tbuckley/cabot-search huggingface dataset:
Pulmonary Function Studies with Radio-Active Gases
Authors: J B West
Journal: Annual Review of Medicine (1967)

acceleration of interest in the measurement of regional function in the lung with radioactive gases. The rate of acceleration has been particularly fast in the last year, with the result that this article is written during a period of rapid change. However, it now seems that the factors con­ trolling the normal distribution of blood flow and ventilation in the lung are beginning to be understood so that this is an opportune moment for review. It is likely that the next ten years will see a considerable application of this new knowledge to the investigation of the patho-physiologi cal processes of lung disease. METHODS
Effectiveness of an Early Versus a Conservative Invasive Treatment Strategy in Acute Coronary Syndromes
Authors: Kim Wadt Hansen, Rikke Sorensen, Mette Madsen, Jan Kyst Madsen, Jan Skov Jensen, Lene Mia von Kappelgaard, Poul Erik Mortensen, Theis Lange, Soren Galatius
Journal: Annals of Internal Medicine (2015)

Background: Randomized clinical trials have found that early invasive strategies reduce mortality, myocardial infarction (MI), and rehospitalization compared with a conservative invasive approach in acute coronary syndromes (ACSs), but the effectiveness of such strategies in real-world settings is unknown. Objective: To investigate adverse cardiovascular outcomes of an early versus a conservative invasive strategy in a national cohort of patients with ACSs. Design: Retrospective cohort study. Setting: Administrative health care data on hospitalizations, procedures, and outcomes abstracted from the Danish national registries and covering all acute invasive procedures in patients presenting with an ACS. Patients: 19 704 propensity score–matched patients hospitalized with a first ACS between 1 January 2005 and 31 December 2011. Measurements: Risk for cardiac death or rehospitalization for MI within 60 days of hospitalization. Results: Compared with a conservative approach, early invasive strategies were associated with a lower risk for cardiac death (cumulative incidence, 5.9% vs. 7.6%; adjusted hazard ratio [HR], 0.75 [95% CI, 0.66 to 0.84]; P < 0.001). Similar results were found for rehospitalization for MI (cumulative incidence, 3.4% vs. 5.0%; adjusted odds ratio, 0.67 [CI, 0.58 to 0.77]; P < 0.001) and all-cause death (cumulative incidence, 7.3% vs. 10.6%; adjusted HR, 0.65 [CI, 0.59 to 0.72]; P < 0.001). Limitation: Potential residual confounding due to lack of core clinical variables. Conclusion: In this real-world cohort of patients with a first hospitalization for an ACS, the use of an early invasive treatment strategy was associated with a lower risk for cardiac death and rehospitalization for MI compared with a conservative invasive approach. Primary Funding Source: Department of Cardiology, University Hospital Gentofte.
Treatment of recurrent and refractory pediatric solid tumors with high-dose busulfan and cyclophosphamide followed by autologous bone marrow rescue.
Authors: M L Graham, A M Yeager, B G Leventhal, J M Wiley, C I Civin, L C Strauss, C A Hurwitz, R L Dubowy, M D Wharam, P M Colombani
Journal: Journal of Clinical Oncology (1992)

PURPOSE The purpose of this study was to determine the toxicities of and responses to high-dose busulfan and cyclophosphamide with autologous bone marrow transplant (ABMT) in patients with recurrent or refractory pediatric solid tumors. PATIENTS AND METHODS We treated 18 patients (ages, 2 to 38 years; median, 14) who had tumors that were resistant to conventional chemotherapy and radiotherapy with busulfan 16 mg/kg and cyclophosphamide 200 mg/kg. Seventeen patients received bone marrow purged with 4-hydroperoxycyclophosphamide; one received unpurged marrow. RESULTS Despite extensive prior treatment, including radiotherapy in 16 patients, toxicity generally was acceptable. For seven patients with measurable disease, there were three partial responses of 2, 10, and 20 months' duration, three patients with stable disease (SD), and one early, toxic death. Of the 11 patients with no measurable disease at the time of transplantation, one patient with osteosarcoma continues in remission at 57+ months and one third of the patients survived for at least 16 months. Mucositis was the predominant nonhematopoietic toxicity. CONCLUSION Although the high-dose busulfan and cyclophosphamide combination showed modest activity, changes in the preparative regimen should be considered to improve the response rate in refractory tumors.
Making Antibodies by Phage Display Technology
Authors: Greg Winter, Andrew D. Griffiths, Robert E. Hawkins, Hennie R. Hoogenboom
Journal: Annual Review of Immunology (1994)

Antibody fragments of predetermined binding specificity have recently been constructed from repertoires of antibody V genes, bypassing hybridoma technology and even immunization. The V gene repertoires are harvested from populations of lymphocytes, or assembled in vitro, and cloned for display of associated heavy and light chain variable domains on the surface of filamentous bacteriophage. Rare phage are selected from the repertoire by binding to antigen; soluble antibody fragments are expressed from infected bacteria; and the affinity of binding of selected antibodies is improved by mutation. The process mimics immune selection, and antibodies with many different binding specificities have been isolated from the same phage repertoire. Thus human antibody fragments have been isolated with specificities against both foreign and self antigens, including haptens, carbohydrates, secreted and cell surface proteins, viral coat proteins, and intracellular antigens from the lumen of the endoplasmic reticulum and the nucleus. Such antibodies have potential as reagents for research and in therapy.
Kinins and Endothelial Control of Vascular Smooth Muscle
Authors: J V Mombouli, P M Vanhoutte
Journal: The Annual Review of Pharmacology and Toxicology (1995)

Plasma and vascular kinins stimulate the production of endothelium-derived nitric oxide, prostacyclin and hyperpolarizing factor (which regulates the function of vascular smooth muscle), and endothelial interactions with blood cells. The role of kinins in vasomotion is determined by the rate of production of the peptides by kininogenases and their degradation by kininases, in particular angiotensin-converting enzyme (ACE). Acute increases in plasma kinin levels during exercise or myocardial ischemia indicate that the metabolism of the peptides is fine tuned to the systemic or local metabolic demands. The release of endothelial vasodilators is impaired (or counterbalanced by the release of chemical or functional antagonists) in atherosclerosis, hypertension, diabetes, subarachidonic hemorrhage, and following postischemic injury. ACE-inhibitors potentiate the action of kinins and normalize endothelial function. In septic shock, hypotension triggered by overproduction of kinins leads to cardiovascular impairment and end-organ damage. Thus the balance in the metabolism of kinins modulates the control of blood flow by the endothelium.
A strategy to reduce cardiovascular disease by more than 80%
Journal: BMJ (2003)

The objective of this article is to determine the combination of drugs and vitamins, and their doses, for use in a single daily pill to achieve a large effect in preventing cardiovascular disease with minimal adverse effects. The strategy was to simultaneously reduce four cardiovascular risk factors (low density lipoprotein cholesterol, blood pressure, serum homocysteine, and platelet function) regardless of pretreatment levels.
Differentiation therapy for hepatocellular carcinoma: Multifaceted effects of miR‐148a on tumor growth and phenotype and liver fibrosis
Authors: Kwang Hwa Jung, Jing Zhang, Chong Zhou, Hong Shen, Mihai Gagea, Cristian Rodriguez‐Aguayo, Gabriel Lopez‐Berestein, Anil K. Sood, Laura Beretta
Journal: Hepatology (2015)

The death rate from hepatocellular carcinoma (HCC) is increasing, and liver cancer is the second leading cause of cancer‐related mortality worldwide. Most patients with HCC have underlying liver cirrhosis and compromised liver function, limiting treatment options. Cirrhosis is associated with cell dedifferentiation and expansion of hepatocholangiolar progenitor cells. We identified a microRNA signature associated with HCC and hepatocytic differentiation of progenitor cells. We further identified miR‐148a as an inducer of hepatocytic differentiation that is down‐regulated in HCC. MiR‐148a‐mimetic treatment in vivo suppressed tumor growth, reduced tumor malignancy and liver fibrosis, and prevented tumor development. These effects were associated with an increased differentiated phenotype and mediated by IκB kinase alpha/NUMB/NOTCH signaling. Conclusion: miR‐148a is an inhibitor of the IκB kinase alpha/NUMB/NOTCH pathway and an inducer of hepatocytic differentiation that when deregulated promotes HCC initiation and progression. Differentiation‐targeted therapy may be a promising strategy to treat and prevent HCC. (H epatology 2016;63:864–879)
Low Carbohydrate–Diet Scores and Long-term Risk of Type 2 Diabetes Among Women With a History of Gestational Diabetes Mellitus: A Prospective Cohort Study
Authors: Wei Bao, Shanshan Li, Jorge E. Chavarro, Deirdre K. Tobias, Yeyi Zhu, Frank B. Hu, Cuilin Zhang
Journal: Diabetes Care (2015)

Low-carbohydrate diets (LCDs) may improve short-term glycemic control in patients with gestational diabetes mellitus (GDM), but the long-term effect on progression from GDM to type 2 diabetes mellitus (T2DM) is unknown. We aimed to examine the long-term risk of T2DM in association with a low-carbohydrate dietary pattern among women with a history of GDM.Overall, 4,502 women with a history of GDM from the Nurses' Health Study II (NHSII) cohort, as part of the Diabetes & Women's Health (DWH) study, were followed up from 1991 to 2011. Overall, animal, or vegetable LCD scores, which represent adherence to different low-carbohydrate dietary patterns, were calculated using diet intake information assessed every 4 years since 1991 by validated food-frequency questionnaires. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs.We documented 722 incident cases of T2DM during 68,897 person-years of observation. The multivariable-adjusted HRs (95% CIs) of T2DM, comparing the highest with lowest quintiles, were 1.36 (1.04-1.78) for overall LCD score (P = 0.003 for trend), 1.40 (1.06-1.84) for animal LCD score (P = 0.004 for trend), and 1.19 (0.91-1.55) for vegetable LCD score (P = 0.50 for trend).Among women with a history of GDM, a low-carbohydrate dietary pattern, particularly with high protein and fat intake mainly from animal-source foods, is associated with higher T2DM risk, whereas a low-carbohydrate dietary pattern with high protein and fat intake from plant-source foods is not significantly associated with risk of T2DM.
Active IKKβ promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma
Authors: Nitin K. Agarwal, Chae H. Kim, Kranthi Kunkalla, Hiroyasu Konno, Youley Tjendra, Deukwoo Kwon, Marzenna Blonska, Goldi A. Kozloski, Vincent T. Moy, Ramiro E. Verdun, Glen N. Barber, Izidore S. Lossos, Francisco Vega
Journal: Blood (2015)
Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort
Authors: J. Mazières, F. Barlesi, T. Filleron, B. Besse, I. Monnet, M. Beau-Faller, S. Peters, E. Dansin, M. Früh, M. Pless, R. Rosell, M. Wislez, P. Fournel, V. Westeel, F. Cappuzzo, A. Cortot, D. Moro-Sibilot, J. Milia, O. Gautschi
Journal: Annals of Oncology (2015)
Acute coronary syndromes: key role of rehabilitation and primary care in long term secondary prevention
Authors: Hasnain M Dalal, Jenny Wingham, Rod S Taylor
Journal: BMJ (2015)

Timmis’s review on the management of acute coronary syndrome is timely and comprehensive but fails to mention the role of primary care in the aftercare of patients discharged from hospital.1 The review acknowledges that with recent advances patients admitted with acute myocardial infarction are discharged home after 48-72 hours and secondary prevention aimed at reducing the risk of recurrent acute coronary syndrome should …
Practical guidelines for B-cell receptor repertoire sequencing analysis
Authors: Gur Yaari, Steven H. Kleinstein
Journal: Genome Medicine (2015)

High-throughput sequencing of B-cell immunoglobulin repertoires is increasingly being applied to gain insights into the adaptive immune response in healthy individuals and in those with a wide range of diseases. Recent applications include the study of autoimmunity, infection, allergy, cancer and aging. As sequencing technologies continue to improve, these repertoire sequencing experiments are producing ever larger datasets, with tens- to hundreds-of-millions of sequences. These data require specialized bioinformatics pipelines to be analyzed effectively. Numerous methods and tools have been developed to handle different steps of the analysis, and integrated software suites have recently been made available. However, the field has yet to converge on a standard pipeline for data processing and analysis. Common file formats for data sharing are also lacking. Here we provide a set of practical guidelines for B-cell receptor repertoire sequencing analysis, starting from raw sequencing reads and proceeding through pre-processing, determination of population structure, and analysis of repertoire properties. These include methods for unique molecular identifiers and sequencing error correction, V(D)J assignment and detection of novel alleles, clonal assignment, lineage tree construction, somatic hypermutation modeling, selection analysis, and analysis of stereotyped or convergent responses. The guidelines presented here highlight the major steps involved in the analysis of B-cell repertoire sequencing data, along with recommendations on how to avoid common pitfalls.
Treatment with MOPP or ChlVPP chemotherapy only for all stages of childhood Hodgkin's disease.
Authors: H Ekert, K D Waters, P J Smith, I Toogood, D Mauger
Journal: Journal of Clinical Oncology (1988)

Fifty-three children with Hodgkin's disease were clinically staged and treated with chemotherapy alone. Forty-six received mechlorethamine (Mustargen; Merk Sharpe &amp; Dohme, West Point, PA), vincristine (Oncovin; Eli Lilly and Company, Indianapolis), procarbazine, and prednisolone (MOPP) and 7 chlorambucil, vinblastine, prednisolone, and procarbazine (ChlVPP). There were four events in the 38 children with stage I and II disease. One patient with massive mediastinal disease failed to remit and subsequently failed mantle irradiation and changes of chemotherapy. Another relapsed at the site of local disease and was salvaged with involved field irradiation and further courses of MOPP. Two other children died as a result of acute graft-v-host disease (GVHD) following transfusion. At autopsy there was no evidence of Hodgkin's disease. Fifteen children had stage III and IV disease and 14 achieved complete remission (CR) and none have relapsed. The child who failed to achieve remission died of virus infections. A mediastinal mass greater than 1/3 the thoracic width was present in 19 children of whom 18 achieved remission and none relapsed. An infradiaphragmatic presentation occurred in eight, all achieved remission and none relapsed. Overall at a median follow-up time of 45 months survival was 94%; the percent of patients without treatment failure was 92; and the percent without relapse was 98.
Abstract 1691: SL-401 activity against AML blasts correlates with CD123 levels and does not down-regulate CD123 expression
Authors: Rajeswaran Mani, Bhavani Gopalakrishnan, Xiaokui Mo, Chris Brooks, William Blum, Gerard Lozanski, Sumithira Vasu, Natarajan Muthusamy
Journal: Cancer Research (2015)

Abstract Despite the progress, the current therapies for acute myeloid leukemia (AML) are not curative partly due to failure to eradicate the leukemic stem cells (LSCs) that repopulate the leukemia. CD123 is the alpha-chain of interleukin-3 receptor (IL-3R) that is expressed on AML and AML LSCs, while it is undetectable in normal hematopoietic stem cells. We report here time and dose dependent cytotoxic activity of SL-401(Stemline Therapeutics, Inc), a diphtheria toxin interleukin-3 fusion protein which is designed to selectively bind, internalize and induce apoptosis of CD123+ primary AML cells isolated from patients. AML blasts were obtained from leukapheresis of patients and cultured in RPMI1640 with 20% fetal bovine serum and antibiotics and supplemented with growth factors GM-CSF and SCF (10ng/ml) overnight before treatment with increasing concentrations of SL-401. CD123 expression of AML blasts was analyzed using multicolor flow cytometry before and 24 hours after treatment with SL-401. The viability of the cells before and after treatment with increasing concentrations of SL-401 was measured by annexinV-FITC and propidium iodide staining. SL-401 induced dose-dependent (SL-401: 10, 100, 1000ng/ml) cytotoxicity in primary AML in nanomolar range (trend p = 0.0002 at 48hr), which correlated with surface expression levels of CD123. AML CD34+CD33+ blasts showed high CD123 expression levels and were susceptible to cytotoxicity with SL-401 (P&amp;lt;0.0001,1000ng/ml at 48hr). CD34−CD33+ committed leukemic cells were also CD123+ and responded to SL-401. To determine if SL-401 modulated CD123 levels after exposure, AML blasts pre-treated with SL-401 for 24hr were analyzed by flow cytometry for receptor expression. Importantly, SL-401 treatment after 24 hours did not down-regulate CD123 expression on primary AML blasts indicating a lack of an escape mechanism for malignant cells. These results provide evidence that time- and dose-dependent activity of SL-401 against CD123+ AML blasts correlates with CD123 expression. Moreover, treatment does not down-regulate IL-3R expression. Clinical studies of SL-401 in patients with relapsed/refractory AML with evaluation of CD123 expression and blastic plasmacytoid dendritic cell neoplasm (BPDCN) are ongoing. Citation Format: Rajeswaran Mani, Bhavani Gopalakrishnan, Xiaokui Mo, Chris Brooks, William Blum, Gerard Lozanski, Sumithira Vasu, Natarajan Muthusamy. SL-401 activity against AML blasts correlates with CD123 levels and does not down-regulate CD123 expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1691. doi:10.1158/1538-7445.AM2015-1691
Diesel exhaust augments allergen-induced lower airway inflammation in allergic individuals: a controlled human exposure study
Authors: Chris Carlsten, Anders Blomberg, Mandy Pui, Thomas Sandstrom, Sze Wing Wong, Neil Alexis, Jeremy Hirota
Journal: Thorax (2015)

Rationale Traffic-related air pollution has been shown to augment allergy and airway disease. However, the enhancement of allergenic effects by diesel exhaust in particular is unproven in vivo in the human lung, and underlying details of this apparent synergy are poorly understood. Objective To test the hypothesis that a 2 h inhalation of diesel exhaust augments lower airway inflammation and immune cell activation following segmental allergen challenge in atopic subjects. Methods 18 blinded atopic volunteers were exposed to filtered air or 300 µg PM 2.5 /m 3 of diesel exhaust in random fashion. 1 h post-exposure, diluent-controlled segmental allergen challenge was performed; 2 days later, samples from the challenged segments were obtained by bronchoscopic lavage. Samples were analysed for markers and modifiers of allergic inflammation (eosinophils, Th2 cytokines) and adaptive immune cell activation. Mixed effects models with ordinal contrasts compared effects of single and combined exposures on these end points. Results Diesel exhaust augmented the allergen-induced increase in airway eosinophils, interleukin 5 (IL-5) and eosinophil cationic protein (ECP) and the GSTT1 null genotype was significantly associated with the augmented IL-5 response. Diesel exhaust alone also augmented markers of non-allergic inflammation and monocyte chemotactic protein (MCP)-1 and suppressed activity of macrophages and myeloid dendritic cells. Conclusion Inhalation of diesel exhaust at environmentally relevant concentrations augments allergen-induced allergic inflammation in the lower airways of atopic individuals and the GSTT1 genotype enhances this response. Allergic individuals are a susceptible population to the deleterious airway effects of diesel exhaust. Trial registration number NCT01792232.
Association of Physician Certification in Interventional Cardiology With In-Hospital Outcomes of Percutaneous Coronary Intervention
Authors: Paul N. Fiorilli, Karl E. Minges, Jeph Herrin, John C. Messenger, Henry H. Ting, Brahmajee K. Nallamothu, Rebecca S. Lipner, Brian J. Hess, Eric S. Holmboe, Joseph J. Brennan, Jeptha P. Curtis
Journal: Circulation (2015)

Background— The value of American Board of Internal Medicine certification has been questioned. We evaluated the Association of Interventional Cardiology certification with in-hospital outcomes of patients undergoing percutaneous coronary intervention (PCI) in 2010. Methods and Results— We identified physicians who performed ≥10 PCIs in 2010 in the CathPCI Registry and determined interventional cardiology (ICARD) certification status using American Board of Internal Medicine data. We compared in-hospital outcomes of patients treated by certified and noncertified physicians using hierarchical multivariable models adjusted for differences in patient characteristics and PCI volume. Primary end points were all-cause in-hospital mortality and bleeding complications. Secondary end points included emergency coronary artery bypass grafting, vascular complications, and a composite of any adverse outcome. With 510 708 PCI procedures performed by 5175 physicians, case mix and unadjusted outcomes were similar among certified and noncertified physicians. The adjusted risks of in-hospital mortality (odds ratio, 1.10; 95% confidence interval, 1.02–1.19) and emergency coronary artery bypass grafting (odds ratio, 1.32; 95% confidence interval, 1.12–1.56) were higher in the non–ICARD-certified group, but the risks of bleeding and vascular complications and the composite end point were not statistically significantly different between groups. Conclusions— We did not observe a consistent association between ICARD certification and the outcomes of PCI procedures. Although there was a significantly higher risk of mortality and emergency coronary artery bypass grafting in patients treated by non–ICARD-certified physicians, the risks of vascular complications and bleeding were similar. Our findings suggest that ICARD certification status alone is not a strong predictor of patient outcomes and indicate a need to enhance the value of subspecialty certification.