tbuckley/cabot-search huggingface dataset:
Unusual patterns of immunoglobulin gene rearrangement and expression during human B cell ontogeny: human B cells can simultaneously express cell surface kappa and lambda light chains.
Authors: M E Pauza, J A Rehmann, T W LeBien
Journal: The Journal of Experimental Medicine (1993)

Immunoglobulin gene rearrangement during mammalian B cell development generally follows an ordered progression, beginning with heavy (H) chain genes and proceeding through kappa and lambda light (L) chain genes. To determine whether the predicted kappa--&amp;gt;lambda hierarchy was occurring in vitro, we generated Epstein-Barr virus-transformed cell lines from cultures undergoing human pre-B cell differentiation. A total of 143 cell lines were established. 24 expressed cell surface mu/lambda by flow cytometry and were clonal by Southern blotting. Surprisingly, two of the mu/lambda-expressing cell lines contained both kappa alleles in germline configuration, and synthesis/expression of conventional lambda L chains was directly proven by immunoprecipitation/sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) in one of them. Thus, human fetal bone marrow B lineage cells harbor the capacity to make functional lambda L chain gene rearrangements without rearranging or deleting either kappa allele. A third unusual cell line, designated 30.30, was observed to coexpress cell surface kappa and lambda L chains associated with mu H chains. The 30.30 cell line had a diploid karyotype, a single H chain rearrangement, both kappa alleles rearranged, and a single lambda rearrangement. Immunoprecipitation/SDS-PAGE confirmed that 30.30 cells synthesized and expressed kappa and lambda L chains. Multiparameter flow cytometry was used to demonstrate the existence of kappa+/lambda+ cells in fetal bone marrow and fetal spleen at frequencies of 2-3% of the total surface Ig+ B cell population. The flow cytometry data was confirmed by two-color immunofluorescence microscopy. The existence of normal human B cells expressing cell surface kappa and lambda refutes the widely accepted concept that expression of a single L chain isotype is immutable. The kappa+/lambda+ cells may represent transients undergoing L chain isotype switching.
Hypertension and coronary artery disease in non-insulin dependent diabetes--cause and effect?
Authors: J S Yudkin
Journal: Journal of the American Society of Nephrology (1992)

There is a log-linear increase in the risk of coronary heart disease with elevation of levels of blood pressure. Allowing for the phenomenon of regression dilution bias, this corresponds to around a 20 to 25% increase in risk for each 5 to 6 mm Hg elevation in usual diastolic blood pressure. In diabetic subjects, a similar relationship occurs, but of somewhat lesser degree. Recent overviews of therapy suggest that in nondiabetics, reducing blood pressure reverses around 50% of the excess coronary heart disease risk, but this has not yet been conclusively shown in patients with diabetes. The reduction in risk with therapy is a prerequisite to defining the antecedent as a causal influence on outcome, but it is as likely that the incomplete reversibility of excess risk represents other pathways of connection between hypertension and coronary heart disease as a consequent of iatrogenic effects of current treatments. Several alternative mechanisms are outlined, and the suggestion is made that only in the context of randomized controlled studies could the possible benefits on coronary heart disease of agents influencing such mechanisms be assessed.
Abstract SF1-2: Improving access to innovative anticancer medicines: a clinicians viewpoint
Authors: Jan H. M. Schellens
Journal: Cancer Research (2015)

Abstract For most forms of cancer there is high unmet need. This is especially the case for advanced cancer. Improved understanding of mechanisms of unresponsiveness to currently available treatments and identification of novel drugable targets have boosted anticancer drug development, often leading to so-called breakthrough medicines, i.e. drugs that can dramatically improve cure rate and survival. The monoclonal antibodies (mAb) trastuzumab and rituximab and the tyrosine kinase inhibitor (TKI) imatinib, developed in the recent past, deserved this qualification. These drugs have not only changed the standard of practice, they also served as template for new drug development leading to EMA &amp; FDA approval of &amp;gt;30 novel mAbs and TKIs for cancer indications since the introduction of rituximab in 1998. However, this does not guarantee swift patient access to new medicines nor to equal access for all indicated patients. Also, some drugs with high anticancer potential in well defined cancer populations simply seem to be stuck in development. One of the examples of missed opportunities is the group of the PARP inhibitors (PARPi): first patient included in phase I was in the year 2005 and now almost a decade later there is still no availability worldwide for well characterized populations with BRCAm, including breast and ovarian cancer, of PARPi treatment. Clearly, there is room for improvement, for which there is a range of good opportunities: shorten time to registration, shorten time to reimbursement, improve patient selection, limit to well defined subsets and expand later, setup global biomarker networks, setup global well controlled access programs and lastly take more risk. These opportunities will be discussed and examples will be given. Citation Format: Jan H. M. Schellens. Improving access to innovative anticancer medicines: a clinicians viewpoint [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr SF1-2.
Increased Cardiometabolic Risk Factors and Inflammation in Adipose Tissue in Obese Subjects Classified as Metabolically Healthy
Authors: Javier Gómez-Ambrosi, Victoria Catalán, Amaia Rodríguez, Patricia Andrada, Beatriz Ramírez, Patricia Ibáñez, Neus Vila, Sonia Romero, María A. Margall, María J. Gil, Rafael Moncada, Víctor Valentí, Camilo Silva, Javier Salvador, Gema Frühbeck
Journal: Diabetes Care (2014)

It has been suggested that individuals with the condition known as metabolically healthy obesity (MHO) may not have the same increased risk for the development of metabolic abnormalities as their non-metabolically healthy counterparts. However, the validity of this concept has recently been challenged, since it may not translate into lower morbidity and mortality. The aim of the current study was to compare the cardiometabolic/inflammatory profile and the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (T2D) in patients categorized as having MHO or metabolically abnormal obesity (MAO).We performed a cross-sectional analysis to compare the cardiometabolic/inflammatory profile of 222 MHO and 222 MAO patients (62% women) matched by age, including 255 lean subjects as reference (cohort 1). In a second cohort, we analyzed the adipokine profile and the expression of genes involved in inflammation and extracellular matrix remodeling in visceral adipose tissue (VAT; n = 82) and liver (n = 55).The cardiometabolic and inflammatory profiles (CRP, fibrinogen, uric acid, leukocyte count, and hepatic enzymes) were similarly increased in MHO and MAO in both cohorts. Moreover, above 30%of patients classified as MHO according to fasting plasma glucose exhibited IGT or T2D [corrected]. The profile of classic (leptin, adiponectin, resistin) as well as novel (serum amyloid A and matrix metallopeptidase 9) adipokines was almost identical in MHO and MAO groups in cohort 2. Expression of genes involved in inflammation and tissue remodeling in VAT and liver showed a similar alteration pattern in MHO and MAO individuals.The current study provides evidence for the existence of a comparable adverse cardiometabolic profile in MHO and MAO patients; thus the MHO concept should be applied with caution. A better identification of the obesity phenotypes and a more precise diagnosis are needed for improving the management of obese individuals.
The Role of Apoptosis in the Regulation of Hematopoietic Stem Cells
Authors: Jos Domen, Samuel H. Cheshier, Irving L. Weissman
Journal: The Journal of Experimental Medicine (2000)

Hematopoietic stem cells (HSC) give rise to cells of all hematopoietic lineages, many of which are short lived. HSC face developmental choices: self-renewal (remain an HSC with long-term multilineage repopulating potential) or differentiation (become an HSC with short-term multilineage repopulating potential and, eventually, a mature cell). There is a large overcapacity of differentiating hematopoietic cells and apoptosis plays a role in regulating their numbers. It is not clear whether apoptosis plays a direct role in regulating HSC numbers. To address this, we have employed a transgenic mouse model that overexpresses BCL-2 in all hematopoietic cells, including HSC: H2K-BCL-2. Cells from H2K-BCL-2 mice have been shown to be protected against a wide variety of apoptosis-inducing challenges. This block in apoptosis affects their HSC compartment. H2K-BCL-2–transgenic mice have increased numbers of HSC in bone marrow (2.4× wild type), but fewer of these cells are in the S/G2/M phases of the cell cycle (0.6× wild type). Their HSC have an increased plating efficiency in vitro, engraft at least as well as wild-type HSC in vivo, and have an advantage following competitive reconstitution with wild-type HSC.
Vernon Frederick ("Sam") Hall David Marsden Fletcher James Edward Hilton Lancelot Craig Montgomery Leslie Gordon Morrison Helen Duncanson Tennent Smith John Edward Utting Alan Richardson Wilson
Authors: M. Hall, A. Jackson, R. A A R Lawrence, K D Stewart, J R Evans, G Johnston, L. Reay, B. Taylor, D. Philips, R S Ahearn, J E Wilson
Journal: BMJ (1999)

1951-65 (b
Function of pulmonary M2 muscarinic receptors in antigen-challenged guinea pigs is restored by heparin and poly-L-glutamate.
Authors: A D Fryer, D B Jacoby
Journal: Journal of Clinical Investigation (1992)

The effect of heparin and poly-L-glutamate on the function of inhibitory M2 muscarinic autoreceptors on parasympathetic nerves in the lung was tested in antigen-challenged guinea pigs. After antigen challenge, M2 receptor function is decreased, thus increasing release of acetylcholine from the vagus and potentiating vagally induced bronchoconstriction. Guinea pigs were anesthetized, tracheostomized, vagotomized, paralyzed, and ventilated. Electrical stimulation of the vagi caused bronchoconstriction and bradycardia. In controls, pilocarpine attenuated vagally induced bronchoconstriction by stimulating neuronal M2 muscarinic receptors. Conversely, blocking these autoreceptors with gallamine potentiated vagally induced bronchoconstriction. In challenged animals the effects of both drugs were markedly reduced, confirming M2 receptor dysfunction. 20 min after heparin or poly-L-glutamate, the effects of both pilocarpine and gallamine on vagally induced bronchoconstriction were restored, demonstrating recovery of M2 receptor function. Neither heparin nor poly-L-glutamate affected vagally induced responses in control animals. Thus antigen-induced dysfunction of M2 receptors can be reversed by polyanionic polysaccharides (heparin) or polyanionic peptides (poly-L-glutamate). This suggests that a polycationic substance such as eosinophil major basic protein, cationic protein, or peroxidase may be responsible for antigen-induced pulmonary M2 receptor dysfunction.
Distinctive MicroRNA Profiles Relating to Patient Survival in Esophageal Squamous Cell Carcinoma
Authors: Yong Guo, Zhaoli Chen, Liang Zhang, Fang Zhou, Susheng Shi, Xiaoli Feng, Baozhong Li, Xin Meng, Xi Ma, Mingyong Luo, Kang Shao, Ning Li, Bin Qiu, Keith Mitchelson, Jing Cheng, Jie He
Journal: Cancer Research (2008)

Abstract Esophageal cancer is the sixth leading cause of death from cancer and one of the least studied cancers worldwide. The global microRNA expression profile of esophageal cancer has not been reported previously. Here, for the first time, we have investigated expressed microRNAs in cryopreserved esophageal cancer tissues using advanced microRNA microarray techniques. Our microarray analyses identified seven microRNAs that could distinguish malignant esophageal cancer lesions from adjacent normal tissues. Some microRNAs could be correlated with the different clinicopathologic classifications. High expression of hsa-miR-103/107 correlated with poor survival by univariate analysis as well as by multivariate analysis. These results indicate that microRNA expression profiles are important diagnostic and prognostic markers of esophageal cancer, which might be analyzed simply using economical approaches such as reverse transcription-PCR. [Cancer Res 2008;68(1):26–33]
Evidence of serum immunoglobulin abnormalities up to 9.8 years before diagnosis of chronic lymphocytic leukemia: a prospective study
Authors: Huei-Ting Tsai, Neil E. Caporaso, Robert A. Kyle, Jerry A. Katzmann, Angela Dispenzieri, Richard B. Hayes, Gerald E. Marti, Maher Albitar, Paolo Ghia, S. Vincent Rajkumar, Ola Landgren
Journal: Blood (2009)
Performance Characteristics of Computed Tomography in Detecting Lymph Node Metastases in Contemporary Patients with Prostate Cancer Treated with Extended Pelvic Lymph Node Dissection
Authors: Alberto Briganti, Firas Abdollah, Alessandro Nini, Nazareno Suardi, Andrea Gallina, Umberto Capitanio, Marco Bianchi, Manuela Tutolo, Niccolò Maria Passoni, Andrea Salonia, Renzo Colombo, Massimo Freschi, Patrizio Rigatti, Francesco Montorsi
Journal: European Urology (2011)
Phase I Trial of Weekly Paclitaxel and BMS-214662 in Patients with Advanced Solid Tumors
Authors: Howard H. Bailey, Dona B. Alberti, James P. Thomas, Daniel L. Mulkerin, Kimberly A. Binger, Marco M. Gottardis, Robert E. Martell, George Wilding
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacodynamics, and antitumor activity of continuous weekly-administered paclitaxel and BMS-214662, a novel farnesyl transferase inhibitor. Experimental Design: Patients were treated every week as tolerated with i.v. paclitaxel (fixed dose, 80 mg/m2/wk) administered over 1 h followed by i.v. BMS-214662 (escalating doses, 80–245 mg/m2/wk) over 1 h starting 30 min after completion of paclitaxel. Results: Twenty-six patients received 94 courses (one course, 21 days) of study treatment. Two patients received five courses of BMS-214662 as a weekly 24-h infusion (209 mg/m2/wk). The most common toxicities were grade 1 to 2 nausea/vomiting and/or diarrhea. DLTs observed at or near the MTD (200 mg/m2/wk) were grade 4 febrile neutropenia with sepsis occurring on day 2 of course 1 (245 mg/m2/wk), reversible grade 3 to 4 serum transaminase increases on day 2, and grade 3 diarrhea (200 and 245 mg/m2/wk). Objective partial responses were observed in patients with pretreated head and neck, ovarian, and hormone-refractory prostate carcinomas, and leiomyosarcoma. The observed pharmacokinetics of paclitaxel and BMS-214662 imply no interaction between the two. Significant inhibition (&amp;gt;80%) of farnesyl transferase activity in peripheral mononuclear cells was observed at the end of BMS-214662 infusion. Conclusions: Pretreated patients with advanced malignancies can tolerate weekly paclitaxel and BMS-214662 at doses that achieve objective clinical benefit. Due to multiple DLTs occurring at the expanded MTD, the recommended phase 2 dose and schedule is paclitaxel (80 mg/m2 over 1 h) and BMS-214662 (160 mg/m2 over 1 h) administered weekly.
Randomised comparison of implantation of heparin-coated stents with balloon angioplasty in selected patients with coronary artery disease (Benestent II)
Authors: Patrick W Serruys, Ben van Hout, Hans Bonnier, Victor Legrand, Eulogio Garcia, Carlos Macaya, Eduardo Sousa, Wim van der Giessen, Antonio Colombo, Ricardo Seabra-Gomes, Ferdinand Kiemeneij, Peter Ruygrok, John Ormiston, Håkan Emanuelsson, Jean Fajadet, Michael Haude, Silvio Klugmann, Marie-Angèle Morel
Journal: The Lancet (1998)
Functional Cooperation Between Smad Proteins and Activator Protein-1 Regulates Transforming Growth Factor-β–Mediated Induction of Endothelin-1 Expression
Authors: Fernando Rodríguez-Pascual, Mariano Redondo-Horcajo, Santiago Lamas
Journal: Circulation Research (2003)

Endothelin-1 (ET-1) is a 21-amino-acid potent vasoconstrictor peptide that is mainly produced by vascular endothelial cells. Expression of the ET-1 gene is subject to complex regulation by numerous factors, among which transforming growth factor-beta (TGF-beta) is one of the most important. It has been widely documented that TGF-beta increases ET-1 mRNA and peptide levels. We have explored the mechanism by which TGF-beta upregulates ET-1 expression in endothelial cells. Transcriptional activation of the ET-1 promoter accounted for the TGF-beta-induced increase in ET-1 mRNA levels. We have identified within the ET-1 promoter two DNA elements indispensable for TGF-beta-mediated induction of ET-1: an activator protein-1 (AP-1) site at -108/-102, known to be important for constitutive and induced expression, and a novel regulatory sequence located at -193/-171, which constitutes a specific binding site for Smad transcription factors. Mutation of both elements abolished TGF-beta responsiveness. Binding of Smad3/Smad4 and c-Jun to their corresponding DNA elements was evidenced by electrophoretic mobility shift assays. Furthermore, the coactivator CREB-binding protein (CBP)/p300 was found to play an essential role in the induction of the gene. The simultaneous requirement for two distinct and independent DNA elements suggests that Smads and activator protein-1 functionally cooperate through CBP/p300 to mediate TGF-beta-induced transcriptional activation of the ET-1 gene.
Shortening the duration of treatment for cervical tuberculous lymphadenitis
Authors: JH van Loenhout-Rooyackers, RJ Laheij, C Richter, AL Verbeek
Journal: European Respiratory Journal (2000)

The aim of the study was to determine the optimal duration of treatment for patients with tuberculous lymphadenitis. The Medline database was searched for relevant articles published between 1978-1997. Inclusion criteria were study populations of patients with predominantly cervical tuberculous lymphadenitis in whom the diagnosis had been confirmed bacteriologically and/or histologically, or was made probable by using clinical and laboratory markers. Treatment management had to include at least isoniazid, rifampicin and pyrazinamide and a follow-up of at least 12 months after the end of treatment. Patients with resistance to rifampicin and pyrazinamide and previous treatment for tuberculosis were excluded. The number of patients who relapsed after treatment was calculated. The study population in eight out of the 35 articles retrieved were suitable for analysis. Some concerned comparative studies. There were eight treatment schedules of 6 months' duration and three schedules of 9 months' duration. Treatment for 6 months resulted in a tuberculous lymphadenitis relapse rate of 13/422=3.3% (95% confidence interval: 1.7-5.5), with a mean follow-up of 31 months after completion of treatment. Treatment for 9 months resulted in a relapse rate of 3/112=2.7% (95% confidence interval: 0.6-7.8), with a mean follow-up of 20 months. Despite the limitations of the literature available, 6 months of therapy is probably sufficient for patients with tuberculous lymphadenitis.
The biochemical basis of sports performance
Authors: D Humphries
Journal: British Journal of Sports Medicine (2006)

Authored by Ron Maughan, Michael Gleeson. Published by Oxford University Press, 2004, £22.99, pp 257, softcover. ISBN 0199269246

The challenge is to take a topic that many have found difficult, confusing, and tedious (the biochemistry of exercise) and turn it into an entertaining, memorable, and relevant one. The authors succeed admirably. They have stripped the traditional teaching format away and used a series of athlete profiles (the weightlifter, the middle distance athlete, the games player, etc) as a method of providing a sound foundation in all aspects of the biochemistry of exercise.

Each chapter offers a very accessible format. Firstly, a …
Primary Open-Angle Glaucoma
Authors: Young H. Kwon, John H. Fingert, Markus H. Kuehn, Wallace L.M. Alward
Journal: New England Journal of Medicine (2009)

Glaucoma is one of the leading causes of blindness worldwide. This review discusses the clinical features, genetics, molecular biology, and cell biology of glaucoma. The authors present a typical case of glaucoma, together with the ocular findings.
Pulmonary vascular volumes and airways obstruction in SCD patients
Authors: Anne Greenough, Alan Lunt
Journal: Thorax (2014)

Dear Editor

We read with interest the recent paper by Chaudry et al 1 in which the authors describe an obstructive ventilatory defect in children with sickle cell disease (SCD) which was not linked to bronchial hyper-responsiveness, as assessed by methacholine challenge testing, or to eosinophillic inflammation. Their results further demonstrate that the airflow obstruction …
Coronary Heart Disease: Reducing The Risk
Authors: Gerd Assmann, Rafael Carmena, Paul Cullen, Jean-Charles Fruchart, Fabrizio Jossa, Barry Lewis, Mario Mancini, Rodolfo Paoletti
Journal: Circulation (1999)

the International Task Force for the Prevention of Coronary Heart Disease W orldwide, cardiovascular diseases are now the most common cause of death and a substantial source of chronic disability and health costs.In the light of new data from clinical trials and a fuller understanding of risk factors, the International Task Force for the Prevention of Coronary Heart Disease, in cooperation with the International Atherosclerosis Society, prepared a revised and comprehensive statement regarding the scientific basis of the primary and secondary prevention of cardiovascular disease.The following is a short account of the clinical implications of this statement.It is best read in conjunction with the full document, which can be found at http://www.chd-taskforce.com Assessing the Global Risk of Cardiovascular DiseaseAssessing a patient's overall or global risk of cardiovascular disease is the first step in preventive care, for it enables the physician to identify and provide the appropriate level of treatment for risk factors.Much can be learned from measuring even a few risk factors.The fuller the knowledge of the patient's risk status, the sounder the treatment decisions.Initial costs may be offset by long-term rational treatment.The goals of treatment and, hence, the extent of dietary change and the need for (and choice and dosage of) drug treatment all depend on global risk assessment.Two methods for determining global risk follow. Method INote and tabulate the following risk factors, including those laboratory investigations that are available. Age, Sex, and Menopausal StatusRisk increases progressively with adult age, and coronary heart disease (CHD) is most common after the age of 60 years.In premenopausal women, CHD is rare (except in those who use oral contraceptives and smoke).After menopause, risk increases steeply, approaching that of men after the age of 70 years. History of Cardiovascular DiseaseThe risk of further CHD events or stroke is much higher in persons with a history of myocardial infarction, angina, stroke, or intermittent claudication and in those who have ischemic changes on resting or exercise ECG than in persons without such findings.Any of these features confers grade III status (high risk; Table 1) and warrants vigorous reduction of all risk factors. Positive Family History of CHD, Stroke, or Peripheral Vascular DiseaseNote any reliable cardiovascular family history, and grade its severity on the basis of the following.