tbuckley/cabot-search huggingface dataset:
Cellular Effects and Antitumor Activity of RET Inhibitor RPI-1 on MEN2A-Associated Medullary Thyroid Carcinoma
Authors: G. Cuccuru, C. Lanzi, G. Cassinelli, G. Pratesi, M. Tortoreto, G. Petrangolini, E. Seregni, A. Martinetti, D. Laccabue, C. Zanchi, F. Zunino
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: The RET proto-oncogene encodes a receptor tyrosine kinase. RET oncogenes arise through sporadic and inherited gene mutations and are involved in the etiopathogenesis of medullary thyroid carcinoma, a cancer that responds poorly to conventional chemotherapy. Medullary thyroid carcinoma is a component of multiple endocrine neoplasia type 2 or MEN2 syndromes. Methods: We investigated the cellular effects of RPI-1, a novel 2-indolinone Ret tyrosine kinase inhibitor on cells that express RET C634 oncogenic mutants common in the MEN2A syndrome: NIH3T3 fibroblasts transfected with RET C634R and human medullary thyroid carcinoma TT cells that express endogenous RET C634W . RPI-1 antiproliferative activity was determined by cell proliferation and anchorage-independent growth assays. Expression and phosphorylation of Ret and of proteins involved in downstream signaling pathways were examined by immunoblotting. Antitumor activity of oral RPI-1 treatment was tested by using two dosing levels in nude mice bearing subcutaneous TT xenograft tumors. All statistical tests were two-sided. Results: The RPI-1 IC 50 value for cell proliferation was 3.6 μ M (95% confidence interval [CI] = 1.8 to 5.4 μ M ) in NIH3T3 cells expressing the Ret mutant compared with 16 μ M (95% CI = 12.3 to 19.7 μ M ) in non-transfected NIH3T3 cells, and that for colony formation in soft agar was 2.4 μ M (95% CI = 0.8 to 4.0 μ M ) and 26 μ M (95% CI = 17 to 35 μ M ) in RET mutant–transfected and H-RAS-transfected NIH3T3 cells, respectively. In NIH3T3 cells expressing the Ret mutant, Ret protein and tyrosine phosphorylation were undetectable after 24 hours of RPI-1 treatment. In TT cells, RPI-1 inhibited proliferation, Ret tyrosine phosphorylation, Ret protein expression, and the activation of PLCγ, ERKs and AKT. In mice, oral daily RPI-1 treatment inhibited the tumor growth of TT xenografts by 81% ( P <.001 versus control mice) and reduced the plasma levels of the specific biomarker calcitonin ( P = .01 versus control mice). Twenty-five percent of RPI-1-treated mice were tumor-free. Conclusions: Ret oncoproteins represent exploitable targets for therapeutic intervention in MEN2A-associated medullary thyroid carcinoma. The antitumor efficacy and oral bioavailability of RPI-1 support its therapeutic potential.
Neutral lateral fingertip-to-floor distance can be derived from height
Authors: Sofia Ramiro, Astrid van Tubergen, Carmen Stolwijk, Désirée van der Heijde, Robert Landewé
Journal: Annals of the Rheumatic Diseases (2014)

Spinal mobility is one of the core outcome measures used in axial spondyloarthritis as recommended by the Assessment of SpondyloArthritis international Society (ASAS).1 ,2 Among the commonly used spinal mobility measures, lateral spinal flexion (LSF) is considered to be the most sensitive to change and has therefore been included as one of the domains in the ASAS 5/6 response criteria.3 ,4

LSF is measured as the difference between two marks placed on the thigh, one in a neutral standing position and the other in maximum lateral flexion.2 Alternatively, LSF can be calculated as the difference in the lateral distances between middle fingertip-to-floor (FTF) in the neutral position (neutral FTF) and middle FTF in maximum latero-flexion (maximum flexion FTF).2 In this second LSF measurement, it may sometimes erroneously and accidentally happen that …
Whole-genome resequencing of Escherichia coli K-12 MG1655 undergoing short-term laboratory evolution in lactate minimal media reveals flexible selection of adaptive mutations
Authors: Tom M Conrad, Andrew R Joyce, M Kenyon Applebee, Christian L Barrett, Bin Xie, Yuan Gao, Bernhard Ø Palsson
Journal: Genome biology (2009)

Abstract Background Short-term laboratory evolution of bacteria followed by genomic sequencing provides insight into the mechanism of adaptive evolution, such as the number of mutations needed for adaptation, genotype-phenotype relationships, and the reproducibility of adaptive outcomes. Results In the present study, we describe the genome sequencing of 11 endpoints of Escherichia coli that underwent 60-day laboratory adaptive evolution under growth rate selection pressure in lactate minimal media. Two to eight mutations were identified per endpoint. Generally, each endpoint acquired mutations to different genes. The most notable exception was an 82 base-pair deletion in the rph - pyrE operon that appeared in 7 of the 11 adapted strains. This mutation conferred an approximately 15% increase to the growth rate when experimentally introduced to the wild-type background and resulted in an approximately 30% increase to growth rate when introduced to a background already harboring two adaptive mutations. Additionally, most endpoints had a mutation in a regulatory gene ( crp or relA , for example) or the RNA polymerase. Conclusions The 82 base-pair deletion found in the rph - pyrE operon of many endpoints may function to relieve a pyrimidine biosynthesis defect present in MG1655. In contrast, a variety of regulators acquire mutations in the different endpoints, suggesting flexibility in overcoming regulatory challenges in the adaptation.
Rhesus Macaques Develop Metabolic Syndrome With Reversible Vascular Dysfunction Responsive to Pioglitazone
Authors: Xiuqin Zhang, Rongli Zhang, Susanne Raab, Wen Zheng, Jue Wang, Na Liu, Tiangang Zhu, Lifang Xue, Zhentao Song, Jiaming Mao, Kaitao Li, Huiliang Zhang, Yan Zhang, Chao Han, Yi Ding, Hui Wang, Ning Hou, Yuli Liu, Shujiang Shang, Chuanyun Li, Elena Sebokova, Heping Cheng, Paul L. Huang
Journal: Circulation (2011)

The metabolic syndrome (MetS) is a constellation of clinical features that include central obesity, hypertension, atherogenic dyslipidemia, and insulin resistance. However, the concept remains controversial; it has been debated whether MetS represents nothing more than simultaneous co-occurrence of individual risk factors or whether there are common shared pathophysiological mechanisms that link the individual components.
Does exercise test modality influence dyspnoea perception in obese patients with COPD?
Authors: Casey E. Ciavaglia, Jordan A. Guenette, Josuel Ora, Katherine A. Webb, J. Alberto Neder, Denis E. O’Donnell
Journal: European Respiratory Journal (2013)

The purpose of this study was to investigate whether differences in physiological responses to weight-bearing (walking) and weight-supported (cycle) exercise influence dyspnoea perception in obese chronic obstructive pulmonary disease (COPD) patients, where such discrepancies are probably exaggerated. We compared metabolic, ventilatory and perceptual responses during incremental treadmill and cycle exercise using a matched linearised rise in work rate in 18 (10 males and eight females) obese (mean± sd body mass index 36.4±5.0 kg·m −2 ) patients with COPD (forced expiratory volume in 1 s 60±11% predicted). Compared with cycle testing, treadmill testing was associated with a significantly higher oxygen uptake, lower ventilatory equivalent for oxygen and greater oxyhaemoglobin desaturation at a given work rate (p&lt;0.01). Cycle testing was associated with a higher respiratory exchange ratio (p&lt;0.01), earlier ventilatory threshold (p&lt;0.01) and greater peak leg discomfort ratings (p=0.01). Ventilation, breathing pattern and operating lung volumes were similar between tests, as were dyspnoea/work rate and dyspnoea/ventilation relationships. Despite significant between-test differences in physiological responses, ventilation, operating lung volumes and dyspnoea intensity were similar at any given external power output during incremental walking and cycling exercise in obese COPD patients. These data provide evidence that either exercise modality can be selected for reliable evaluation of exertional dyspnoea in this population in research and clinical settings.
Eosinophil's Role Remains Uncertain as Anti–Interleukin-5 only Partially Depletes Numbers in Asthmatic Airway
Authors: Patrick T. Flood-Page, Andrew N. Menzies-Gow, A. Barry Kay, Douglas S. Robinson
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

The role of eosinophils as effector cells in asthma pathogenesis has been questioned since an anti–interleukin (IL)-5 monoclonal antibody (mepolizumab), which depleted blood and sputum eosinophils, failed to inhibit allergen-induced bronchoconstriction and airway hyperresponsiveness. However, the effect of IL-5 blockade on tissue eosinophils was not examined. We sought to determine whether mepolizumab depletes airway tissue eosinophils and their products. Twenty-four patients with mild asthma received three intravenous doses of either 750 mg of mepolizumab or placebo in a randomized, double-blind, parallel-group fashion over 20 weeks. Mepolizumab produced a median decrease from baseline of 55% for airway eosinophils (interquartile range, 29–89%; p = 0.009 versus placebo), 52% for bone marrow eosinophils (45–76%, p = 0.003), and 100% for blood eosinophils (range, 67–100%, p = 0.02). Mepolizumab had no appreciable effect on bronchial mucosal staining of eosinophil major basic protein. There were no significant changes in clinical measures of asthma (airway hyperresponsiveness, FEV1, and peak flow recordings) between the mepolizumab and placebo-treated groups. Anti–IL-5 treatment reduces but does not deplete airway or bone marrow eosinophils. The role of the eosinophil remains uncertain. Further clinical studies in asthma with more effective antieosinophil strategies are required.
Matrix Metalloproteinase-3 Producing Diffuse Large B-Cell Lymphoma, Not Otherwise Specified Associated With Rheumatoid Arthritis
Authors: Shoko Nakayama-Ichiyama, Taiji Yokote, Nobuya Hiraoka, Kazuki Iwaki, Ayami Takayama, Yuji Hirata, Takuji Miyoshi, Satoko Oka, Toshikazu Akioka, Shigeki Makino, Motomu Tsuji, Toshiaki Hanafusa
Journal: Journal of Clinical Oncology (2011)
Melanocytic naevi and melanoma: an epidemiological perspective
Authors: A.J. SWERDLOW, ADELE GREEN
Journal: British Journal of Dermatology (1987)

There is growing evidence that individuals at high risk of cutaneous melanoma can be identified by the use of simple measures of benign melanocytic naevi--raised risk occurring in persons who have large numbers of naevi, or naevi with atypical clinical features. Very high risk of melanoma appears to exist in two rare groups: persons with dysplastic naevi whose families include at least two individuals who have had melanoma, and persons with giant congenital naevi. Risks of melanoma in other individuals with dysplastic naevi and in persons with small congenital naevi have not yet been quantified. Much of the published work on risk of melanoma in relation to naevi has been based on clinical series or assemblage of case reports, with great potential for bias. In such studies, naevi have often been classified into dichotomies or syndromes originally defined for pathological or clinical purposes, frequently using poorly reproducible criteria. Case-control and cohort studies of the relationship of naevi to melanoma are needed, which use reproducible criteria and designs minimizing bias, and which examine risk in relation to graded clinical and histological measures of naevi.
The Immunology of CD1- and MR1-Restricted T Cells
Authors: Lucia Mori, Marco Lepore, Gennaro De Libero
Journal: Annual Review of Immunology (2016)

CD1- and MHC-related molecule-1 (MR1)-restricted T lymphocytes recognize nonpeptidic antigens, such as lipids and small metabolites, and account for a major fraction of circulating and tissue-resident T cells. They represent a readily activated, long-lasting population of effector cells and contribute to the early phases of immune response, orchestrating the function of other cells. This review addresses the main aspects of their immunological functions, including antigen and T cell receptor repertoires, mechanisms of nonpeptidic antigen presentation, and the current evidence for their participation in human and experimental diseases.
Osteochondroma of the rib: an unusual cause of haemothorax.
Authors: N K Harrison, J Wilkinson, J O'Donohue, D Hansell, M N Sheppard, P G Goldstraw, A G Davison, A J Newman Taylor
Journal: Thorax (1994)

The case is described of a 36 year old woman who presented with a large left sided haemothorax. A thoracic computed tomographic (CT) scan suggested there was a bony outgrowth arising from the fourth rib. This was resected surgically and found to be an osteochondroma which was surrounded by blood clot. No definite site of bleeding was identified, but it is thought that the tumour may have traumatised the lung, the pericardiacophrenic artery, or the superior pulmonary vein, resulting in life threatening haemorrhage.
The CD16+ (FcγRIII+) Subset of Human Monocytes Preferentially Becomes Migratory Dendritic Cells in a Model Tissue Setting
Authors: Gwendalyn J. Randolph, Guzman Sanchez-Schmitz, Ronald M. Liebman, Knut Schäkel
Journal: The Journal of Experimental Medicine (2002)

Much remains to be learned about the physiologic events that promote monocytes to become lymph-homing dendritic cells (DCs). In a model of transendothelial trafficking, some monocytes become DCs in response to endogenous signals. These DCs migrate across endothelium in the ablumenal-to-lumenal direction (reverse transmigration), reminiscent of the migration into lymphatic vessels. Here we show that the subpopulation of monocytes that expresses CD16 (Fcγ receptor III) is predisposed to become migratory DCs. The vast majority of cells derived from CD16+ monocytes reverse transmigrated, and their presence was associated with migratory cells expressing high levels of CD86 and human histocompatibility leukocyte antigen (HLA)-DR, and robust capacity to induce allogeneic T cell proliferation. A minority of CD16− monocytes reverse transmigrated, and these cells stimulated T cell proliferation less efficiently. CD16 was not functionally required for reverse transmigration, but promoted cell survival when yeast particles (zymosan) were present as a maturation stimulus in the subendothelial matrix. The cell surface phenotype and migratory characteristics of CD16+ monocytes were inducible in CD16− monocytes by preincubation with TGFβ1. We propose that CD16+ monocytes may contribute significantly to precursors for DCs that transiently survey tissues and migrate to lymph nodes via afferent lymphatic vessels.
Ligation of CD38 suppresses human B lymphopoiesis.
Authors: M Kumagai, E Coustan-Smith, D J Murray, O Silvennoinen, K G Murti, W E Evans, F Malavasi, D Campana
Journal: The Journal of Experimental Medicine (1995)

CD38 is a transmembrane glycoprotein expressed in many cell types, including lymphoid progenitors and activated lymphocytes. High levels of CD38 expression on immature lymphoid cells suggest its role in the regulation of cell growth and differentiation, but there is no evidence demonstrating a functional activity of CD38 on these cells. We used stroma-supported cultures of B cell progenitors and anti-CD38 monoclonal antibodies (T16 and IB4) to study CD38 function. In cultures of normal bone marrow CD19+ cells (n = 5), addition of anti-CD38 markedly reduced the number of cells recovered after 7 d. Cell loss was greatest among CD19+ sIg- B cell progenitors (mean cell recovery +/- SD = 7.2 +/- 11.7% of recovery in control cultures) and extended to CD19+CD34+ B cells (the most immature subset; 7.6 +/- 2.2%). In contrast, CD38 ligation did not substantially affect cell numbers in cultures of normal peripheral blood or tonsillar B cells. In stroma-supported cultures of 22 B-lineage acute lymphoblastic leukemia cases, anti-CD38 suppressed recovery of CD19+ sIg- leukemic cells. CD38 ligation also suppressed the growth of immature lymphoid cell lines cultured on stroma and, in some cases, in the presence of stroma-derived cytokines (interleukin [IL] 7, IL-3, and/or stem cell factor), but did not inhibit growth in stroma- or cytokine-free cultures. DNA content and DNA fragmentation studies showed that CD38 ligation of stroma-supported cells resulted in both inhibition of DNA synthesis and induction of apoptosis. It is known that CD38 catalyzes nicotinamide adenine dinucleotide (NAD+) hydrolysis into cyclic ADP-ribose (cADPR) and ADPR. However, no changes in NAD+ hydrolysis or cADPR and ADPR production after CD38 ligation were found by high-performance liquid chromatography; addition of NAD+, ADPR, or cADPR to cultures of lymphoid progenitors did not offset the inhibitory effects of anti-CD38. Thus, anti-CD38 does not suppress B lymphopoiesis by altering the enzymatic function of the molecule. In conclusion, these data show that CD38 ligation inhibits the growth of immature B lymphoid cells in the bone marrow microenvironment, and suggest that CD38 interaction with a putative ligand represents a novel regulatory mechanism of B lymphopoiesis.
A patient who changed my practice: His own way
Authors: G. Bowbrick
Journal: BMJ (2002)

I was looking forward to my brother's wedding—at last he was settling down, and it was a chance to see my family, including my grandfather. It was a bright, sunny September morning, but Grandad did not look right—a bit pale and short of breath. After a few puffs of his glyceryl trinitrate spray, however, he felt better. The ceremony went without a hitch, but I sat next to Grandad to make sure he was all right. Then the photographs were taken—everyone was …
Asthma: pathogenesis and novel drugs for treatment
Authors: J. T. Olin, M. E. Wechsler
Journal: BMJ (2014)

Asthma affects almost 20 million people in the United States and more than 300 million people worldwide. Of these, 10-15% have severe asthma, which is refractory to commonly available drugs. New drugs are needed because those that are currently available cannot control symptoms and exacerbations in all patients and can cause adverse reactions. In the past 10 years, there have been substantial advances in the understanding of asthma genetics, airway biology, and immune cell signaling. These advances have led to the development of small molecule therapeutics and biologic agents that may improve asthma care in the future. Several new classes of asthma drugs—including ultra long acting β agonists and modulators of the interleukin 4 (IL-4), IL-5, IL-13, and IL-17 pathways—have been evaluated in randomized controlled trials. Other new drug classes—including dissociated corticosteroids, CXC chemokine receptor 2 antagonists, toll-like receptor 9 agonists, and tyrosine kinase inhibitors—remain in earlier phases of development. Despite some preliminary efficacy data, there is insufficient evidence to make strong recommendations about the use of these newer agents. Future research on the clinical efficacy of these biologic agents, the effect of newer agents on severe asthma in pediatric patients, and the biology of non-eosinophilic and corticosteroid resistant asthma is needed to reduce the morbidity of asthma worldwide.
An ultrastructural basis for electrocardiographic alterations associated with Duchenne's progressive muscular dystrophy.
Authors: S K Sanyal, W W Johnson, M K Thapar, S E Pitner
Journal: Circulation (1978)

Electrocardiographic abnormalities were identified in 63 (84%) of 75 patients with Duchenne's progressive muscular dystrophy. A tall R wave over V1 with an abnormal R/S ratio was seen in 64% of the patients, a deep and narrow Q wave greater than 4 mm over leads I, V5, and V6 in 44%, sinus tachycardia in 32% and right axis deviation in 16%. Other ECG abnormalities included an abnormal PV1 index in 14% of patients and a short P-R interval in 6%. Ultrastructural characteristics of the heart were determined for two patients with characteristic electrocardiographic abnormalities. Common to both hearts was a total loss of thick as well as thin myofilaments, which gave a "moth-eaten" appearance to the myofiber. This feature, combined with preservation of the transverse tubular system, formed the most characteristic ultrastructural finding and was seen most consistently in the posterobasal area of the left ventricle. Alterations of Z-band material; accumulation of mitochondria, occasionally containing electron-dense bodies and showing loss or discontinuity of cristae; dilatation of sarcoplasmic reticulum with striking ectasia of cisternae; depletion of glycogen particles; a paucity of lipoid or lipochrome granules; and the absence of virus-like particles were other consistent ultrastructural features. Comparison of skeletal and cardiac muscle disclosed identical subcellular changes. These observations support the contention that the distinctive ECG pattern associated with Duchenne's dystrophy results from multifocal degenerative changes involving myocardium, predominantly the posterobasal region of the left ventricle and the posterior papillary muscle.
Précis of<i>Vaulting Ambition: Sociobiology and the Quest for Human Nature</i>
Authors: Philip Kitcher
Journal: Behavioral and Brain Sciences (1987)

Abstract The debate about the credentials of sociobiology has persisted because scholars have failed to distinguish the varieties of sociobiology and because too little attention has been paid to the details of the arguments that are supposed to support the provocative claims about human social behavior. I seek to remedy both deficiencies. After analysis of the relationships among different kinds of sociobiology and contemporary evolutionary theory, I attempt to show how some of the studies of the behavior of nonhuman animals meet the methodological standards appropriate to evolutionary research. I contend that the efforts of E. O. Wilson, Richard Alexander, Charles Lumsden, and others to generate conclusions about human nature are flawed, both because they apply evolutionary ideas in an unrigorous fashion and because they use dubious assumptions to connect their evolutionary analyses with their conclusions. This contention rests on analyses of many of the major sociobiological proposals about human social behavior, including: differences in sex roles, racial hostility, homosexuality, conflict between parents and adolescent offspring, incest avoidance, the avunculate, alliances in combat, female infanticide, and gene–culture coevolution. Vaulting Ambition thus seeks to identify what is good in sociobiology, to expose the errors of premature speculations about human nature, and to prepare the way for serious study of the evolution of human social behavior.