tbuckley/cabot-search huggingface dataset:
Unknown Primary Head and Neck Squamous Cell Carcinoma: Molecular Identification of the Site of Origin
Authors: J. Califano, W. H. Westra, W. Koch, G. Meininger, A. Reed, L. Yip, J. O. Boyle, F. Lonardo, D. Sidransky
Journal: JNCI Journal of the National Cancer Institute (1999)

Unknown primary head and neck squamous cell carcinoma (HNSCC) presents as a cervical lymph node metastasis without identification of the primary tumor, despite thorough diagnostic work-up that includes physical examination, computed tomography, esophagoscopy, laryngoscopy, bronchoscopy, and multiple surveillance biopsies. We investigated whether the site of origin of the primary tumor could be localized in the upper aerodigestive tract mucosa by detection of genetic alterations identical to those found in metastatic lesions.Microsatellite analysis was performed on metastatic tumors obtained from 18 patients with unknown primary HNSCC. Histologically benign surveillance biopsy specimens were also analyzed. Patients were followed up to 13 years with continuing surveillance for primary mucosal tumors. Most patients were treated with neck dissection followed by radiation therapy to the affected neck and ipsilateral Waldeyer's ring.In 10 (55%) of the 18 patients, at least one histopathologically benign mucosal biopsy specimen from defined anatomic sites (i.e., most likely sites for an occult primary tumor) demonstrated a pattern of genetic alterations identical to that present in cervical lymph node metastases. One patient harboring genetic alterations in the base of the tongue and two patients harboring genetic alterations in a tonsillar fossa subsequently developed HNSCC in the identical or adjacent mucosal region; all three of the primary head and neck mucosal tumors that eventually appeared between 1 and 13 years later in these patients had genetic changes identical to those in the benign mucosal biopsy specimens and in the metastatic lymph nodes.These data support the hypothesis that histopathologically benign mucosa of the upper aerodigestive tract may harbor foci of clonal, preneoplastic cells that are genetically related to metastatic HNSCC and that such mucosal sites are the sites of origin of unknown primary HNSCC. Microsatellite analysis may represent a clinically useful tool for determining such sites.
Comparative efficacy and potency of ipratropium via Turbuhaler and pressurized metered-dose inhaler in reversible airflow obstruction
Authors: FG Bollert, SP Matusiewicz, MH Dewar, GM Brown, A McLean, AP Greening, GK Crompton
Journal: European Respiratory Journal (1997)

Ipratropium bromide (IB), typically delivered by pressurized metered dose inhaler (pMDI), is used to treat patients with reversible airways obstruction. Use of the pMDI, unlike the Turbuhaler (TH), demands co-ordination of actuation with inspiration for efficient use. Two studies were carried out to compare the relative efficacy and potency of IB delivered by TH or pMDI. Both studies were of a randomized, double-blind and cross-over design. For the efficacy study, 15 patients received a cumulative dose of 160 microg IB via TH or pMDI as doses of 20, 20, 40 and 80 microg at 45 min intervals on two days. Forced expiratory volume in one second (FEV1) was measured prior to and 40 min after dosing. For the potency study, 33 patients received 10, 20 or 40 microg of IB via TH, 20 microg IB via pMDI, or placebo, on five days. FEV1 was recorded prior to and 15-360 min after dosing. For the efficacy study, there was no difference in FEV1 response to a cumulative dose of IB via pMDI and TH. More than 80% of the maximum effect was seen at the lowest dose (20 microg of IB). Regarding the potency study, the FEV1 response to 20 microg IB administered via pMDI was similar to that of 10 microg via TH; 20 microg via TH was significantly more effective than 20 microg via pMDI (p&lt;0.05). In conclusion, the efficacy study showed that maximum FEV1 occurred at low doses of IB, negating any opportunity to identify differences between devices. The potency study indicated that the 10 microg dose via TH was of similar efficacy to the 20 microg dose via pMDI, confirming an efficacy ratio of 1.5-2.0:1 for the TH device.
Improvement of Aspirin-Intolerant Asthma by Montelukast, a Leukotriene Antagonist
Authors: SVEN-ERIK DAHLÉN, KERSTIN MALMSTRÖM, EWA NIZANKOWSKA, BARBRO DAHLÉN, PIOTR KUNA, MAREK KOWALSKI, WILLIAM R. LUMRY, CÉSAR PICADO, DONALD D. STEVENSON, JEAN BOUSQUET, ROMAIN PAUWELS, STEPHEN T. HOLGATE, ADITI SHAHANE, JI ZHANG, THEODORE F. REISS, ANDREW SZCZEKLIK
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Leukotriene antagonists block the proinflammatory actions of leukotrienes (LT) and have been introduced as new treatments for asthma. Conventional therapy with glucocorticosteroids does not inhibit the biosynthesis of leukotrienes. We therefore tested whether addition of the leukotriene receptor antagonist montelukast was of therapeutic benefit in a group of aspirin-intolerant patients with asthma of whom 90% already were treated with moderate to high doses of glucocorticosteroids. Under double-blind conditions, 80 aspirin-intolerant patients with asthma were randomized to receive 4 wk oral treatment of either 10 mg of montelukast or placebo once daily at bedtime. Pulmonary function was measured as forced expiratory volume in 1 s (FEV1) once a week in the clinic and daily as morning and evening peak expiratory flow rate (PEFR). Asthma symptoms and use of rescue bronchodilator were also recorded daily. Asthma specific quality of life (QoL) was assessed before and after the treatments. The group receiving montelukast showed a remarkable improvement of their asthma, whereas the group given placebo showed no change. Thus, from equal baseline values, the mean difference between the groups over the 4-wk treatment period was 10.2% for FEV1 and 28.0 L for morning PEFR (p for both < 0.001). The improved pulmonary function in the group receiving montelukast occurred at the same time as 27% less bronchodilator was used (p < 0.05), and it was associated with fewer asthma symptoms than in the group given placebo, including 1.3 nights more of sleep per week and 54% fewer asthma exacerbations (p < 0.05). There was also an improvement in asthma-specific QoL (p < 0.05). The therapeutic response to montelukast was consistent across patients with different baseline characteristics and did not correlate with baseline urinary LTE4. Addition of a leukotriene receptor antagonist such as montelukast improves asthma in aspirin-intolerant patients over and above what can be achieved by glucocorticosteroids.
Not so fast! Sick sinus syndrome is a complex and incompletely understood disease that might prove hard to model in animals
Authors: Gwilym Matthew Morris, Oliver Monfredi, Mark Richard Boyett
Journal: Cardiovascular Research (2011)

We read with great interest the paper by Herrmann et al .1 describing the effects of inducible HCN4-positive cell deletion in the mouse. This novel study using Cre- lox P adds to their previous work using this system to knock down HCN4 expression in adult mice and is a valuable contribution to unravelling the complexities of sinoatrial node (SAN) function and disease.1 The authors claim that their DTA/KiT mouse represents an accurate analogue of human sick sinus syndrome (SSS). For example, in the DTA/KiT mouse, following HCN4-positive cell deletion, there is a marked cell loss and fibrosis in the SAN. Literature is cited that alleges age-related degenerative fibrosis is the primary pathological mechanism of SSS. However, careful analysis of the published literature casts doubt on …
GERONTAL CONSTIPATION AND ITS TREATMENT
Authors: W. A. Hollis
Journal: BMJ (1916)

A. Prostatic EnlIrgement.IT lhas been estimated that 30 per cent. of men over 60 years ot age suffer from lhyperplasia of the prostate.If to these sufferers we add otlhers in wlhom a very large prostate "may give rise to no appreciable symptoms,' and miay consequently remain undiscovered, tlle total percentage of elderly nmen in wliom this organ is ab- normally large is probably still higlher.Situated as tlie prostate is between the bouy unyielding synmplhysis and the rectum, any general enlargement of the organ exerts a flattening piessure upon the gut wlhere it is in relation with the sacrum and coccyx.Tlle gerontal tumnotur will be in tlle upper rectum just below the sigmoid flexure, and close to one of the usual sites of intestinal stasis.During tlhe act of defaecation thje plastic cointents of tllm lower coloni require a free passage into tile rectum.A comparatively sliglht obstruction at tilis point may lead to a serious block.B. Ine ective Peristals is.Rec'ent investigations suggest tlhat, so far as the propul- sion of its conitents is concerned, tlle alimentary canal can
Coronary artery stenosis in rats affects β-adrenergic receptor signaling in myocytes
Authors: L Meggs
Journal: Cardiovascular Research (1997)

Objective: The purpose of this study was to determine whether the early chronic ischemic cardiomyopathy produced by non-occlusive coronary artery constriction was characterized by alterations in the regulation of β-adrenoreceptor (β-AR) signaling. Methods: Coronary artery narrowing was surgically induced in rats and the animals sacrified at 7 and 14 days. The changes in the biochemical properties of the multiple components of the β-AR pathway were examined in enzymatically dissociated myocytes. Results: Coronary stenosis, involving an average 55% reduction in luminal diameter, was associated with left ventricular failure and right ventricular dysfunction at both time intervals. A decrease in the quantity of β-AR was detected at 7 days and preceded the loss of high-affinity binding sites. This regulatory modification was characterized by a reduction in β1 and β2 receptors and a shift in the isoproterenol dose response curve indicating a functional correlation between the decrease in β-AR and attenuated inotropic support of the myocardium. The percentage of β-AR binding agonist with high affinity decreased significantly at 14 days along with a further reduction in the density of β1 and β2 receptors. Reconstitution studies with cyc−S49 lymphoma cells did not detect an impairment of Gsα functional activity, but the quantity of Giα was increased at both intervals. Finally, activation of the catalytic unit of adenylyl cyclase by forskolin and GTP was not altered by coronary stenosis, however, basal cyclic AMP in myocytes was depressed at 14 days. Conclusions: Coronary stenosis induces distinct and progressive modifications in the β-AR signaling cascade which may contribute to the impaired ventricular performance in this model of myocardial ischemia.
The ebb and flow of asthma
Authors: B G Toelle
Journal: Thorax (2005)

More studies reporting international time trends will put us in a better position to explain the changing prevalence of asthma

Without ever fully understanding the reasons for the global increase in the prevalence of asthma during the later part of the 20th century, we are now faced with the challenge of explaining an apparent decrease in prevalence. A challenge indeed! During the 1980s and early 1990s several repeat cross sectional studies, conducted in widely varying regions of the world, reported an increase in the prevalence of symptoms of asthma, diagnosed asthma, and medication use for asthma.1,2 Although most studies relied on self-reported symptoms and diagnoses—and hence could be subject to reporting bias—at least one3 observed substantial changes in airway hyperresponsiveness, lending credence to the view that this was not simply related to changes in disease classification and labelling. Parallel increases in hospitalisation rates4 and mortality rates5 also were consistent with a true rising tide of asthma. This trend led to major national and international initiatives to control the disease.6–9 …
Introduction of François M. Abboud
Authors: Michael J. Welsh
Journal: Journal of Clinical Investigation (2010)

President Kieff, President-Elect Collins, members, and guests of the Association, I am honored to present to you Dr. Francois M. Abboud, the recipient of the 2009 Kober Medal of the Association of American Physicians (Figure ​(Figure1).1). This is the Association’s highest award, given to individuals who have made transformational contributions to American medicine. 



Figure 1

Dr. Francois M. Abboud, 2009 Kober medalist.
Direct evidence that natural killer cells in nonimmune spleen cell populations prevent tumor growth in vivo
Authors: M Kasai, JC Leclerc, L McVay-Boudreau, FW Shen, H Cantor
Journal: The Journal of Experimental Medicine (1979)

Relatively large numbers of nonimmune spleen cells do not protect against the local growth of two lymphomas. However, this heterogeneous population of splenic lymphocytes contains a subset of cells that efficiently protects against in vivo tumor growth. This cell population (cell-surface phenotype Thyl.2(-)Ig(-)Ly5.1(+)) represents less than 5 percent of the spleen cell population and is responsible for in vitro NK-mediated lysis. Although these studies clearly and directly demonstrate that Ly5(+) NK cells selected from a heterogeneous lymphoid population from nonimmune mice can protect syngeneic mice against local in vivo growth of two different types of tumor cells (in contrast to other lymphocyte sets within the spleen), they do not directly bear upon the role of NK cells in immunosurveillance. They do indicate that highly enriched Ig(-)Thyl(-)Ly5(+) cells, which account for virtually all in vitro NK activity, can retard tumor growth in vivo. It is difficult to ascribe all anti-tumor surveillance activity to NK cells, because they probably do not recirculate freely throughout the various organ systems of the body. Perhaps NK ceils may play a role in prevention of neoplastic growth within discrete anatomic compartments where there is rapid differentiation of stem cells to mature progeny (e.g., bone marrow, spleen, and portions of the gastrointestinal tract)and may normally act to regulate the growth and differentiation of non-neoplastic stem cells. Long-term observation of chimeric mice repopulated with bone marrow from congenic or mutant donors expressing very low or very high NK activity may help to answer these questions.
Prognostic significance of von willebrand factor in cirrhosis: A possible mechanism
Authors: Chundamannil E. Eapen, Joshua E. Elias, Ian Mackie, Elwyn Elias
Journal: Hepatology (2013)

Ferlitsch et al. report on the utility of von Willebrand factor (vWF) in predicting portal hypertension (PH), decompensation, and death in patients with cirrhosis.1 We wish to comment on a potential mechanism to account for this association. Physiologically, vWF facilitates platelet adhesion at sites of endothelial damage. vWF is normally secreted by the endothelium as ultralarge vWF (ULvWF) multimers and cleaved into smaller forms by ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13).2 The presence of ULvWF multimers may reflect reduced ADAMTS13 activity. Decreased ADAMTS13 activity is associated with microvascular occlusion in thrombotic microangiopathies.2 If operative within the liver, these factors would potentially influence the natural history of liver disease, intensify PH,3 and thus account for their prognostic significance. We reported an association of gut disorders with idiopathic noncirrhotic intrahepatic PH (NCIPH), which results from portal venular obliteration.4 Serum levels of inflammatory cytokines, which are known to stimulate ULvWF multimer release and inhibit ADAMTS13 synthesis,5, 6 are elevated in patients with celiac disease.7 Therefore, we studied vWF/ADAMTS13 balance in NCIPH. We found ADAMTS13 deficiency and ULvWF multimers in NCIPH patients in both portal8 and portopulmonary9 hypertension and deduced that the above-described mechanisms may be causatively implicated. The assay used by Ferlitsch et al.1 would have detected all molecular sizes of vWF, without differentiating between them. It would be interesting to analyze whether ULvWF multimers and ADAMTS13 also have prognostic significance in these patients. CHUNDAMANNIL E. EAPEN, M.D., D.M.1 JOSHUA E. ELIAS, B.SC., M.B.CH.B.2 IAN MACKIE, B.SC., PH.D., FRCPATH3 ELWYN ELIAS, B.SC., M.D., FRCP4 1Hepatology Department, Christian Medical College, Vellore, India 2Department of Medicine, University Hospitals of Leicester, Leicester, UK 3Hemostasis Research Unit, Department of Hematology, University College London, London, UK 4Liver Unit, University Hospitals of, Birmingham, Birmingham, UK
Polymorphisms of the β<sub>2</sub>-Adrenergic Receptor and Asthma
Authors: STEPHEN B. LIGGETT
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Section:ChooseTop of pageAbstract <<IDENTIFICATION OF β2AR PO...IN VITRO PHENOTYPES OF β2...TRANSGENIC MOUSE STUDIESADDITIONAL CLINICAL STUDI...ReferencesCITING ARTICLES
Deep Brain Stimulation for Psychiatric Disorders
Authors: Paul E. Holtzheimer, Helen S. Mayberg
Journal: Annual Review of Neuroscience (2011)

Medications, psychotherapy, and other treatments are effective for many patients with psychiatric disorders. However, with currently available interventions, a substantial number of patients experience incomplete resolution of symptoms, and relapse rates are high. In the search for better treatments, increasing interest has focused on focal neuromodulation. This focus has been driven by improved neuroanatomical models of mood, thought, and behavior regulation, as well as by more advanced strategies for directly and focally altering neural activity. Deep brain stimulation (DBS) is one of the most invasive focal neuromodulation techniques available; data have supported its safety and efficacy in a number of movement disorders. Investigators have produced preliminary data on the safety and efficacy of DBS for several psychiatric disorders, as well. In this review, we describe the development and justification for testing DBS for various psychiatric disorders, carefully consider the available clinical data, and briefly discuss potential mechanisms of action.
Regulation of Id1 Expression by Src: Implications for Targeting of the Bone Morphogenetic Protein Pathway in Cancer
Authors: Oliver Gautschi, Clifford G. Tepper, Phillip R. Purnell, Yoshihiro Izumiya, Christopher P. Evans, Tim P. Green, Pierre Y. Desprez, Primo N. Lara, David R. Gandara, Philip C. Mack, Hsing-Jien Kung
Journal: Cancer Research (2008)

Abstract Deregulated activation of the Src tyrosine kinase and heightened Id1 expression are independent mediators of aggressive tumor biology. The present report implicates Src signaling as a critical regulator of Id1 gene expression. Microarray analyses showed that Id family genes were among the most highly down-regulated by incubation of A549 lung carcinoma cells with the small-molecule Src inhibitor AZD0530. Id1 transcript and protein levels were potently reduced in a dose-dependent manner concomitantly with the reduction of activated Src levels. These effects were conserved across a panel of lung, breast, prostate, and colon cancer cell lines and confirmed by the ability of PP2, Src siRNA, and Src-blocking peptides to suppress Id1 expression. PP2, AZD0530, and dominant-negative Src abrogated Id1 promoter activity, which was induced by constitutively active Src. The Src-responsive region of the Id1 promoter was mapped to a region 1,199 to 1,360 bps upstream of the translation start site and contained a Smad-binding element. Src was also required for bone morphogenetic protein-2 (BMP-2)–induced Id1 expression and promoter activity, was moderately activated by BMP-2, and complexed with Smad1/5. Conversely, Src inhibitors blocked Smad1/5 nuclear translocation and binding to the Src-responsive region of the Id1 promoter. Consistent with a role for Src and Id1 in cancer cell invasion, Src inhibitors and Id1 siRNA decreased cancer cell invasion, which was increased by Id1 overexpression. Taken together, these results reveal that Src positively interacts with the BMP-Smad-Id pathway and provide new ways for targeted inhibition of Id1. [Cancer Res 2008;68(7):2250–8]
S107 Explaining The Mortality Gap In Copd Patients After Myocardial Infarction: Data From The Uk Myocardial Ischaemia National Audit Project (minap)
Authors: K. Rothnie, L. Smeeth, E. Herrett, N. Pearce, H. Hemingway, A. Timmis, J. Wedzicha, J. Quint
Journal: Thorax (2014)

<h3>Introduction</h3> COPD patients are at increased risk of myocardial infarction (MI) and have increased mortality after an MI. Although some of this increased risk may be due to COPD itself, differences in management after an MI may play a role.<sup>1</sup> We therefore investigated whether the increased in-hospital and 180 day mortality for COPD patients could be explained by differences in in-hospital and discharge treatment. <h3>Methods</h3> Patients with a first MI between 2003–2013 were identified from the UK MINAP database. COPD patients had a record of obstructive airway disease, smoking history and were aged &gt;35 years. Logistic regression was used to compare mortality in-hospital and at 180 days post-discharge between COPD and non-COPD patients. All models were adjusted for age, sex, smoking, previous cardiovascular disease, renal failure, diabetes and cardiovascular drugs used on admission. Variables relating to in-hospital management (delay in diagnosis, use of reperfusion and time to reperfusion/use of angiography in-hospital) and use of secondary prevention on discharge were then sequentially added to models to assess the extent to which they explained the mortality difference. <h3>Results</h3> 300,146 patients with a first MI were identified. 34,027 (11.3%) had COPD. In-hospital mortality was greater for COPD patients after a STEMI (see Table 1), this difference was reduced after adjusting for in-hospital factors. Mortality was also greater for COPD patients at 180 days; this was not reduced after adjustment for in-hospital factors, but was reduced after adjusting for use of secondary prevention. In-hospital mortality was also greater for COPD patients after a non-STEMI, this was reduced after adjusting for in-hospital factors. Mortality at 180-days after a non-STEMI was greater for COPD patients, this was reduced after adjusting for in-hospital factors, but not after adjusting for use of secondary prevention. <h3>Conclusions</h3> Improved recognition and timely use of reperfusion treatments after a STEMI may significantly reduce the in-hospital mortality for COPD patients. Longer term mortality in COPD patients after a STEMI may be improved by increased use of secondary prevention drugs. Increased use of timely angiography may improve mortality for COPD patients after a non-STEMI. <h3>Reference</h3> Quint, JK <i>et al</i>. <i>BMJ</i>. 2013;347:f6650
Risk of cardiovascular disease in relation to achieved office and ambulatory blood pressure control in treated hypertensive subjects
Authors: Paolo Verdecchia, Gianpaolo Reboldi, Carlo Porcellati, Giuseppe Schillaci, Sergio Pede, Maurizio Bentivoglio, Fabio Angeli, Silvia Norgiolini, Giuseppe Ambrosio
Journal: Journal of the American College of Cardiology (2002)