinoblastoma (Rb) tumor suppressor protein. Here, we report the characterization of a potent, selective and orally-available small molecule inhibitor of CDK4/6 for treating Rb-positive cancer. The inhibitor was over 1000-fold more potent in inhibiting CDK4 than CDK1. It also showed Rb-dependent anti-proliferative activity both in cancer cell lines and in xenograft tumor models. A greater degree of variation in sensitivity to the inhibitor was observed in colon cancer cell lines compared to the other cell lines tested. To understand this difference in sensitivity, we isolated CDK4/6 inhibitor-resistant colon cancer cells by growing sensitive cells in the presence of the inhibitor. Gene expression in the parental and the resistant cells was analyzed and compared. Cyclin E1, a CDK2 cyclin, was found to be the most significantly overexpressed gene in the resistant cells. Consistent with this, CDK2-associated cyclin E1 protein and CDK2 kinase activity were also significantly increased in the cells. These results suggest that high expression of cyclin E1 may make tumors less sensitive to CDK4/6 inhibition and could be a potential sensitivity marker for patient selection for treatment with a CDK4/6 inhibitor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-249. doi:1538-7445.AM2012-LB-249
All‐oral 12‐week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY‐3 phase III study
Authors: David R. Nelson, James N. Cooper, Jacob P. Lalezari, Eric Lawitz, Paul J. Pockros, Norman Gitlin, Bradley F. Freilich, Ziad H. Younes, William Harlan, Reem Ghalib, Godson Oguchi, Paul J. Thuluvath, Grisell Ortiz‐Lasanta, Mordechai Rabinovitz, David Bernstein, Michael Bennett, Trevor Hawkins, Natarajan Ravendhran, Aasim M. Sheikh, Peter Varunok, Kris V. Kowdley, Delphine Hennicken, Fiona McPhee, Khurram Rana, Eric A. Hughes
Journal: Hepatology (2015)

Treatment options for patients with hepatitis C virus (HCV) genotype 3 infection are limited, with the currently approved all‐oral regimens requiring 24‐week treatment and the addition of ribavirin (RBV). This phase III study (ALLY‐3; ClinicalTrials.gov: NCT02032901) evaluated the 12‐week regimen of daclatasvir (DCV; pangenotypic nonstructural protein [NS]5A inhibitor) plus sofosbuvir (SOF; pangenotypic NS5B inhibitor) in patients infected with genotype 3. Patients were either treatment naïve (n = 101) or treatment experienced (n = 51) and received DCV 60 mg plus SOF 400 mg once‐daily for 12 weeks. Coprimary endpoints were the proportions of treatment‐naïve and treatment‐experienced patients achieving a sustained virological response (SVR) at post‐treatment week 12 (SVR12). SVR12 rates were 90% (91 of 101) and 86% (44 of 51) in treatment‐naïve and treatment‐experienced patients, respectively; no virological breakthrough was observed, and ≥99% of patients had a virological response (VR) at the end of treatment. SVR12 rates were higher in patients without cirrhosis (96%; 105 of 109) than in those with cirrhosis (63%; 20 of 32). Five of seven patients who previously failed treatment with an SOF‐containing regimen and 2 of 2 who previously failed treatment with an alisporivir‐containing regimen achieved SVR12. Baseline characteristics, including gender, age, HCV‐RNA levels, and interleukin‐28B genotype, did not impact virological outcome. DCV plus SOF was well tolerated; there were no adverse events (AEs) leading to discontinuation and only 1 serious AE on‐treatment, which was unrelated to study medications. The few treatment‐emergent grade 3/4 laboratory abnormalities that were observed were transient. Conclusion : A 12‐week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3–infected patients with cirrhosis is underway. (H epatology 2015;61:1127–1135)
Collagenase in scleroderma.
Authors: A H Brady
Journal: Journal of Clinical Investigation (1975)

Collagenase activity was measured by direct assay in skins from 12 patients afflicted with systemic sclerosis. In seven of those cases where extensive involvement of the forearm and trunk skin existed, collagenase activity of the involved skin was minimal or absent. Moreover, in the same patient, regions of marked skin involvement (e.g., forearm) showed no collagenase activity, when clinically uninvolved areas (thigh) exhibited normal or nearly normal levels of enzyme activity. In other patients where clinical symptoms were systemic and not associated significantly with the skin, collagenase activity approximated normal levels. Measurements of collagenase activity and tensile strength in another condition (basal cell carcinoma) that includes changes in mechanical properties of skin that any be regarded as the opposite end of the spectrum from those of sclerodermatous skin support a general correlation between collagenase activity and tensile strength. These studies indicate that the major defect responsible for the hidebound skin lesions of scleroderma may be decreased collagenase activity.
Effect of an NK1 receptor antagonist (CP-99,994) on hypertonic saline-induced bronchoconstriction and cough in male asthmatic subjects.
Authors: J V Fahy, H H Wong, P Geppetti, J M Reis, S C Harris, D B Maclean, J A Nadel, H A Boushey
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

To investigate the role of NK1 receptors in the pathogenesis of bronchoconstriction and cough in asthma, we performed a randomized, double-blind, crossover study on the effects of a selective non-peptide tachykinin NK1 receptor antagonist (CP-99,994) on baseline measures of lung function and on hypertonic saline-induced bronchoconstriction and cough in 14 male subjects with mild asthma. CP-99,994 (250 micrograms/2 hours) and placebo were administered intravenously in 2-h infusions during consecutive visits 5 to 7 d apart. Specific airway resistance (SRaw) was measured and spirometry was performed at baseline and at 35 and 60 min. Next, hypertonic saline challenge was performed by delivering 10 breaths of saline of increasing concentration (0.9 to 7% in 1% increments at 5-min intervals) via an ultrasonic nebulizer until SRaw increased from baseline by 200% or 20 units, whichever was greater. Throughout the challenge cough was counted from a taped record made from two microphones placed close to the subject's larynx. We found that CP-99,994 did not significantly affect SRaw or spirometric measures of lung function during the first hour of infusion. Although CP-99,994 infusion markedly attenuated the bronchoconstrictor response to the saline challenge in two subjects, it did not significantly decrease the area under curves obtained for SRaw and cough during saline challenge for the group as a whole (p = 0.9 for SRaw;p = 0.8 for cough). We conclude that administration of 250 micrograms/kg of CP-99,994 over 2 h does not significantly inhibit hypertonic saline-induced bronchoconstriction or cough in subjects with mild asthma and does not have acute bronchodilator activity in these subjects.
Blood Pressure and Same-Day Exposure to Air Pollution at School: Associations with Nano-Sized to Coarse PM in Children
Authors: Nicky Pieters, Gudrun Koppen, Martine Van Poppel, Sofie De Prins, Bianca Cox, Evi Dons, Vera Nelen, Luc Int Panis, Michelle Plusquin, Greet Schoeters, Tim S. Nawrot
Journal: Environmental Health Perspectives (2015)

Ultrafine particles (UFP) may contribute to the cardiovascular effects of particulate air pollution, partly because of their relatively efficient alveolar deposition.In this study, we assessed associations between blood pressure and short-term exposure to air pollution in a population of schoolchildren.In 130 children (6-12 years of age), blood pressure was determined during two periods (spring and fall 2011). We used mixed models to study the association between blood pressure and ambient concentrations of particulate matter and ultrafine particles measured in the schools' playground.Independent of sex, age, height, and weight of the child, parental education, neighborhood socioeconomic status, fish consumption, heart rate, school, day of the week, season, wind speed, relative humidity, and temperature on the morning of examination, an interquartile range (860 particles/cm3) increase in nano-sized UFP fraction (20-30 nm) was associated with a 6.35 mmHg (95% CI: 1.56, 11.14; p = 0.01) increase in systolic blood pressure. For the total UFP fraction, systolic blood pressure was 0.79 mmHg (95% CI: 0.07, 1.51; p = 0.03) higher, but no effects on systolic blood pressure were found for the nano-sized fractions with a diameter > 100 nm, nor PM2.5, PMcoarse, and PM10. Diastolic blood pressure was not associated with any of the studied particulate mass fractions.Children attending school on days with higher UFP concentrations (diameter < 100 nm) had higher systolic blood pressure. The association was dependent on UFP size, and there was no association with the PM2.5 mass concentration.
Use of designer recombinant mitochondrial antigens in the diagnosis of primary biliary cirrhosis
Authors: Patrick S. C. Leung, Takashi Iwayama, Thomas Prindiville, David T. Chuang, Aftab A. Ansari, Max R. Wynn, Rollie Dickson, Ross Coppel, Eric M. Gershwin
Journal: Hepatology (1992)

The appearance of autoantibodies against mitochondria in patients with primary biliary cirrhosis has been known for more than 25 yr. In the past, based on the biochemical complexity of the mitochondrion and the use of crude extracts for immunodiagnosis, a degree of nonspecificity in assaying for antibodies to mitochondria has been present. This problem has been largely circumvented by the cloning of the mitochondrial antigens and the identification of the E2 subunits of the pyruvate dehydrogenase complex and the branched chain 2-oxo-acid dehydrogenase complex as the major and immunodominant autoantigens of primary biliary cirrhosis. More than 90% of patients with primary biliary cirrhosis have been shown to react with one or both of these enzymes using either recombinant antigen or purified native protein. Approximately 10% of patients recognize only E2 subunits of branched chain 2-oxo-acid dehydrogenase complex and not pyruvate dehydrogenase complex. Such patients would be missed by diagnostic assay that has a low sensitivity to antibodies against E2 subunits of branched chain 2-oxo-acid dehydrogenase complex. The use of recombinant and biochemically pure antigens has permitted structural and conformational analysis of epitope mapping. We have taken advantage of the antigenic mapping studies of both primary biliary cirrhosis and branched chain 2-oxo-acid dehydrogenase complex E2 subunits and designed a molecule that expresses the immunodominant epitopes of both. Using this dual-headed molecule that coexpresses the epitope of two different antigens, we report herein a sensitive and reproducible assay for antibodies to mitochondria in patients with primary biliary cirrhosis. We believe that this recombinant protein is the first example of the use of designer molecules for immunodiagnosis. (Hepatology 1992; 15:367-372).
Proper Use of Words
Authors: G. W. Pickering
Journal: BMJ (1958)

The effects of wine yeasts and malolactic bacteria on the anthocyanin profile of Sangiovese wines produced by both commercial- and laboratory-scale winemaking processes were investigated. The mean anthocyanin profile of the wines obtained from commercial winemaking processes, carried out in several wineries in Tuscany, showed a distinctive anthocyanin pattern characterized by high percentages of malvidin-3-glucoside, without appreciable levels of acylated anthocyanins. This anthocyanin pattern, also shared by all wines produced in the laboratory, reproduces the peculiar profile of Sangiovese grapes and distinguishes Sangiovese wines from Merlot and Cabernet Sauvignon wines. Principal component analysis of all anthocyanin data showed that the Sangiovese wines did not group on the basis of wine-producing area, harvest year, or winery but were distributed along a longitudinal axis, owning to the variability of cyanidin-3-glucoside, peonidin-3-glucoside, and malvidin-3-glucoside percentages. This variability was independent of the yeast ecology during fermentation, at least if the yeast ecology was described at the level of yeast species. In both commercial and experimental wines, higher percentages of vitisin A, a malvidin-3-glucoside derivative, were dependent on the growth and dominance of <i>Candida zemplinina</i> in the early stages of vinification. The anthocyanin profile of the Sangiovese wines was also maintained after malolactic fermentation.
Recombinant <i>Mycobacterium bovis</i> BCG producing IL‐18 reduces IL‐5 production and bronchoalveolar eosinophilia induced by an allergic reaction
Authors: F. Biet, C. Duez, L. Kremer, P. Marquillies, L. Amniai, A.‐B. Tonnel, C. Locht, J. Pestel
Journal: Allergy (2005)

Allergic reactions occur through the exacerbated induction of a Th2 cell type expression profile and can be prevented by agents favoring a Th1 profile. Bacillus Calmette-Guérin (BCG) is able to induce high IFN-gamma levels and has been shown to decrease experimentally induced allergy. The induction of IFN-gamma is mediated by interleukin (IL)-12 known to be secreted upon mycobacterial infections and can be enhanced by IL-18 acting in synergy with IL-12.We evaluated the ability of a recombinant BCG strain producing IL-18 (rBCG) to modify the Th2 type responses in a murine model of ovalbumin (OVA)-dependent allergic reaction.Mice were injected intraperitoneally or intranasally with OVA at days 0 and 15 and exposed to an OVA aerosol challenge at days 29, 30, 31 and 34. At days 0 and 15, two additional groups of mice received OVA together with 5 x 10(6) colony forming units of either rBCG or nonrecombinant BCG.A time-course analysis of OVA-specific immunoglobulin (Ig)E, IgG1 and IgG2a levels indicated no significant difference between the three groups of mice. However, following in vitro stimulation with OVA, lymph node cells from rBCG-treated mice produced less IL-5 and more IFN-gamma than those of mice injected with nonrecombinant BCG. In addition, 48 h after the last OVA challenge, a strong reduction of bronchoalveolar eosinophilia was found in the rBCG-injected mice compared to the nontreated or nonrecombinant BCG-treated groups.These results indicate that the production of IL-18 by rBCG may enhance the immunomodulatory properties of BCG that suppress pulmonary Th2 responses and, in particular, decrease airway eosinophilia.
Let's talk shit
Authors: F. Godlee
Journal: BMJ (2010)

Back in 2000 when most of the world’s nations committed themselves to the millennium development goals (MDGs) to reduce poverty, hunger, lack of education, illness, and premature death, the deadline of 2015 must have seemed a comfortable distance away. Suddenly there’s only five years to go. When world leaders meet next week at the United Nations in New York to review progress, they can be in no doubt of the immense and immediate challenges ahead.

As Joy Lawn recounts in her editorial (doi:10.1136/bmj.c5045), 8.8 million of the world’s children still die each year, including 3.6 million newborns, and at least 342 900 women die as a result of …
Myeloablative therapy with autologous bone marrow transplantation as consolidation of remission in patients with follicular lymphoma
Authors: A.Z.S. Rohatiner, C.G.A. Price, S. Arnott, A. Norton, M.L. Evans, F. Cotter, E. Dorey, C.L. Davis, P. Clark, J. Sterlini, J. Lim, M. Horton, T.A. Lister
Journal: Annals of Oncology (1991)
Accumulation of chlorpyrifos on residential surfaces and toys accessible to children.
Authors: S Gurunathan, M Robson, N Freeman, B Buckley, A Roy, R Meyer, J Bukowski, P J Lioy
Journal: Environmental Health Perspectives (1998)

Quantitative examination of major pathways and routes of exposure to pesticides is essential for determining human risk. The current study was conducted in two apartments and examines the accumulation of the pesticide chlorpyrifos in childrens' toys after the time suggested for reentry after application. It has been established for the first time that a semivolatile pesticide will accumulate on and in toys and other sorbant surfaces in a home via a two-phase physical process that continues for at least 2 weeks postapplication. A summation of the above for a 3-6-year-old child yielded an estimated nondietary total dose of 208 microg/kg/day. Potential exposure from the inhalation pathway was negligible, while dermal and nondietary oral doses from playing with toys contributed to 39 and 61% of the total dose, respectively. If children with high frequency mouthing behavior are considered as candidates for acute exposure to chlorpyrifos residues, the estimated acute dose could be as high as 356 microg/kg/day. Routine reapplication of pesticides could lead to continued accumulation in toys and other sorbant surfaces, e.g., pillows, with large sorbant reservoirs, which can become a long-term source of exposure to a child. Estimates of a child's nondietary exposure to chlorpyrifos associated with toys and other sorbant surfaces for a period of 1 week following application appear to be of public health concern, and studies of actual childhood exposure from this pathway are warranted in the home environment. The above information should be used to determine if current procedures for postapplication reentry are sufficient and to evaluate the need for procedures to store frequently used household toys, pillows, and other sorbant objects during insecticidal application.
Dynamic Contrast-Enhanced Magnetic Resonance Imaging As an Imaging Biomarker
Authors: Nola Hylton
Journal: Journal of Clinical Oncology (2006)

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is being used in oncology as a noninvasive method for measuring properties of the tumor microvasculature. There is potential for DCE-MRI to be used as an imaging biomarker to measure antiangiogenic effects of cancer treatments. This article reviews the general methodology for performing DCE-MRI and discusses existing data and challenges to applying DCE-MRI for treatment response assessment in clinical trials.
Commentary: Patient's view
Authors: M. Barroso
Journal: BMJ (2009)

Being involved in this interactive case report has been a rare but interesting experience. My doctors gave me their undivided attention, and it seemed only fair to give something in return, especially when it could help the scientific community to learn about my condition.

Some months before the admission, around the middle of my menstrual cycle I had sudden abdominal pain associated with a feeling of warmth, sweating, and flushing, similar to the symptoms of menopausal women that I know. I was diagnosed …
Pathologic and Clinical Findings to Predict Tumor Extent of Nonpalpable (Stage T1 c) Prostate Cancer
Authors: Jonathan I. Epstein
Journal: JAMA (1994)

<h3>Objectives.</h3> —We examined preoperative clinical and pathologic parameters in men with clinical stage T1c disease who underwent radical prostatectomy and correlated these findings with the pathologic extent of disease in the surgical specimen in an attempt to identify a subset of patients with potentially biologically insignificant tumor who might be followed up without immediate treatment. <h3>Design and Patients.</h3> —A case series of 157 consecutive men who underwent radical prostatectomy for clinical stage T1c disease compared with 64 similarly treated clinical stage T1a cancers (incidental minimal cancers found on transurethral resection of prostate) and 439 clinical stage T2 (palpable) cancers. <h3>Main Outcome Measures.</h3> —Pathologic stage, grade, and margins; tumor volume; and tumor location. <h3>Results.</h3> —Sixteen percent of tumors were insignificant (&lt;0.2 cm<sup>3</sup>and confined to the prostate, with a Gleason score &lt;7); 10% were minimal (0.2 to 0.5 cm<sup>3</sup>and confined to the prostate, with a Gleason score &lt;7); 37% were moderate (&gt;0.5 cm<sup>3</sup>or capsular penetration, with a Gleason score &lt;7); and 37% were advanced (capsular penetration, with a Gleason score ≥7 or positive margins, seminal vesicles, or lymph nodes). These findings are intermediate between those found in clinical stage T1a and stage T2 disease. The following parameters were not predictive of tumor extent: age, reason for evaluation, method of detection, and transrectal ultrasound. The best model predicting insignificant tumor was prostate-specific antigen (PSA) density less than 0.1 ng/mL per gram and no adverse pathologic findings on needle biopsy, or PSA density of 0.1 to 0.15 ng/mL per gram, with a lowto intermediate-grade cancer smaller than 3 mm found in only one needle biopsy core specimen. The positive predictive value of the model was 95%, with a negative predictive value of 66%. We accurately predicted 73% of cases with insignificant tumor. <h3>Conclusions.</h3> —Eighty-four percent of nonpalpable prostate cancers diagnosed by screening techniques are significant tumors and warrant definitive therapy. However, 16% are insignificant. Serum PSA level, PSA density, and needle biopsy pathologic findings are accurate predictors of tumor extent. It may be reasonable to follow up some patients whose tumors are most likely insignificant with serial PSA measurements and repeated biopsies. (<i>JAMA</i>. 1994;271:368-374)