tbuckley/cabot-search huggingface dataset:
Using transcriptomics to identify and validate novel biomarkers of human skeletal muscle cancer cachexia
Authors: Nathan A Stephens, Iain J Gallagher, Olav Rooyackers, Richard J Skipworth, Ben H Tan, Troels Marstrand, James A Ross, Denis C Guttridge, Lars Lundell, Kenneth C Fearon, James A Timmons
Journal: Genome Medicine (2010)

Cancer cachexia is a multi-organ tissue wasting syndrome that contributes to morbidity and mortality in many cancer patients. Skeletal muscle loss represents an established key feature yet there is no molecular understanding of the disease process. In fact, the postulated molecular regulators of cancer cachexia originate largely from pre-clinical models and it is unclear how these translate to the clinical environment.Rectus abdominis muscle biopsies were obtained from 65 upper gastrointestinal (UGI) cancer patients during open surgery and RNA profiling was performed on a subset of this cohort (n = 21) using the Affymetrix U133+2 platform. Quantitative analysis revealed a gene signature, which underwent technical validation and independent confirmation in a separate clinical cohort.Quantitative significance analysis of microarrays produced an 83-gene signature that was able to identify patients with greater than 5% weight loss, while this molecular profile was unrelated to markers of systemic inflammation. Selected genes correlating with weight loss were validated using quantitative real-time PCR and independently studied as general cachexia biomarkers in diaphragm and vastus lateralis from a second cohort (n = 13; UGI cancer patients). CaMKIIbeta correlated positively with weight loss in all muscle groups and CaMKII protein levels were elevated in rectus abdominis. TIE1 was also positively associated with weight loss in both rectus abdominis and vastus lateralis muscle groups while other biomarkers demonstrated tissue-specific expression patterns. Candidates selected from the pre-clinical literature, including FOXO protein and ubiquitin E3 ligases, were not related to weight loss in this human clinical study. Furthermore, promoter analysis identified that the 83 weight loss-associated genes had fewer FOXO binding sites than expected by chance.We were able to discover and validate new molecular biomarkers of human cancer cachexia. The exercise activated genes CaMKIIbeta and TIE1 related positively to weight-loss across muscle groups, indicating that this cachexia signature is not simply due to patient inactivity. Indeed, excessive CaMKIIbeta activation is a potential mechanism for reduced muscle protein synthesis. Our genomics analysis also supports the view that the available preclinical models do not accurately reflect the molecular characteristics of human muscle from cancer cachexia patients.
Prevention and Reversal of Premature Endothelial Cell Senescence and Vasculopathy in Obesity-Induced Diabetes by Ebselen
Authors: Sergey V. Brodsky, Olga Gealekman, Jun Chen, Fan Zhang, Nobuhiko Togashi, Mark Crabtree, Steven S. Gross, Alberto Nasjletti, Michael S. Goligorsky
Journal: Circulation Research (2003)

Although the accelerated atherosclerosis and premature aging of the cardiovascular system in patients with metabolic syndrome have been appreciated, the mechanisms of their development and potential therapeutic interventions remain unresolved. Our previous studies implicated advanced glycosylation end products in development of premature senescence preventable with a peroxynitrite scavenger, ebselen. Therefore, the effect of ebselen on endothelial senescence and vasculopathy in a model of metabolic syndrome--Zucker diabetic rats (ZDF)--was investigated. Ebselen decreased the abundance of 3-nitrotyrosine-modified proteins in ZDF rats. A 6-fold increase in the number of senescent endothelial cells in 22-week-old ZDF was prevented by ebselen. Development of vasculopathy, as collectively judged by the acetylcholine-induced vasorelaxation, NO production, angiogenic competence, and number of circulating microparticles, was almost completely prevented when ebselen was administered from 8 to 22 weeks and partially reversed when the treatment interval was 13 to 22 weeks. In conclusion, premature senescence of endothelial cells is progressively rampant in ZDF rats and is associated with the signs of severe vasculopathy. In addition, prevention of premature senescence of vascular endothelium through controlled decrease in nitrotyrosine formation was chronologically associated with the amelioration of vasculopathy, lending support to the idea of the pathogenetic role of premature senescence of endothelial cells in diabetic macrovasculopathy.
Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials
Authors: E. P. Navarese, F. Andreotti, V. Schulze, M. Ko odziejczak, A. Buffon, M. Brouwer, F. Costa, M. Kowalewski, G. Parati, G. Y. H. Lip, M. Kelm, M. Valgimigli
Journal: BMJ (2015)

<b>Objective</b> To assess the benefits and risks of short term (&lt;12 months) or extended (&gt;12 months) dual antiplatelet therapy (DAPT) versus standard 12 month therapy, following percutaneous coronary intervention with drug eluting stents. <b>Design</b> Meta-analysis of randomised controlled trials. <b>Data sources </b>PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, Scopus, Web of Science, Cochrane Library, and major congress proceedings, searched from 1 January 2002 to 16 February 2015. <b>Review methods</b> Trials comparing short term (&lt;12 months) or extended (&gt;12 months) DAPT regimens with standard 12 month duration of therapy. Primary outcomes were cardiovascular mortality, myocardial infarction, stent thrombosis, major bleeding, and all cause mortality. <b>Results</b> 10 randomised controlled trials (n=32 287) were included. Compared to 12 month DAPT, a short term course of therapy was associated with a significant reduction in major bleeding (odds ratio 0.58 (95% confidence interval 0.36 to 0.92); P=0.02) with no significant differences in ischaemic or thrombotic outcomes. Extended versus 12 month DAPT yielded a significant reduction in the odds of myocardial infarction (0.53 (0.42 to 0.66); P&lt;0.001) and stent thrombosis (0.33 (0.21 to 0.51); P&lt;0.001), but more major bleeding (1.62 (1.26 to 2.09); P&lt;0.001). All cause but not cardiovascular death was also significantly increased (1.30 (1.02 to 1.66); P=0.03). <b>Conclusions</b> Compared with a standard 12 month duration, short term DAPT (&lt;12 months) after drug eluting stent implementation yields reduced bleeding with no apparent increase in ischaemic complications, and could be considered for most patients. In selected patients with low bleeding risk and very high ischaemic risk, extended DAPT (&gt;12 months) could be considered. The increase in all cause but not cardiovascular death with extended DAPT requires further investigation.
The Anatomy and Physiology of Primate Neurons that Control Rapid Eye Movements
Authors: A K Moschovakis, S M Highstein
Journal: Annual Review of Neuroscience (1994)

Primates are frontal eyed animals possessing a sophisticated retina endowed with a highly differentiated foveal region with which the visual scene can be examined in detail. Vision is very important to these animals and is probably the predominant sensory modality with which they orient themselves and interact with the world. The relationship between the visual system and the motor system that moves the eyes (oculomotor) is intimate. Motion of the visual scene across the retina, particularly the fovea, can degrade visual acuity. Hence there is a necessity for accurate oculomotor control. Not surprisingly, a considerable portion of the brain� including the superior colliculus (sq, the frontal eye field (FEF), the thalamus, and the cerebellum as well as several brainstem nuclei, is entrusted with the control of eye movements (Hepp et al 1989). The most ubiquitous movements of the eyes are the rapid ones (also called saccadic) that reorient the eyes quickly toward interesting features of the surrounding world. During a saccade, two or more of six extraocular muscles
Proximal Fluid Proteome Profiling of Mouse Colon Tumors Reveals Biomarkers for Early Diagnosis of Human Colorectal Cancer
Authors: Remond J.A. Fijneman, Meike de Wit, Maral Pourghiasian, Sander R. Piersma, Thang V. Pham, Marc O. Warmoes, Mehrdad Lavaei, Chloe Piso, Fiona Smit, Pien M. Delis-van Diemen, Sietze T. van Turenhout, Jochim S. Terhaar sive Droste, Chris J.J. Mulder, Marinus A. Blankenstein, Els C. Robanus-Maandag, Ron Smits, Riccardo Fodde, Victor W.M. van Hinsbergh, Gerrit A. Meijer, Connie R. Jimenez
Journal: Clinical Cancer Research (2012)

Early detection of colorectal cancer (CRC) and its precursor lesions is an effective approach to reduce CRC mortality rates. This study aimed to identify novel protein biomarkers for the early diagnosis of CRC.Proximal fluids are a rich source of candidate biomarkers as they contain high concentrations of tissue-derived proteins. The FabplCre;Apc(15lox/+) mouse model represents early-stage development of human sporadic CRC. Proximal fluids were collected from normal colon and colon tumors and subjected to in-depth proteome profiling by tandem mass spectrometry. Carcinoembryonic antigen (CEA) and CHI3L1 human serum protein levels were determined by ELISA.Of the 2,172 proteins identified, quantitative comparison revealed 192 proteins that were significantly (P < 0.05) and abundantly (>5-fold) more excreted by tumors than by controls. Further selection for biomarkers with highest specificity and sensitivity yielded 52 candidates, including S100A9, MCM4, and four other proteins that have been proposed as candidate biomarkers for human CRC screening or surveillance, supporting the validity of our approach. For CHI3L1, we verified that protein levels were significantly increased in sera from patients with adenomas and advanced adenomas compared with control individuals, in contrast to the CRC biomarker CEA.These data show that proximal fluid proteome profiling with a mouse tumor model is a powerful approach to identify candidate biomarkers for early diagnosis of human cancer, exemplified by increased CHI3L1 protein levels in sera from patients with CRC precursor lesions.
A visible and palpable cause of backache
Authors: E Serhan
Journal: Annals of the Rheumatic Diseases (2000)

Backache with its many causes continues to present a challenge to the examining physician.Careful history taking, inspection and palpation still have an essential role, as well as the most modern imaging techniques.Although extra-pulmonary tuberculosis (TB) has shown a disproportionate increase in recent years, 1 muscular TB is still uncommon.Necropsies of 2224 TB cases revealed only four with TB myositis. 2Petter 3 put the incidence of TB myositis at 0.015%.Here we present one of the rare manifestations of TB infection. Case reportA 46 years old Indian woman was referred to the Department of Rheumatology with a four month history of pain around the right lower rib cage posteriorly.Use of the right upper limb was said to have aggravated the pain, but there were no pleuritic features.She denied sweating, cough, haemoptysis or loss of appetite.Otherwise the patient was in good health without any weight loss.Past history included two episodes of mechanical low back pain in 1970 and in 1995.Both mother in law and brother in law had TB, more than 30 years and eight years ago respectively.They all lived in separate houses.There was no history of recent TB contact or BCG inoculation with the exception of the patient having visited India three years previously.The patient had lived in England for 30 years.There were no known risk factors for HIV infection.On examination the patient had a temperature of 37.1°C.No rash or lymphadenopathy were noted.Musculoskeletal examination revealed a firm, non-tender, non-fluctuant swelling 7 cm × 4 cm to the right of the lower dorsal spine (fig 1).The overlying skin looked normal and was not warm to touch.There was no spinal tenderness, but thoracic spine movements were rather restricted.Further examination of cardiovascular, respiratory and central nervous systems failed to delineate any abnormalities.On palpation of the abdomen, there was no organomegaly or other physical abnormality.At this point there was no working diagnosis and only analgesics were prescribed.After the outpatient consultation the patient was admitted for further evaluation.Erythrocyte sedimentation rate was raised 42 mm 1st h (1-12 mm 1st h).There was slight increase in C reactive protein 10 mg/dl (1-6 mg/dl).She had a normal full blood count, blood glucose and immunoglobulins.Radiographs of chest and dorsolumbar spine revealed no abnormality and in particular no evidence of pulmonary, pleural, mediastinal, rib or spinal TB.
Intravitreal Bevacizumab (Avastin) in the Treatment of Proliferative Diabetic Retinopathy
Authors: Robert L. Avery, Joel Pearlman, Dante J. Pieramici, Melvin D. Rabena, Alessandro A. Castellarin, Ma’an A. Nasir, Matthew J. Giust, Robert Wendel, Arun Patel
Journal: Ophthalmology (2006)
Effect of new beta-adrenergic blocking agent, Atenolol (Tenormin), on pain frequency, trinitrin consumption, and exercise ability.
Authors: P Roy, L Day, E Sowton
Journal: BMJ (1975)

In 11 patients with severe angina pectoris a new beta-blocking drug, atenolol (Tenormin; I.C.I.66082), was found in a double-blind randomized trial to reduce significantly the frequency of anginal attacks (P less than 0-001) and the amount of trinitrin consumed (P less than 0-03) in comparison with practolol and placebo. There was no significant improvement in the patients9 ability to exercise on the bicycle ergometer.
Dynamic Characteristics of the Cardiovascular Autonomic Effects during Severe Arterial Hypoxia in the Unanesthetized Rabbit
Authors: PAUL I. KORNER, JOHN B. UTHER
Journal: Circulation Research (1969)

The reflex autonomic effects due to inhalation of low concentrations of oxygen (Pao 2 30 mm Hg) were assessed in unanesthetized rabbits from the differences in responses between groups of normal and autonomically "deefferented" rabbits and those with selective effector block. Changes due to autonomic effects were estimated for heart rate, total and regional (portal, renal, muscle, and cutaneous) peripheral resistance, and the rate of epinephrine secretion. The autonomic effects could be described by an early component having a time course similar to the initial vagal effects, where the maximum change occurred soon after the start of hypoxia and then declined to 37% of this value in 5 minutes, and a late component similar to the neural effects in muscle, starting 5 minutes after the start of hypoxia and rising slowly to 63% of the maximum in 15 minutes. Four autonomic effector patterns involving different combinations of early and late components were distinguished: (1) vasoconstriction in the portal and renal beds followed the time course of the sum of early and late components; (2) inhibition of cutaneous constrictor tone was the mirror image of the above response; (3) the biphasic sympathoadrenal effect on heart rate was the sum of a negative early and positive late component; (4) the neural constrictor effect in muscle and the rate of epinephrine secretion had only a late component. The early effects resulted in reduction in cardiac output and major redistribution of peripheral blood flow, probably due to chemoreceptor stimulation. During the late phase, cardiac output rose and blood flow was redistributed further, probably mainly through baroreceptor mechanisms.
Inflammatory responses predict long-term mortality risk in community-acquired pneumonia
Authors: C. Guertler, B. Wirz, M. Christ-Crain, W. Zimmerli, B. Mueller, P. Schuetz
Journal: European Respiratory Journal (2010)

Long-term outcomes in patients surviving community-acquired pneumonia (CAP) are still incompletely understood. This study investigates the association of clinical parameters and blood markers with long-term mortality. We prospectively followed 877 CAP patients from a previous multicentre trial for 18 months follow-up and investigated all-cause mortality following hospital discharge. Overall mortality was 17.3% (95% CI 14.8-19.8%) with a 12.8% (95% CI 10.9-15.0%) mortality incidence rate per year. Initial risk assignment using the Pneumonia Severity Index was accurate during the 18 month follow-up. Multivariable regression models (hazard ratio, 95% CI) designated the following as independent risk factors for long-term mortality: male sex (1.7, 1.2-2.5); chronic obstructive pulmonary disease (1.5, 1.1-2.1); neoplastic disease (2.5, 1.7-3.7); and highest quartile of peak pro-adrenomedullin level (3.3, 1.7-6.2). Initial presentation with temperature>38.7°C (0.4, 0.2-0.6), chills (0.6, 0.4-0.99) and highest quartile of the inflammatory marker C-reactive-protein (0.3, 0.2-0.5) were independent protective factors. A weighted risk score based on these variables showed good discrimination (area under receiver operating characteristic curve 0.78, 95% CI 0.74-0.82). Pronounced clinical and laboratory signs of systemic inflammatory host response upon initial hospital stay were associated with favourable long-term prognosis. Further studies should address whether closer monitoring of high-risk CAP patients after hospital discharge favourably impacts long-term mortality.
A Lamellar Unit of Aortic Medial Structure and Function in Mammals
Authors: HARVEY WOLINSKY, SEYMOUR GLAGOV
Journal: Circulation Research (1967)

The close association of elastin, collagen, and smooth muscle in the mammalian aortic media results in viscoelastic properties that account for many of its static and dynamic mechanical features. The structural components of the media are precisely oriented in concentric layers, or lamellar units, of fairly uniform composition. A comparative study of the adult thoracic aorta in 10 mammalian species, including 15 canine breeds, showed that the number of lamellar units in the media of adult mammalian aortas is very nearly proportional to aortic radius regardless of species or variations in measured wall thickness. Estimated wall tensions ranged from 7,820 dynes/cm in a 28-g mouse to 203,000 dynes/cm in a 200,000-g sow, but the average tension per lamellar unit of an aortic media was remarkably constant regardless of species, ranging from 1,090 to 3,010 dynes/cm. The findings suggest that the elastin lamella and the contents of its adjacent interlamellar zone represent the unit of structure and function of the mammalian aortic wall.
Football and altitude: a FIFA vision
Authors: Michel D'Hooghe
Journal: British Journal of Sports Medicine (2013)

In the world of football, the visiting national teams are sometimes confronted with different environmental conditions: heat, cold and different relative humidities are good examples, but the most important one is the practice of football at altitude.

In 2007, the Medical Committee of Federation Internationale de Football Association (FIFA) had organised a consensus meeting, with 12 international scientists, who have performed their own research in this respect. The consensus provided recommendations and guidelines …
Receptor Editing Occurs Frequently during Normal B Cell Development
Authors: Marc W. Retter, David Nemazee
Journal: The Journal of Experimental Medicine (1998)

Allelic exclusion is established in development through a feedback mechanism in which the assembled immunoglobulin (Ig) suppresses further V(D)J rearrangement. But Ig expression sometimes fails to prevent further rearrangement. In autoantibody transgenic mice, reactivity of immature B cells with autoantigen can induce receptor editing, in which allelic exclusion is transiently prevented or reversed through nested light chain gene rearrangement, often resulting in altered B cell receptor specificity. To determine the extent of receptor editing in a normal, non-Ig transgenic immune system, we took advantage of the fact that λ light chain genes usually rearrange after κ genes. This allowed us to analyze κ loci in IgMλ+ cells to determine how frequently in-frame κ genes fail to suppress λ gene rearrangements. To do this, we analyzed recombined VκJκ genes inactivated by subsequent recombining sequence (RS) rearrangement. RS rearrangements delete portions of the κ locus by a V(D)J recombinase-dependent mechanism, suggesting that they play a role in receptor editing. We show that RS recombination is frequently induced by, and inactivates, functionally rearranged κ loci, as nearly half (47%) of the RS-inactivated VκJκ joins were in-frame. These findings suggest that receptor editing occurs at a surprisingly high frequency in normal B cells.
CD11c depletion severely disrupts Th2 induction and development in vivo
Authors: Alexander T. Phythian-Adams, Peter C. Cook, Rachel J. Lundie, Lucy H. Jones, Katherine A. Smith, Tom A. Barr, Kristin Hochweller, Stephen M. Anderton, Günter J. Hämmerling, Rick M. Maizels, Andrew S. MacDonald
Journal: The Journal of Experimental Medicine (2010)

Although dendritic cells (DCs) are adept initiators of CD4+ T cell responses, their fundamental importance in this regard in Th2 settings remains to be demonstrated. We have used CD11c–diphtheria toxin (DTx) receptor mice to deplete CD11c+ cells during the priming stage of the CD4+ Th2 response against the parasitic helminth Schistosoma mansoni. DTx treatment significantly depleted CD11c+ DCs from all tissues tested, with 70–80% efficacy. Even this incomplete depletion resulted in dramatically impaired CD4+ T cell production of Th2 cytokines, altering the balance of the immune response and causing a shift toward IFN-γ production. In contrast, basophil depletion using Mar-1 antibody had no measurable effect on Th2 induction in this system. These data underline the vital role that CD11c+ antigen-presenting cells can play in orchestrating Th2 development against helminth infection in vivo, a response that is ordinarily balanced so as to prevent the potentially damaging production of inflammatory cytokines.
PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target
Authors: Jiarong Li, Andrew C. Karaplis, Dao C. Huang, Peter M. Siegel, Anne Camirand, Xian Fang Yang, William J. Muller, Richard Kremer
Journal: Journal of Clinical Investigation (2011)

Parathyroid hormone-related protein (PTHrP) is a secreted factor expressed in almost all normal fetal and adult tissues. It is involved in a wide range of developmental and physiological processes, including serum calcium regulation. PTHrP is also associated with the progression of skeletal metastases, and its dysregulated expression in advanced cancers causes malignancy-associated hypercalcemia. Although PTHrP is frequently expressed by breast tumors and other solid cancers, its effects on tumor progression are unclear. Here, we demonstrate in mice pleiotropic involvement of PTHrP in key steps of breast cancer - it influences the initiation and progression of primary tumors and metastases. Pthrp ablation in the mammary epithelium of the PyMT-MMTV breast cancer mouse model caused a delay in primary tumor initiation, inhibited tumor progression, and reduced metastasis to distal sites. Mechanistically, it reduced expression of molecular markers of cell proliferation (Ki67) and angiogenesis (factor VIII), antiapoptotic factor Bcl-2, cell-cycle progression regulator cyclin D1, and survival factor AKT1. PTHrP also influenced expression of the adhesion factor CXCR4, and coexpression of PTHrP and CXCR4 was crucial for metastatic spread. Importantly, PTHrP-specific neutralizing antibodies slowed the progression and metastasis of human breast cancer xenografts. Our data identify what we believe to be new functions for PTHrP in several key steps of breast cancer and suggest that PTHrP may constitute a novel target for therapeutic intervention.