tbuckley/cabot-search huggingface dataset:
Surgery's Relevance to an Understanding of Basic Biology
Authors: J. Englebert Dunphy
Journal: JAMA (1967)

When J. D. Watson received the Nobel Prize in medicine in 1962, a prize which he shared with Francis Crick and Maurice Wilkins, he demonstrated in his lecture at Stockholm that the synthesis of protein<sup>1</sup>required the ordered interaction of deoxyribonucleic acid and at least three types of functional ribonucleic acid. In the introduction he tells of the anxieties and concerns which he and Crick felt when they were first trying to elucidate the structure of DNA. He wrote, During the next eighteen months, until the structure became elucidated, we frequently discussed the necessity that the correct structure have a capacity for replication and, in pessimistic moods we often worried that the structure might be dull, that it would suggest absolutely nothing and excite us no more than something inert, like collagen. Watson's view of collagen is illustrative of the powerful vision of a great mind finding a new
The incidence of oesophageal adenocarcinoma in non-dysplastic Barrett's oesophagus: a meta-analysis
Authors: Tusar K Desai, Kumar Krishnan, Niharika Samala, Jashanpreet Singh, John Cluley, Subaiah Perla, Colin W Howden
Journal: Gut (2011)

<h3>Introduction</h3> The risk of oesophageal adenocarcinoma (OAC) in non-dysplastic Barrett9s oesophagus (BO) may have been overestimated. The objective was to estimate the incidence of OAC in patients with BO without dysplasia. <h3>Methods</h3> The authors searched MEDLINE and EMBASE from 1966 to 2011 and performed a bibliographic review of previous publications, excluding abstracts, non-peer-reviewed publications and those not published in English, for prospective or retrospective studies of the incidence of OAC in patients with BO. They excluded patients with any degree of dysplasia at baseline and those without documented intestinal metaplasia. Studies were independently reviewed by two individuals. 57 of 3450 studies were included. The authors extracted information on number of patients with BO, length of follow-up, incident cases of OAC, mean age of patients, country of origin, whether prospective or retrospective, mean length of BO segments and mortality from causes other than OAC. Study quality was assessed by the Ottawa Newcastle criteria. <h3>Results</h3> The 57 included studies comprised 11 434 patients and 58 547 patient-years of follow-up. The pooled annual incidence of OAC was 0.33% (95% CI 0.28% to 0.38%). Among 16 studies that provided appropriate information on mortality, there were 56 incident cases of OAC but 684 deaths from apparently unrelated causes. Among 16 studies that provided information on patients with short-segment BO, the annual incidence of OAC was only 0.19%. <h3>Conclusions</h3> The incidence of OAC in non-dysplastic BO is around 1 per 300 patients per year. The incidence of OAC in short-segment BO is under 1 per 500 patients per year.
Increased Susceptibility to LPS-induced Endotoxin Shock in Secretory Leukoprotease Inhibitor (SLPI)-deficient Mice
Authors: Akira Nakamura, Yuriko Mori, Koichi Hagiwara, Takuji Suzuki, Tomohiro Sakakibara, Toshiaki Kikuchi, Takayuki Igarashi, Masahito Ebina, Tatsuya Abe, Junichi Miyazaki, Toshiyuki Takai, Toshihiro Nukiwa
Journal: The Journal of Experimental Medicine (2003)

Secretory leukoprotease inhibitor (SLPI) protects tissue against the destructive action of neutrophil elastase at the site of inflammation. Recent studies on new functions of SLPI have demonstrated that SLPI may play a larger role in innate immunity than merely as a protease inhibitor. To clarify the functions of SLPI in bacterial infections, we generated SLPI-deficient mice (SLPI(-/-) mice) and analyzed their response to experimental endotoxin shock induced by lipopolysaccharide (LPS). SLPI(-/-) mice showed a higher mortality from endotoxin shock than did wild type mice. This may be explained in part by our observation that SLPI(-/-) macro-phages show higher interleukin 6 and high-mobility group (HMG)-1 production and nuclear factor kappaB activities after LPS treatment than do SLPI(+/+) macrophages. SLPI also affects B cell function. SLPI(-/-) B cells show more proliferation and IgM production after LPS treatment than SLPI(+/+) B cells. Our results suggest that SLPI attenuates excessive inflammatory responses and thus assures balanced functioning of innate immunity.
Molecular Gene Expression Profiling to Predict the Tissue of Origin and Direct Site-Specific Therapy in Patients With Carcinoma of Unknown Primary Site: A Prospective Trial of the Sarah Cannon Research Institute
Authors: John D. Hainsworth, Mark S. Rubin, David R. Spigel, Ralph V. Boccia, Samuel Raby, Raven Quinn, F. Anthony Greco
Journal: Journal of Clinical Oncology (2012)

Molecular tumor profiling is a promising diagnostic technique to determine the tissue of origin in patients with carcinoma of unknown primary site (CUP). However, the clinical value of these molecular predictions is unknown. We used tumor profiling results to direct site-specific therapy for patients with CUP.Tumor biopsy specimens from previously untreated patients with CUP were tested with a 92-gene reverse transcriptase polymerase chain reaction cancer classification assay. When a tissue of origin was predicted, patients who were treatment candidates received standard site-specific first-line therapy.Of 289 patients enrolled, 252 had successful assays performed, and 247 (98%) had a tissue of origin predicted. Sites most commonly predicted were biliary tract (18%), urothelium (11%), colorectal (10%), and non-small-cell lung (7%). Two hundred twenty-three patients were treatment candidates, and 194 patients received assay-directed site-specific treatment. In these 194 patients, the median survival time was 12.5 months (95% CI, 9.1 to 15.4 months). When the assay predicted tumor types that were clinically more responsive, the median survival was significantly improved when compared with predictions of more resistant tumors (13.4 v 7.6 months, respectively; P = .04).In this large prospective trial, molecular tumor profiling predicted a tissue of origin in most patients with CUP. The median survival time of 12.5 months for patients who received assay-directed site-specific therapy compares favorably with previous results using empiric CUP regimens. Patients with CUP predicted to have more responsive tumor types had longer survival compared with patients with less responsive tumor types. Molecular tumor profiling contributes to the management of patients with CUP and should be a part of their standard evaluation.
POST-EXPOSURE RABIES TREATMENT WITH FETAL BOVINE KIDNEY CELL VACCINE IN PEOPLE BITTEN BY ANIMALS WITH CONFIRMED RABIES
Authors: J. Fremont, C. Gaudiot, J.-P. Malo, A. Courrier, Ph. Simonnet, J. Arbogast, P. Sureau, P.E. Rollin, B. Fritzel, C. Louco, F.N. Marie
Journal: The Lancet (1984)
Mycobacterium xenopi pulmonary infections: a multicentric retrospective study of 136 cases in north-east France
Authors: C Andrejak, F-X Lescure, E Pukenyte, Y Douadi, Y Yazdanpanah, G Laurans, J-L Schmit, V Jounieaux
Journal: Thorax (2008)

Owing to its low incidence, the management of Mycobacterium xenopi pulmonary infections is not clearly defined. A multicentre retrospective study was performed to describe the features of the disease and to evaluate its prognosis.All patients with M xenopi satisfying the 1997 ATS/IDSA criteria from 13 hospitals in north-east France (1983-2003) were included in the study. Clinical, radiological and bacteriological characteristics and data on the management and outcome were collected.136 patients were included in the analysis, only 12 of whom presented with no co-morbidity. Three types of the disease were identified: (1) a classical cavitary form in patients with pre-existing pulmonary disease (n = 39, 31%); (2) a solitary nodular form in immunocompetent patients (n = 41, 33%) and (3) an acute infiltrate form in immunosuppressed patients (n = 45, 36%). 56 patients did not receive any treatment; the other 80 patients received first-line treatment containing rifamycin (87.5%), ethambutol (75%), isoniazid (66.2%), clarithromycin (30%) or fluoroquinolones (21%). After a follow-up of 36 months, 80 patients (69.1%) had died; the median survival was 16 months (range 10-22). Two independent prognostic factors were found: the acute infiltrate form was associated with a bad prognosis (hazard ratio 2.6, p = 0.001) and rifamycin-containing regimens provided protection (hazard ratio 0.325, p = 0.006). Clarithromycin-containing regimens did not improve the prognosis.In contrast to recent guidelines, this study showed three different types of the disease (cavitary, nodular or diffuse infiltrate forms) with a different prognosis. In order to improve survival, all patients with M xenopi infection should be treated with a rifamycin-containing regimen. The usefulness of clarithromycin remains to be evaluated.
Familial polyposis coli associated with extracolonic abnormalities
Authors: T. G. Parks, H. J. R. Bussey, H. E. Lockhart-Mummery
Journal: Gut (1970)

The pedigree of a polyposis coli family, in which several individuals had extracolonic abnormalities associated with the condition, is presented. Some of the problems encountered in management are discussed. The literature is reviewed and a simple classification of the extracolonic abnormalities is suggested.
Randomized, Controlled Dose-Ranging Study of the Selective Adenosine A <sub>2A</sub> Receptor Agonist Binodenoson for Pharmacological Stress as an Adjunct to Myocardial Perfusion Imaging
Authors: James E. Udelson, Gary V. Heller, Frans J.Th. Wackers, Andrew Chai, David Hinchman, Patrick S. Coleman, Vasken Dilsizian, Marcello DiCarli, Rory Hachamovitch, James R. Johnson, Richard J. Barrett, Raymond J. Gibbons
Journal: Circulation (2004)

Dipyridamole and adenosine cause frequent side effects as a result of nonspecific adenosine receptor stimulation. Selective agonism of the adenosine A2A receptor should result in a similar degree of coronary vasodilation (and thus similar perfusion images) with fewer side effects.In a multicenter, randomized, single-blind, 2-arm crossover trial, 240 patients underwent 2 single photon emission computed tomographic (SPECT) imaging studies in random order, first after pharmacological stress with adenosine and a second study with the selective adenosine A2A receptor agonist binodenoson, using 1 of 4 dosing regimens. Safety, tolerability, and SPECT image concordance between the 2 agents were examined. Exact categorical agreement in the extent and severity of reversible perfusion defects ranged from 79% to 87%, with kappa values from 0.69 to 0.85, indicating very good to excellent agreement between binodenoson and adenosine. The risk of any safety event/side effect was significantly lower with any dose of binodenoson than with adenosine (P< or =0.01) because of a dose-related reduction in subjective side effects, as objective events were infrequent. There was a reduction in the severity of chest pain, dyspnea, and flushing in all binodenoson doses compared with adenosine (P<0.01), and the magnitude of severity reduction was dose-related.The selective adenosine A2A receptor agonist binodenoson results in an extent and severity of reversible perfusion defects on SPECT imaging similar to nonselective adenosine receptor stimulation, accompanied by a dose-related reduction in the incidence and severity of side effects.
Erythropoietin promotes endothelial progenitor cell proliferative and adhesive properties in a PI 3-kinase-dependent manner
Authors: J GEORGE, E GOLDSTEIN, A ABASHIDZE, D WEXLER, S HAMED, H SHMILOVICH, V DEUTSCH, H MILLER, G KEREN, A ROTH
Journal: Cardiovascular Research (2005)

Patients with congestive heart failure (CHF) suffer considerable morbidity and mortality despite advances in therapy. Treatment with erythropoietin (Epo) has shown promise in CHF patients, yet its mechanisms of action remain elusive. Endothelial progenitor cells (EPC) contribute to postnatal angiogenesis and vasculogenesis, and Epo was shown to promote EPC mobilization. We explored the effect of chronic treatment with Epo on the numbers and functional properties of EPC in CHF patients.Twenty-eight patients with CHF treated with Epo for a mean period of 28 months were compared to a matched group (n = 28) with regard to the number of circulating hematopoietic and endothelial stem cells (either CD34+, CD34+/CD45+, CD34+/CD133+, CD34+/VEGF-R2+ or CD34+/CD133+/VEGF-R2+) as well as their proliferative and adhesive capacity. In vitro, Epo was added to cultured EPC from healthy subjects to test proliferation and adhesion. No differences were observed in circulating numbers of hematopoietic and endothelial stem cells between CHF patients chronically treated with Epo or untreated. EPC from Epo-treated patients exhibited enhanced proliferation as well as a trend towards adhesion to cultured endothelial cells prior to and following stimulation with TNF-alpha. Addition of Epo to EPC from healthy subjects dose-dependently increased their proliferation and adhesion to fibronectin, cultured endothelial cells, and cardiomyocytes. These effects were significantly reduced in the presence of phosphatidylinositol (PI) 3-kinase inhibitors.Chronic Epo treatment is associated with an increase in the adhesive and proliferative properties of circulating EPC in patients with CHF.
Cost-Effectiveness of Antiseptic-Impregnated Central Venous Catheters for the Prevention of Catheter-Related Bloodstream Infection
Authors: David L. Veenstra
Journal: JAMA (1999)

ContextA recent randomized controlled trial and meta-analysis indicated that central venous catheters impregnated with an antiseptic combination of chlorhexidine and silver sulfadiazine are efficacious in reducing the incidence of catheter-related bloodstream infection (CR-BSI); however, the ultimate clinical and economic consequences of their use have not been formally evaluated.ObjectiveTo estimate the incremental clinical and economic outcomes associated with the use of antiseptic-impregnated vs standard catheters.DesignDecision analytic model using data from randomized controlled trials, meta-analyses, and case-control studies, as well as safety data from the US Food and Drug Administration.Setting and PatientsA hypothetical cohort of hospitalized patients at high risk for catheter-related infections (eg, patients in intensive care units, immunosuppressed patients, and patients receiving total parenteral nutrition) requiring use of a central venous catheter.InterventionShort-term use (2-10 days) of chlorhexidine–silver sulfadiazine–impregnated multilumen central venous catheters and nonimpregnated catheters.Main Outcome MeasuresExpected incidence of CR-BSI and death attributable to antiseptic-impregnated and standard catheter use; direct medical costs for both types of catheters.ResultsIn the base-case analysis, use of antiseptic-impregnated catheters resulted in a decrease in the incidence of CR-BSI of 2.2% (5.2% for standard vs 3.0% for antiseptic-impregnated catheters), a decrease in the incidence of death of 0.33% (0.78% for standard vs 0.45% for antiseptic-impregnated), and a decrease in costs of $196 per catheter used ($532 for standard vs $336 for antiseptic-impregnated). The decrease in CR-BSI ranged from 1.2% to 3.4%, the decrease in death ranged from 0.09% to 0.78%, and the costs saved ranged from $68 to $391 in a multivariate sensitivity analysis.ConclusionOur analyses suggest that use of chlorhexidine–silver sulfadiazine–impregnated central venous catheters in patients at high risk for catheter-related infections reduces the incidence of CR-BSI and death and provides significant saving in costs. Use of these catheters should be considered as part of a comprehensive nosocomial infection control program.
The HIF-1α Hypoxia Response in Tumor-Infiltrating T Lymphocytes Induces Functional CD137 (4-1BB) for Immunotherapy
Authors: Asís Palazón, Iván Martínez-Forero, Alvaro Teijeira, Aizea Morales-Kastresana, Carlos Alfaro, Miguel F. Sanmamed, Jose Luis Perez-Gracia, Iván Peñuelas, Sandra Hervás-Stubbs, Ana Rouzaut, Manuel Ortiz de Landázuri, Maria Jure-Kunkel, Julian Aragonés, Ignacio Melero
Journal: Cancer Discovery (2012)

The tumor microenvironment of transplanted and spontaneous mouse tumors is profoundly deprived of oxygenation as confirmed by positron emission tomographic (PET) imaging. CD8 and CD4 tumor-infiltrating T lymphocytes (TIL) of transplanted colon carcinomas, melanomas, and spontaneous breast adenocarcinomas are CD137 (4-1BB)-positive, as opposed to their counterparts in tumor-draining lymph nodes and spleen. Expression of CD137 on activated T lymphocytes is markedly enhanced by hypoxia and the prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG). Importantly, hypoxia does not upregulate CD137 in hypoxia-inducible factor (HIF)-1α-knockout T cells, and such HIF-1α-deficient T cells remain CD137-negative even when becoming TILs, in clear contrast to co-infiltrating and co-transferred HIF-1α-sufficient T lymphocytes. The fact that CD137 is selectively expressed on TILs was exploited to confine the effects of immunotherapy with agonist anti-CD137 monoclonal antibodies to the tumor tissue. As a result, low-dose intratumoral injections avoid liver inflammation, achieve antitumor systemic effects, and permit synergistic therapeutic effects with PD-L1/B7-H1 blockade.CD137 (4-1BB) is an important molecular target to augment antitumor immunity. Hypoxia in the tumor microenvironment as sensed by the HIF-1α system increases expression of CD137 on tumor-infiltrating lymphocytes that thereby become selectively responsive to the immunotherapeutic effects of anti-CD137 agonist monoclonal antibodies as those used in ongoing clinical trials.
Insulin-Like Growth Factor Binding Protein–Related Protein 1 (IGFBP-rP1/MAC25) Is Linked to Endothelial-Dependent Vasodilation in High-Ferritin Type 2 Diabetes
Authors: Abel López-Bermejo, Javad Khosravi, Wifredo Ricart, Antoni Castro, Vivian Hwa, Katherine L. Pratt, Roser Casamitjana, Ron G. Rosenfeld, José Manuel Fernández-Real
Journal: Diabetes Care (2007)

Type 2 diabetes is characterized by variable degrees of vascular dysfunction (1,2). We have recently reported improved vasomotor responses in high-ferritin type 2 diabetic patients following bloodletting (3), an intervention that is believed to reduce the deleterious effects of circulating iron on vascular function (4,5).

Insulin-like growth factor binding protein–related protein 1 (IGFBP-rP1) is a 30 kDa modular glycoprotein known to be secreted by vascular and nonvascular cells (6–8). Besides its involvement in developmental processes and tumor growth (9,10), IGFBP-rP1 may play a role in the vasculature, given its abundance as an endothelial marker (11–13), its stimulatory actions on prostacyclin synthesis (7), and its vasodilatory effects on the retina of diabetic rats (14).

To our knowledge, no clinical studies have examined the role of serum IGFBP-rP1 as a vascular factor. We hypothesized that circulating IGFBP-rP1 is linked to the vasomotor responses that follow iron depletion in high-ferritin type 2 diabetes.

The study subjects ( n = 24 male patients, mean ± SD age 55.5 ± 8.1 years, BMI 29.1 ± 3.6 kg/m2, and A1C 6.2 ± 0.9%), are part of a well-characterized sample of high-ferritin type 2 diabetic patients subjected to bloodletting as previously reported by us (3,15). In the original cohort, 28 diabetic patients with elevated serum ferritin concentrations were randomized to either iron depletion (intervention group; n = 13) or to observation ( n = 15) according to a randomization table that included age, BMI, and A1C. The two groups were also matched for pharmacological treatment and chronic diabetes complications. The iron depletion intervention …
Lysophosphatidic Acid Induces Neointima Formation Through PPARγ Activation
Authors: Chunxiang Zhang, Daniel L. Baker, Satoshi Yasuda, Natalia Makarova, Louisa Balazs, Leonard R. Johnson, Gopal K. Marathe, Thomas M. McIntyre, Yong Xu, Glenn D. Prestwich, Hoe-Sup Byun, Robert Bittman, Gabor Tigyi
Journal: The Journal of Experimental Medicine (2004)

Neointimal lesions are characterized by accumulation of cells within the arterial wall and are a prelude to atherosclerotic disease. Here we report that a brief exposure to either alkyl ether analogs of the growth factor-like phospholipid lysophosphatidic acid (LPA), products generated during the oxidative modification of low density lipoprotein, or to unsaturated acyl forms of LPA induce progressive formation of neointima in vivo in a rat carotid artery model. This effect is completely inhibited by the peroxisome proliferator-activated receptor (PPAR)gamma antagonist GW9662 and mimicked by PPARgamma agonists Rosiglitazone and 1-O-hexadecyl-2-azeleoyl-phosphatidylcholine. In contrast, stearoyl-oxovaleryl phosphatidylcholine, a PPARalpha agonist and polypeptide epidermal growth factor, platelet-derived growth factor, and vascular endothelial growth factor failed to elicit neointima. The structure-activity relationship for neointima induction by LPA analogs in vivo is identical to that of PPARgamma activation in vitro and disparate from that of LPA G protein-coupled receptor activation. Neointima-inducing LPA analogs up-regulated the CD36 scavenger receptor in vitro and in vivo and elicited dedifferentiation of cultured vascular smooth muscle cells that was prevented by GW9662. These results suggest that selected LPA analogs are important novel endogenous PPARgamma ligands capable of mediating vascular remodeling and that activation of the nuclear transcription factor PPARgamma is both necessary and sufficient for neointima formation by components of oxidized low density lipoprotein.
Definition and taxonomy of interval colorectal cancers: a proposal for standardising nomenclature
Authors: S Sanduleanu, C M C le Clercq, E Dekker, G A Meijer, L Rabeneck, M D Rutter, R Valori, G P Young, R E Schoen
Journal: Gut (2014)

Interval colorectal cancers (interval CRCs), that is, cancers occurring after a negative screening test or examination, are an important indicator of the quality and effectiveness of CRC screening and surveillance. In order to compare incidence rates of interval CRCs across screening programmes, a standardised definition is required. Our goal was to develop an internationally applicable definition and taxonomy for reporting on interval CRCs.Using a modified Delphi process to achieve consensus, the Expert Working Group on interval CRC of the Colorectal Cancer Screening Committee of the World Endoscopy Organization developed a nomenclature for defining and characterising interval CRCs.We define an interval CRC as a "colorectal cancer diagnosed after a screening or surveillance exam in which no cancer is detected, and before the date of the next recommended exam". Guidelines and principles for describing and reporting on interval CRCs are provided, and clinical scenarios to demonstrate the practical application of the nomenclature are presented.The Working Group on interval CRC of the World Endoscopy Organization endorses adoption of this standardised nomenclature. A standardised nomenclature will facilitate benchmarking and comparison of interval CRC rates across programmes and regions.