tbuckley/cabot-search huggingface dataset:
Roux-en-y gastric bypass attenuates hepatic mitochondrial dysfunction in mice with non-alcoholic steatohepatitis
Authors: Jef Verbeek, Matthias Lannoo, Eija Pirinen, Dongryeol Ryu, Pieter Spincemaille, Ingrid Vander Elst, Petra Windmolders, Karin Thevissen, Bruno P A Cammue, Jos van Pelt, Sabine Fransis, Peter Van Eyken, Chantal Ceuterick-De Groote, Paul P Van Veldhoven, Pierre Bedossa, Frederik Nevens, Johan Auwerx, David Cassiman
Journal: Gut (2014)

<h3>Objective</h3> No therapy for non-alcoholic steatohepatitis (NASH) has been approved so far. Roux-en-y gastric bypass (RYGB) is emerging as a therapeutic option, although its effect on NASH and related hepatic molecular pathways is unclear from human studies. We studied the effect of RYGB on pre-existent NASH and hepatic mitochondrial dysfunction—a key player in NASH pathogenesis—in a novel diet-induced mouse model nicely mimicking human disease. <h3>Design</h3> C57BL/6J mice were fed a high-fat high-sucrose diet (HF-HSD). <h3>Results</h3> HF-HSD led to early obesity, insulin resistance and hypercholesterolaemia. HF-HSD consistently induced NASH (steatosis, hepatocyte ballooning and inflammation) with fibrosis already after 12-week feeding. NASH was accompanied by hepatic mitochondrial dysfunction, characterised by decreased mitochondrial respiratory chain (MRC) complex I and IV activity, ATP depletion, ultrastructural abnormalities, together with higher 4-hydroxynonenal (HNE) levels, increased uncoupling protein 2 (UCP2) and tumour necrosis factor-α (TNF-α) mRNA and free cholesterol accumulation. In our model of NASH and acquired mitochondrial dysfunction, RYGB induced sustained weight loss, improved insulin resistance and inhibited progression of NASH, with a marked reversal of fibrosis. In parallel, RYGB preserved hepatic MRC complex I activity, restored ATP levels, limited HNE production and decreased TNF-α mRNA. <h3>Conclusions</h3> Progression of NASH and NASH-related hepatic mitochondrial dysfunction can be prevented by RYGB. RYGB preserves respiratory chain complex activity, thereby restoring energy output, probably by limiting the amount of oxidative stress and TNF-α. These data suggest that modulation of hepatic mitochondrial function contributes to the favourable effect of RYBG on established NASH.
IGF-IR tyrosine kinase interacts with NPM-ALK oncogene to induce survival of T-cell ALK+ anaplastic large-cell lymphoma cells
Authors: Ping Shi, Raymond Lai, Quan Lin, Abid S. Iqbal, Leah C. Young, Larry W. Kwak, Richard J. Ford, Hesham M. Amin
Journal: Blood (2009)
Differentiation of hypothalamic-like neurons from human pluripotent stem cells
Authors: Liheng Wang, Kana Meece, Damian J. Williams, Kinyui Alice Lo, Matthew Zimmer, Garrett Heinrich, Jayne Martin Carli, Charles A. Leduc, Lei Sun, Lori M. Zeltser, Matthew Freeby, Robin Goland, Stephen H. Tsang, Sharon L. Wardlaw, Dieter Egli, Rudolph L. Leibel
Journal: Journal of Clinical Investigation (2015)

The hypothalamus is the central regulator of systemic energy homeostasis, and its dysfunction can result in extreme body weight alterations. Insights into the complex cellular physiology of this region are critical to the understanding of obesity pathogenesis; however, human hypothalamic cells are largely inaccessible for direct study. Here, we developed a protocol for efficient generation of hypothalamic neurons from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) obtained from patients with monogenetic forms of obesity. Combined early activation of sonic hedgehog signaling followed by timed NOTCH inhibition in human ESCs/iPSCs resulted in efficient conversion into hypothalamic NKX2.1+ precursors. Application of a NOTCH inhibitor and brain-derived neurotrophic factor (BDNF) further directed the cells into arcuate nucleus hypothalamic-like neurons that express hypothalamic neuron markers proopiomelanocortin (POMC), neuropeptide Y (NPY), agouti-related peptide (AGRP), somatostatin, and dopamine. These hypothalamic-like neurons accounted for over 90% of differentiated cells and exhibited transcriptional profiles defined by a hypothalamic-specific gene expression signature that lacked pituitary markers. Importantly, these cells displayed hypothalamic neuron characteristics, including production and secretion of neuropeptides and increased p-AKT and p-STAT3 in response to insulin and leptin. Our results suggest that these hypothalamic-like neurons have potential for further investigation of the neurophysiology of body weight regulation and evaluation of therapeutic targets for obesity.
Variation in <i>ITGB3</i> Is Associated with Asthma and Sensitization to Mold Allergen in Four Populations
Authors: Lauren A. Weiss, Lucille A. Lester, James E. Gern, Raoul L. Wolf, Rodney Parry, Robert F. Lemanske, Julian Solway, Carole Ober
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Recent genetic studies have implicated integrins in asthma and atopy susceptibility. We therefore evaluated the integrin-beta3 gene (ITGB3), an integrin gene within an asthma linkage peak on chromosome 17, as a candidate for susceptibility to asthma- and atopy-related phenotypes.We genotyped and performed association tests on 19 single nucleotide polymorphisms in ITGB3 in the Hutterites, a founder population, and in three outbred replication populations.Variation in ITGB3 was strongly associated with susceptibility to bronchial hyperresponsiveness and protection from allergic sensitization to mold allergens in this population. Three independent case-control populations representing Caucasians and African Americans were used to replicate this finding, also revealing ITGB3 alleles that are associated with asthma susceptibility and protection from mold allergen sensitization.This study provides evidence that ITGB3 plays a role in the pathogenesis of asthma and sensitization to mold allergens.
Adventitial CXCL1/G-CSF Expression in Response to Acute Aortic Dissection Triggers Local Neutrophil Recruitment and Activation Leading to Aortic Rupture
Authors: Atsushi Anzai, Masayuki Shimoda, Jin Endo, Takashi Kohno, Yoshinori Katsumata, Tomohiro Matsuhashi, Tsunehisa Yamamoto, Kentaro Ito, Xiaoxiang Yan, Kosuke Shirakawa, Ryoko Shimizu-Hirota, Yoshitake Yamada, Satoshi Ueha, Ken Shinmura, Yasunori Okada, Keiichi Fukuda, Motoaki Sano
Journal: Circulation Research (2015)

Rationale: In-hospital outcomes are generally acceptable in patients with type B dissection; however, some patients present with undesirable complications, such as aortic expansion and rupture. Excessive inflammation is an independent predictor of adverse clinical outcomes. Objective: We have investigated the underlying mechanisms of catastrophic complications after acute aortic dissection (AAD) in mice. Methods and Results: When angiotensin II was administered in lysyl oxidase inhibitor–preconditioned mice, AAD emerged within 24 hours. The dissection was initiated at the proximal site of the descending thoracic aorta and propagated distally into an abdominal site. Dissection of the aorta caused dilatation, and ≈70% of the mice died of aortic rupture. AAD triggered CXCL1 and granulocyte-colony stimulating factor expression in the tunica adventitia of the dissected aorta, leading to elevation of circulating CXCL1/granulocyte-colony stimulating factor levels. Bone marrow CXCL12 was reduced. These chemokine changes facilitated neutrophil egress from bone marrow and infiltration into the aortic adventitia. Interference of CXCL1 function using an anti-CXCR2 antibody reduced neutrophil accumulation and limited aortic rupture post AAD. The tunica adventitia of the expanded dissected aorta demonstrated high levels of interleukin-6 (IL-6) expression. Neutrophils were the major sources of IL-6, and CXCR2 neutralization significantly reduced local and systemic levels of IL-6. Furthermore, disruption of IL-6 effectively suppressed dilatation and rupture of the dissected aorta without any influence on the incidence of AAD and neutrophil mobilization. Conclusions: Adventitial CXCL1/granulocyte-colony stimulating factor expression in response to AAD triggers local neutrophil recruitment and activation. This leads to adventitial inflammation via IL-6 and results in aortic expansion and rupture.
Transbronchial needle aspiration in the diagnosis of mediastinal amyloidosis
Authors: V. Leiro-Fernandez, M. Botana-Rial, C. Represas, A. Fernandez-Villar
Journal: Thorax (2010)

We read with interest the pulmonary puzzle by Khor et al 1 on mediastinal lymph node amyloidosis diagnosed by direct real-time endobronchial ultrasound-guided (EBUS) transbronchial needle aspiration (TBNA). The development of EBUS-TBNA is improving the diagnostic yield of mediastinal lymphadenopathy.2 However, we offer some comments about the diagnostic approach used in the case described.

First, in our opinion, conventional TBNA continues …
Brief Communication: A Cancer Treatment Data Base System: A Feasibility Study2
Authors: G. McClatchie
Journal: JNCI Journal of the National Cancer Institute (1974)

The use of computer facilities in clinical data base systems allows the possibility of large accessible data banks with, if a network is available, a wide geographic coverage. Such ventures should not be undertaken without preceding feasibility studies and a thorough assimilation of previous relevant experience. This data base system is a large-scale, computer-dependent, prospective survey into the cancer treatment interaction in 3 hospitals. It is an output-optimizing system dealing explicitly with the major data processing problems of treatment multiplicity, the regular updating of existing records on file, and the need to define and record meaningful sets of response parameters. To date, the system has involved 2.5 man years of programming. It is presented as a study in feasibility.
VEGF-A Induces Angiogenesis by Perturbing the Cathepsin-Cysteine Protease Inhibitor Balance in Venules, Causing Basement Membrane Degradation and Mother Vessel Formation
Authors: Sung-Hee Chang, Keizo Kanasaki, Vasilena Gocheva, Galia Blum, Jay Harper, Marsha A. Moses, Shou-Ching Shih, Janice A. Nagy, Johanna Joyce, Matthew Bogyo, Raghu Kalluri, Harold F. Dvorak
Journal: Cancer Research (2009)

Tumors initiate angiogenesis primarily by secreting vascular endothelial growth factor (VEGF-A(164)). The first new vessels to form are greatly enlarged, pericyte-poor sinusoids, called mother vessels (MV), that originate from preexisting venules. We postulated that the venular enlargement necessary to form MV would require a selective degradation of their basement membranes, rigid structures that resist vascular expansion. To identify the specific proteases responsible for MV formation, we induced angiogenesis in mouse tissues with an adenoviral vector expressing VEGF-A(164) (Ad-VEGF-A(164)) or with VEGF-A-secreting TA3/St mammary tumors. We found that MV formation resulted from greatly increased activity of cathepsins (B>S>L) in venules transitioning into MV, as well as from a reciprocal decrease in the expression of several cysteine protease inhibitors (CPI), stefin A and cystatins B and C, by these same venules. Using a fluorescence probe that selectively binds cellular sites of cathepsin protease activity in vivo, we showed that increased cathepsin activity was localized exclusively to perivenular cells, not to venule endothelial cells. CPI strikingly inhibited angiogenesis in the Matrigel assay, and Ad-VEGF-A(164)-induced angiogenesis was reduced by approximately 50% in cathepsin B-null mice. Thus, VEGF-A, whether expressed by interstitial cells infected with an adenoviral vector or by tumor cells, upsets the normal cathepsin-CPI balance in nearby venules, leading to degradation of their basement membranes, an important first step in angiogenesis.
S‐adenosylmethionine in the chemoprevention and treatment of hepatocellular carcinoma in a rat model†
Authors: Shelly C. Lu, Komal Ramani, Xiaopeng Ou, Mark Lin, Victor Yu, Kwangsuk Ko, Ryan Park, Teodoro Bottiglieri, Hidekazu Tsukamoto, Gary Kanel, Samuel W. French, José M. Mato, Rex Moats, Edward Grant
Journal: Hepatology (2009)

Hepatocellular carcinoma (HCC) remains a common cancer worldwide that lacks effective chemoprevention or treatment. Chronic liver disease often leads to impaired hepatic S-adenosylmethionine (SAMe) biosynthesis, and mice with SAMe deficiency develop HCC spontaneously. SAMe is antiapoptotic in normal hepatocytes but proapoptotic in cancerous hepatocytes. The present study investigated SAMe's effectiveness in prevention and treatment of HCC. Two weeks after injecting 2.5 million H4IIE cells into the liver parenchyma of ACI rats, they typically form a 1-cm tumor. When SAMe (150 mg/kg/day) was delivered through continuous intravenous infusion, hepatic SAMe levels reached 0.7 mM (over 10-fold) 24 hours later. This regimen, started 1 day after injecting H4IIE cells and continued for 10 days, was able to reduce tumor establishment and growth. However, if intravenous SAMe was started after HCC had already developed, it was ineffective in reducing tumor growth for 24 days. Although plasma SAMe levels remained elevated, hepatic SAMe levels were minimally increased (30% higher). Chronic SAMe administration led to induction of hepatic methyltransferases, which prevented SAMe accumulation. To see if SAMe's preventive effect on tumor establishment involves angiogenesis, the effect of SAMe on angiogenesis genes was studied. SAMe treatment of H4IIE cells altered the expression of several genes with the net effect of inhibiting angiogenesis. These changes were confirmed at the protein level and functionally in human umbilical vein endothelial cells. Conclusion: SAMe is effective in preventing HCC establishment but ineffective in treating established HCC because of induction of hepatic methyltransferases, which prevents SAMe level to reach high enough to kill liver cancer cells. SAMe's chemopreventive effect may be related to its proapoptotic action and its ability to inhibit angiogenesis. (HEPATOLOGY 2009.)
Where's the beef? Evidence of culture, imitation, and teaching, in cetaceans?
Authors: Bennett G. Galef
Journal: Behavioral and Brain Sciences (2001)

Vocal imitation does not imply an ability to imitate nonvocal motor patterns. Exponential growth in frequency of a behaviour in a population does not imply diffusion by social learning. Distinguishing analogues from homologues of human culture will avoid confusion in discussion of evolution of culture. Original sources do not demonstrate social learning, imitation, or teaching of intentional beaching or lobtail feeding in cetaceans.
Pulmonary Arterial Hypertension
Authors: Vallerie V. McLaughlin, Michael D. McGoon
Journal: Circulation (2006)

ost practicing cardiologists see patients with pulmo- nary hypertension (PH) on a regular basis.Although this is most commonly in the form of pulmonary venous hypertension related to elevated left heart pressures, the explosion in knowledge of and treatment for pulmonary arterial hypertension (PAH) over the past decade obligates cardiologists to be more cognizant of this disorder.In this review, we will discuss the pathobiology, classification, diagnosis, and treatment of PAH in adults.The term PAH in this context refers specifically to a pulmonary hypertensive state limited predominantly to the arterial component of the pulmonary vasculature and constitutes one of the main classifications of clinical PH diseases.
Ethical, legal and social issues: out in the open
Authors: Rebecca F Furlong
Journal: Genome Medicine (2012)

The field of genomic medicine moves quickly, and previously unrealized ethical issues are becoming apparent as new technologies are invented, novel data emerge and clinical applications are established. In the three years since the launch of Genome Medicine, we have seen discussion panels at genomics conferences tackling such topics as return of research results to participants and physician education in the genomic era, while headlines have been made by the Genetic Information Nondiscrimination Act [1], the Myriad Genetics patent litigation [2], and the US Food and Drug Administration's take on direct-to-consumer testing[3].

Considerations of the ethical implications of genomic technologies and data are crucial to the implementation of genomic advances for improving human health. Work in the ethical, legal and social issues (ELSI) field does not always fit the standard Research article format, but broad, transparent access to these analyses and discussions is essential if they are to be integrated into the field of genomic medicine. In this issue of the journal, we introduce a peer-reviewed open-access article type, Open Debate, to accommodate novel and scholarly arguments that are informed by analysis and discussion, not just practical research. In the first article of this new type, Timothy Caulfield, Shawn Harmon and Yann Joly investigate the conflicts between open science and commercialization in genomics research [4].

Genomics has a culture of open data dating to before the time of the Human Genome Project, with the principles of accessibility formalized in the Bermuda agreement leading to an ongoing general principle that sequencing data should be released into the public domain as soon as possible after they are generated, and at least prior to publication. In the burgeoning field of medical sequencing, this principle has been tempered somewhat by considerations of patient privacy (a topic for another day), but as a rule, openness in genomics research continues to be both integral and essential. For example, it is hard to imagine how the recent explosion of genome-wide association studies, with their huge sample sizes, could have taken place without collaboration and data sharing. However, researchers are also increasingly encouraged to commercialize their research to speed product development and for monetary gain, which implies secrecy and competition. In their article, Caulfield and colleagues carry out an exploratory analysis of these two aspects of the policy guidelines from major funding bodies in the UK, US and Canada, concluding that these two opposing forces in genomics research may not be irreconcilable, but that a flexible middle way must be sought.

In the spirit of openness and fostering debate, we encourage our readers to use the Comments facility available on our website, or tweet @genomemedicine, to join in the discussion. The transition to genomic medicine is dependent upon the participation of researchers, ethicists, lawyers, clinicians and patients, and we'd like to hear your views.
S28 Neuromuscular electrical stimulation (NMES), a new strategy in the pulmonary rehabilitation of patients with severe and very severe MRC 4 and 5 Chronic Obstructive Pulmonary Disease (COPD): Abstract S28 Table 1.
Authors: K Akinlabi, E Main, R Garrod, A Harvey
Journal: Thorax (2013)

<h3>Introduction and Objectives</h3> Current National Institute of Clinical and Health Excellence (NICE) COPD guidelines (2010) recommend that pulmonary rehabilitation (PR) is made available to all appropriate people with COPD. However, house-bound patients with severe and very severe COPD (MRC 4/5) are not always able to access PR. This creates an inequality in access to health care. This pilot study investigated the effectiveness of home provision of neuromuscular electrical stimulation (NMES) and low-intensity symptom-limited exercise (LISLE) on exercise capacity and health related quality of life in severe and very severe COPD patients. <h3>Methods</h3> Patients with severe COPD (MRC 4 and 5) with a mean FEV<sub>1</sub> of 25% predicted ( ± 7.8) were randomised into two 16-session PR programmes, delivered twice weekly for 8 weeks. Group A received NMES and LISLE while Group B only received LISLE. Primary outcomes were the six minute walk test (6MWT) and the St George9s respiratory questionnaire (SGRQ). Secondary outcomes were the London Chest Activity of Daily Living Scale (LCADL), and the Hospital Anxiety and Depression Scale (HADS). <h3>Results</h3> Ten patients (5 males) with severe COPD were recruited (mean age: 76 years ± 7.7, BMI: 26 ± 4, MRC: 5 ± 0.3, FEV<sub>1</sub>:25 ± 7.8). There were no significant between-group differences in the 6MWT, SGRQ or HADS (p &gt; 0.05), but there was a significant improvement in LCADL in group A compared with group B (median difference: -12 vs -1, p &lt; 0.001). Within-groups, there were significant improvements in the 6MWT, SGRQ and LCADL scores in both groups A &amp; B, but no change in the HADS. Within-groups, improvements in the 6MWT and LCADL were likely to be clinically important in group A alone (Table 1). <h3>Conclusion</h3> This study showed that a combination of NMES with LISLE resulted in largely similar improvements to LISLE alone. The addition of NMES may be more effective in improving activities of daily living and exercise tolerance but the cost of providing equipment and specialist staff for delivering this individualised home treatment must be weighed against the clinical benefits. <b>Changes in Primary and secondary outcome measures</b> All changes in outcome measures are explained below and recorded as shown below in Table 1.
Radiotherapy in Arthritis
Authors: M. H. L. Desmarais
Journal: Annals of the Rheumatic Diseases (1953)

Since the discovery of x rays by Roentgen in 1895 we have witnessed great advances in their applica- tion to diagnosis and therapy.In the field of therapy the main effort has been directed towards the cure of malignant diseases, but in the literature we find that this agent has also been applied for many years to the treatment of non-malignant conditions.Sokolow (1897) and Stenbeck (1898) were the first to use x rays in the treatment of joint diseases.Since then many encouraging but conflicting reports regarding the value of x rays in different arthritic conditions have been published, but most of these, except for those of Smyth and others (1941) and Kuhns and Morrison (1946), were not based on carefully controlled experiments.The various authors agreed about the beneficial effects of x rays in ankylosing spondylitis and osteo-arthritis, but they were not in agreement regarding their results in rheumatoid arthritis.Smyth stated that in rheuma- toid arthritis the results were unpredictable and unreliable, and in general, so discouraging that this form of treatment was abandoned altogether, except in rare and obstinate cases in which a psychic effect was desirable.Kuhns and Morrison, on the other hand, in a small controlled series, reported an improvement in 79 per cent. of their rheumatoid cases.The present work was prompted by these con- flicting reports, and a clinical experiment was planned and carried out under strictly controlled conditions in order to assess the value of different dosages of x rays in osteo-arthritis, rheumatoid arthritis, and ankylosing spondylitis.Methods Accordingly, cases coming under treatment were allocated to different dosage groups by random sampling, and treated either by low voltage therapy (L.V.T.) or by high voltage therapy (H.V.T.), using small doses (A),