tbuckley/cabot-search huggingface dataset:
Heparin-Induced Thrombocytopenia: A Ten-Year Retrospective
Authors: Theodore E. Warkentin, MD
Journal: Annual Review of Medicine (1999)

The past decade has seen many important advances in the pathogenesis, clinical and laboratory diagnosis, and management of heparin-induced thrombocytopenia (HIT), one of the most common immune-mediated adverse drug reactions. HIT is caused by IgG antibodies that recognize complexes of heparin and platelet factor 4, leading to platelet activation via platelet FcγIIa receptors. Formation of procoagulant, platelet-derived microparticles, and, possibly, activation of endothelium generate thrombin in vivo. Thrombin generation helps to explain the strong association between HIT and thrombosis, including the newly recognized syndrome of warfarin-induced venous limb gangrene. This syndrome occurs when acquired protein C deficiency during warfarin treatment of HIT and deep venous thrombosis leads to the inability to regulate thrombin generation in the microvasculature. The central role of HIT antibodies in causing HIT, as well as refinements in laboratory assays to detect these antibodies, means that HIT should be considered a clinicopathologic syndrome. The diagnosis can be made confidently when one or more typical clinical events (most frequently, thrombocytopenia with or withoutt thrombosis) occur in a patient with detectable HIT antibodies. The central role of thrombin generation in this syndrome provides a rationale for the use of anticoagulants that reduce thrombin generation (danaparoid) or inhibit thrombin (lepirudin).
Mapping of antigenic and functional epitopes on the alpha- and beta-subunits of two related mouse glycoproteins involved in cell interactions, LFA-1 and Mac-1.
Authors: F Sanchez-Madrid, P Simon, S Thompson, T A Springer
Journal: The Journal of Experimental Medicine (1983)

Mouse Mac-1, a complement receptor-associated surface structure on macrophages, and LFA-1, a function-associated structure on lymphocytes, comprise a novel family of leukocyte differentiation antigens participating in adhesive cell interactions. Mac-1 and LFA-1 contain alpha-subunits of 170,000 and 180,000 Mr, respectively, and beta-subunits of 95,000 Mr noncovalently associated in alpha 1 beta 1 complexes. The structural relation between the alpha- and between the beta-subunits, and the location of functionally important sites on the molecules, have been probed with antibodies. Both non-cross-reactive and cross-reactive monoclonal antibodies (MAb) and antisera prepared to the purified molecules or the LFA-1 alpha-subunits were used. Reactivity with individual subunits was studied by immunoprecipitation after dissociation induced by high pH treatment, or by immunoblotting after SDS-PAGE. Cross-reactive epitopes on Mac-1 and LFA-1 were found to be present on the beta-subunits, which were immunologically identical. Non-cross-reactive epitopes that are distinctive for Mac-1 or LFA-1 were localized to the alpha-subunits. MAb to LFA-1 alpha-subunit epitopes inhibited CTL-mediated killing. Two MAb to Mac-1 alpha-subunit epitopes but not a third MAb to a spatially distinct alpha-epitope inhibited complement receptor function. Neither function was inhibited by a MAb binding to a common beta-subunit epitope. Therefore, sites of Mac-1 and LFA-1 involved in their respective adhesion-related functions, as well as distinctive structural features, have been localized to the alpha-subunits.
Effectiveness of the Quadrivalent Human Papillomavirus Vaccine Against Cervical Dysplasia in Manitoba, Canada
Authors: Salaheddin M. Mahmud, Erich V. Kliewer, Pascal Lambert, Songul Bozat-Emre, Alain A. Demers
Journal: Journal of Clinical Oncology (2014)

Effectiveness of the quadrivalent human papillomavirus (QHPV) vaccine against cervical dysplasia has not been estimated using population-based individual level data. We assessed the vaccine effectiveness (VE) of the QHPV vaccine against cervical dysplasia using data collected routinely in Manitoba.Females ≥ 15 years old who received the QHPV vaccine in Manitoba between September 2006 and April 2010 privately (n = 3,541) were matched on age to up to three nonvaccinated females (n = 9,594). We used Cox regression models to estimate the hazard ratios for three outcomes: atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSILs), and high-grade SILs (HSILs).Among the 15- to 17-year-olds, the adjusted VE estimates were 35% (95% CI, -19% to 65%), 21% (-10% to 43%), and -1% (-44% to 29%) against the detection of HSILs, LSILs, and ASCUS, respectively. The corresponding estimates were higher (46% [0% to 71%], 35% [10% to 54%], and 23% [-8% to 45%]) among those who had ≥ one Pap smear after enrollment. The QHPV vaccine was associated with 23% (-17% to 48%) reduction in HSIL risk among those ≥ 18 with no history of abnormal cytology, but there was no evidence of protection among those with such a history (-8% [-59% to 27%]).A significant percentage of vaccinated women may not be protected against HSIL and lesser dysplasia especially if they were vaccinated at older age (≥ 18) or had abnormal cytology before vaccination. These findings affirm the importance of vaccination before any significant exposure to HPV occurs and underscore the need for screening programs that cover all sexually active women, even if they were vaccinated.
Diverse CD8+ T-Cell Responses to Renal Cell Carcinoma Antigens in Patients Treated with an Autologous Granulocyte-Macrophage Colony-Stimulating Factor Gene-Transduced Renal Tumor Cell Vaccine
Authors: Xianzheng Zhou, Do Youn Jun, Amy Morck Thomas, Xin Huang, Lan-Qing Huang, Josef Mautner, Wa Mo, Paul F. Robbins, Drew M. Pardoll, Elizabeth M. Jaffee
Journal: Cancer Research (2005)

A phase I clinical trial with granulocyte-macrophage colony-stimulating factor tumor cell vaccines in patients with metastatic renal cell carcinoma (RCC) showed immune cell infiltration at vaccine sites and delayed-type hypersensitivity (DTH) responses to autologous tumor cells indicative of T-cell immunity. To further characterize RCC T-cell responses and identify relevant RCC-associated antigens, we did a detailed analysis of CD8+ T-cell responses in two vaccinated RCC patients who generated the greatest magnitude of DTH response and also displayed a strong clinical response to vaccination (>90% reduction in metastatic tumor volume). Three separate CD8+ T-cell lines (and subsequent derived clones) derived from patient 24 recognized distinct RCC-associated antigens. One recognized a shared HLA-A*0201-restricted antigen expressed by both renal cancer cells and normal kidney cells. This recognition pattern correlated with a positive DTH test to normal kidney cells despite no evidence of impairment of renal function by the patient's remaining kidney after vaccination. A second line recognized a shared HLA-C7-restricted antigen that was IFN-gamma inducible. A third line recognized a unique HLA-A*0101-restricted RCC antigen derived from a mutated KIAA1440 gene specific to the tumor. In addition, two independent CTL lines and three clones were also generated from patient 26 and they recognized autologous tumor cells restricted through HLA-A*0205, HLA-A/B/C, and HLA-B/C. These results show that paracrine granulocyte-macrophage colony-stimulating factor tumor vaccines may generate a diverse repertoire of tumor-reactive CD8+ T-cell responses and emphasize the importance of polyvalency in the design of cancer immunotherapies.
An Improved Pilot Tube for Plastic Blood Containers
Authors: A. Richardson Jones
Journal: New England Journal of Medicine (1956)

MANY hemolytic transfusion reactions can be shown to have been due to human fallibility. For example, pilot or specimen tubes may be wrongly labeled; serial numbers may be misread, or blood intended for some other person may be given to the recipient. Although isoimmunization causes some serious reactions this is likely to become less of a problem as improvements are made in serologic technic. However, as blood transfusion becomes more intensively used, the opportunity for purely personal (as opposed to technologic) error increases.The device described here is believed to be of value in preventing some of the mistakes that . . .
Hypermethylation of RASSF1A, CDH13 and DAPK gene play a role in NSCLC pathogenesis
Authors: Milica Kontic, Dragana Jovanovic, Jelena Stojsic, Simona Ognjanovic, Heather Nelson
Journal: European Respiratory Journal (2013)

Introduction: Systemic methylation changes may be a diagnostic marker for tumor development or prognosis. Here, we investigate the relationship between gene methylation in lung tumors relative to normal lung tissue, and whether DNA methylation changes can be detected in paired blood samples.  Material and methods: 65 patients were enrolled in a surgical case series of non-small cell lung cancer (NSCLC). Using bisulfite pyrosequencing, CpG methylation was quantified at five genes (RASSF1A, CDH13, MGMT, ESR1 and DAPK) in lung tumor, pathologically normal lung tissue, and circulating blood. We wanted to determine whether these methylation changes are specific to lung tumors, and test whether these changes are detectable in patients’ blood samples.  Results: We observed that genes RASSF1A, CDH13, and DAPK were significantly hypermethylated in lung tumors compared to matched normal tissue. However, these changes could not be detected in patients’ blood samples, indicating a low feasibility of detecting lung cancer by analyzing these genes in a blood-based test. We confirmed that hypermethylation of RASSF1A, CDH13, and DAPK play a role in NSCLC pathogenesis, but also showed that these genes are not suitable markers for early detection of NSCLC. Lastly, we found that histology and gender were associated with methylation at the CDH13 gene, while stage was associated with methylation at MGMT.  Conclusion: Our results show higher methylation of RASSF1A, CDH13 and DAPK genes in lung tumors compared to normal lung. The lack of reflection of these methylation changes in blood samples from patients with NSCLC indicate their poorly suitability for a screening test.
Sublingual immunotherapy for hazelnut food allergy: A randomized, double-blind, placebo-controlled study with a standardized hazelnut extract
Authors: Ernesto Enrique, Fernando Pineda, Tamim Malek, Joan Bartra, María Basagaña, Raquel Tella, José Vicente Castelló, Rosario Alonso, José Antonio de Mateo, Teresa Cerdá-Trias, María del Mar San Miguel-Moncín, Susana Monzón, María García, Ricardo Palacios, Anna Cisteró-Bahíma
Journal: Journal of Allergy and Clinical Immunology (2005)
From heat maps to clinical tests: Why so few regulatory approved molecular profiles?
Authors: Nicholas C. Dracopoli
Journal: Clinical Cancer Research (2010)

Abstract Currently, only about 10% of oncology compounds entering Phase I clinical trials make it all the way to regulatory approval. The main goals of biomarker research in the pharmaceutical industry are to increase efficiency of the drug development process by improving understanding of the mechanism of action, deeper exploration of PK-PD interactions and predicting response to novel therapies in clinical development. The development of novel biomarkers by analysis of multidimensional clinical and biological data has enormous potential to impact drug development and improve patient outcomes. However, no complex molecular or protein profiles have been approved by the FDA to drive therapeutic use of any drug. Predictive markers are described in the labels for only a minority of the oncology drugs approved in the US since Herceptin in 1998. These markers all measure the status of the drug target or pathway and do not involve complex molecular or protein profiles. This presentation will discuss why this is the case and show how the nature of the clinical trial process, the limited numbers of patients enrolled in clinical trials, and the lack of long-term outcome data have severely limited the impact of molecular profiling in the drug approval process and ultimately clinical practice.
Repurposing staples for viruses: applying peptide design to RSV prophylaxis
Authors: Sarah P. Katen, Terence S. Dermody
Journal: Journal of Clinical Investigation (2014)

Respiratory syncytial virus (RSV) is responsible for lower respiratory tract infections and annually results in 200,000 deaths worldwide. Despite the burden of RSV-associated disease, treatments and preventative measures are limited. In this issue of JCI, Bird and colleagues describe their work using a peptide stapling technique that allowed synthesis of a stable peptide mimic of a portion of the RSV fusion protein. Pretreatment of cells with the stable peptide effectively blocked virus entry. When introduced into mice prior to RSV exposure, the peptide produced a substantial prophylactic effect. This work provides a new way forward in RSV prevention.
Comparison of three screening tools to detect psoriatic arthritis in patients with psoriasis (CONTEST study)
Authors: L.C. Coates, T. Aslam, F. Al Balushi, A.D. Burden, E. Burden-The, A.R. Caperon, R. Cerio, C. Chattopadhyay, H. Chinoy, M.J.D. Goodfield, L. Kay, S. Kelly, B.W. Kirkham, C.R. Lovell, H. Marzo-Ortega, N. McHugh, R. Murphy, N.J. Reynolds, C.H. Smith, E.J.C. Stewart, R.B. Warren, R. Waxman, H.E. Wilson, P.S. Helliwell
Journal: British Journal of Dermatology (2013)

Background Multiple questionnaires to screen for psoriatic arthritis (PsA) have been developed but the optimal screening questionnaire is unknown. Objectives To compare three PsA screening questionnaires in a head‐to‐head study using CASPAR (the Classification Criteria for Psoriatic Arthritis) as the gold standard. Methods This study recruited from 10 U.K. secondary care dermatology clinics. Patients with a diagnosis of psoriasis, not previously diagnosed with PsA, were given all three questionnaires. All patients who were positive on any questionnaire were invited for a rheumatological assessment. Receiver operating characteristic (ROC) curves were used to compare the sensitivity, specificity and area under the curve of the three questionnaires according to CASPAR criteria. Results In total, 938 patients with psoriasis were invited to participate and 657 (70%) patients returned the questionnaires. One or more questionnaires were positive in 314 patients (48%) and 195 (62%) of these patients attended for assessment. Of these, 47 patients (24%) were diagnosed with PsA according to the CASPAR criteria. The proportion of patients with PsA increased with the number of positive questionnaires (one questionnaire, 19·1%; two, 34·0%; three, 46·8%). Sensitivities and specificities for the three questionnaires, and areas under the ROC curve were, respectively: Psoriatic Arthritis Screening Evaluation (PASE), 74·5%, 38·5%, 0·594; Psoriasis Epidemiology Screening Tool (PEST), 76·6%, 37·2%, 0·610; Toronto Psoriatic Arthritis Screen (ToPAS), 76·6%, 29·7%, 0·554. The majority of patients with a false positive response had degenerative or osteoarthritis. Conclusion Although the PEST and ToPAS questionnaires performed slightly better than the PASE questionnaire at identifying PsA, there is little difference between these instruments. These screening tools identify many cases of musculoskeletal disease other than PsA.
Bone histomorphometry and structure in corticosteroid treated chronic active hepatitis.
Authors: A J Stellon, A Webb, J E Compston
Journal: Gut (1988)

Transiliac biopsies from 34 female patients with corticosteroid treated chronic active hepatitis have been examined to determine the contributions made by decreased bone formation and increased bone resorption to bone loss associated with this condition and to determine the structural basis of the bone loss. Mean wall thickness was significantly reduced when compared with control values (p less than 0.001) as was the bone formation rate at tissue (p less than 0.005) and basic multicellular unit (p less than 0.005) level. The osteoid maturation period and the bone formation period were significantly prolonged (p less than 0.02 and 0.05). The total resorption surfaces were significantly increased (p less than 0.02) but the mean interstitial bone thickness was normal. The mean trabecular plate thickness was significantly reduced (p less than 0.005). These findings indicate that decreased bone formation plays a major role in bone loss associated with corticosteroid treated chronic active hepatitis and that the structural basis of bone loss is trabecular thinning.
Epithelial Atypia: A Marker Risk of Concomitant or Subsequent Breast Carcinoma?
Authors: Isabelle de Mascarel, Gaëtan MacGrogan, Anne Vincent-Salomon, Simone Mathoulin-Pélissier, Véronique Brouste, Brigitte Sigal-Zafrani, Marc Debled, Louis Mauriac, Christine Tunon de Lara
Journal: Journal of Clinical Oncology (2008)

breast cancer risk associated with epithelial atypia. In this study, 66 breast cancers (19.9%) occurred among 331 women with ductal and/or lobular atypia (mean follow-up of 13.7 years) from an initial cohort of 9,376 women with benign lesions who underwent surgery between 1967 and 1991. Epithelial atypia were diagnosed on surgical biopsiesthathadbeensampledwithameanof3.2slidesperspecimen. In a recent study, we found a lower absolute risk 2 associated with epithelial atypia in a series of 2,833 surgical biopsies for microcalcifi- cations without any palpable mass, performed at BergonieInstitute between 1975 and 2003. The surgical biopsies in our series were mac- roscopically sectioned every 2 mm (median number of slides per biopsy, 26) and ductal and/or lobular atypia were recorded in 971 cases. 2 A concomitant small ( 5 mm) and low-grade cancer was associated with epithelial atypia in 301 (31%) of 971 of the surgical biopsies. Thus epithelial atypia was isolated, without a concomitant cancer, in 670 of 971 biopsies concerning 415 patients with one or several biopsies and without any previous or synchronous carci- noma in the same or contralateral breast. All these patients were untreated and monitored at our institute (mean follow-up, 13.3 years). Among them, only 18 patients had a subsequent breast cancer (4.3%). Therefore, at 5 and 10 years, the probabilities of developing invasive breast cancer were 2.8% (9 5% CI, 1.4 to 5.5) and 5.5% (95% CI, 3.3 to 9.9), respectively. In light of our experi- ence, we think that the pathologic management of surgical breast biopsies with epithelial atypia is determinant in the estimation of long-term absolute risk of breast cancer. In the study of Degnim et al, 1 as in the other series in the literature, 3-13 estimations of risk associated with epithelial atypia were based on a relatively small number of surgical biopsies with epithelial atypia (n 60 to 332),
A Population-Based Study on Alcohol and High-Risk Sexual Behaviors in Botswana
Authors: Sheri D Weiser, Karen Leiter, Michele Heisler, Willi McFarland, Fiona Percy-de Korte, Sonya M DeMonner, Sheila Tlou, Nthabiseng Phaladze, Vincent Iacopino, David R Bangsberg
Journal: PLoS Medicine (2006)

In Botswana, an estimated 24% of adults ages 15-49 years are infected with HIV. While alcohol use is strongly associated with HIV infection in Africa, few population-based studies have characterized the association of alcohol use with specific high-risk sexual behaviors.We conducted a cross-sectional, population-based study of 1,268 adults from five districts in Botswana using a stratified two-stage probability sample design. Multivariate logistic regression was used to assess correlates of heavy alcohol consumption (>14 drinks/week for women, and >21 drinks/week for men) as a dependent variable. We also assessed gender-specific associations between alcohol use as a primary independent variable (categorized as none, moderate, problem and heavy drinking) and several risky sex outcomes including: (a) having unprotected sex with a nonmonogamous partner; (b) having multiple sexual partners; and (c) paying for or selling sex in exchange for money or other resources. Criteria for heavy drinking were met by 31% of men and 17% of women. Adjusted correlates of heavy alcohol use included male gender, intergenerational relationships (age gap > or =10 y), higher education, and living with a sexual partner. Among men, heavy alcohol use was associated with higher odds of all risky sex outcomes examined, including unprotected sex (AOR = 3.48; 95% confidence interval [CI], 1.65 to 7.32), multiple partners (AOR = 3.08; 95% CI, 1.95 to 4.87), and paying for sex (AOR = 3.65; 95% CI, 2.58 to 12.37). Similarly, among women, heavy alcohol consumption was associated with higher odds of unprotected sex (AOR = 3.28; 95% CI, 1.71 to 6.28), multiple partners (AOR = 3.05; 95% CI, 1.83 to 5.07), and selling sex (AOR = 8.50; 95% CI, 3.41 to 21.18). A dose-response relationship was seen between alcohol use and risky sexual behaviors, with moderate drinkers at lower risk than both problem and heavy drinkers.Alcohol use is associated with multiple risks for HIV transmission among both men and women. The findings of this study underscore the need to integrate alcohol abuse and HIV prevention efforts in Botswana and elsewhere.
Cardiac Studies in Patients Treated with Depsipeptide, FK228, in a Phase II Trial for T-Cell Lymphoma
Authors: Richard L. Piekarz, A. Robin Frye, John J. Wright, Seth M. Steinberg, David J. Liewehr, Douglas R. Rosing, Vandana Sachdev, Tito Fojo, Susan E. Bates
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The histone deacetylase inhibitor depsipeptide (FK228) has activity in patients with cutaneous or peripheral T-cell lymphoma. Electrocardiogram abnormalities, thought to be a class effect, were observed in preclinical animal studies and phase I testing and led to the incorporation of intensive cardiac monitoring in an ongoing efficacy trial. Patients and Methods: This report summarizes the cardiac monitoring of 42 patients enrolled and treated on a phase II trial with depsipeptide. Cardiac evaluations included serial electrocardiograms to evaluate T-wave, ST segment, and QT interval effects and serial serum cardiac troponin I levels and left ventricular ejection fraction (LVEF) evaluations to exclude myocardial damage. Results: Cardiac studies from 282 cycles and 736 doses of depsipeptide included 2,051 electrocardiograms and 161 LVEF evaluations. Although T-wave flattening (grade 1) or ST segment depression (grade 2) was observed in more than half of the electrocardiograms obtained posttreatment, these electrocardiogram abnormalities were not associated with elevation of cardiac troponin I or with altered left ventricular function. No significant changes in LVEF were observed, even in 16 patients treated for ≥6 months and regardless of prior anthracycline exposure. Posttreatment electrocardiograms had a mean heart rate–corrected QT interval prolongation of 14.4 milliseconds compared with baseline. Electrolyte replacement has been instituted to mitigate potential untoward effects. Conclusion: The data obtained in this study show that the administration of depsipeptide is not associated with myocardial damage or impaired cardiac function. The potential effect of heart rate–corrected QT interval prolongation remains under study.