tbuckley/cabot-search huggingface dataset:
EMERGE: A Randomized Phase II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Advanced Glycoprotein NMB–Expressing Breast Cancer
Authors: Denise A. Yardley, Robert Weaver, Michelle E. Melisko, Mansoor N. Saleh, Francis P. Arena, Andres Forero, Tessa Cigler, Alison Stopeck, Dennis Citrin, Ira Oliff, Rebecca Bechhold, Randa Loutfi, Agustin A. Garcia, Scott Cruickshank, Elizabeth Crowley, Jennifer Green, Thomas Hawthorne, Michael J. Yellin, Thomas A. Davis, Linda T. Vahdat
Journal: Journal of Clinical Oncology (2015)

Glycoprotein NMB (gpNMB), a negative prognostic marker, is overexpressed in multiple tumor types. Glembatumumab vedotin is a gpNMB-specific monoclonal antibody conjugated to the potent cytotoxin monomethyl auristatin E. This phase II study investigated the activity of glembatumumab vedotin in advanced breast cancer by gpNMB expression.Patients (n = 124) with refractory breast cancer that expressed gpNMB in ≥ 5% of epithelial or stromal cells by central immunohistochemistry were stratified by gpNMB expression (tumor, low stromal intensity, high stromal intensity) and were randomly assigned 2:1 to glembatumumab vedotin (n = 83) or investigator's choice (IC) chemotherapy (n = 41). The study was powered to detect overall objective response rate (ORR) in the glembatumumab vedotin arm between 10% (null) and 22.5% (alternative hypothesis) with preplanned investigation of activity by gpNMB distribution and/or intensity (Stratum 1 to Stratum 3).Glembatumumab vedotin was well tolerated as compared with IC chemotherapy (less hematologic toxicity; more rash, pruritus, neuropathy, and alopecia). ORR was 6% (five of 83) for glembatumumab vedotin versus 7% (three of 41) for IC, without significant intertreatment differences for predefined strata. Secondary end point revealed ORR of 12% (10 of 83) versus 12% (five of 41) overall, and 30% (seven of 23) versus 9% (one of 11) for gpNMB overexpression (≥ 25% of tumor cells). Unplanned analysis showed ORR of 18% (five of 28) versus 0% (0 of 11) in patients with triple-negative breast cancer (TNBC), and 40% (four of 10) versus 0% (zero of six) in gpNMB-overexpressing TNBC.Glembatumumab vedotin is well tolerated in heavily pretreated patients with breast cancer. Although the primary end point in advanced gpNMB-expressing breast cancer was not met for all enrolled patients (median tumor gpNMB expression, 5%), activity may be enhanced in patients with gpNMB-overexpressing tumors and/or TNBC. A pivotal phase II trial (METRIC [Metastatic Triple-Negative Breast Cancer]) is underway.
Influence of postoperative enteral nutrition on postsurgical infections.
Authors: R Beier-Holgersen, S Boesby
Journal: Gut (1996)

This study was undertaken to test the hypothesis that early enteral nutrition might reduce the incidence of serious complications after major abdominal surgery.In a randomised double blind prospective trial 30 patients received Nutri-drink and 30 patients received placebo through a nasoduodenal feeding tube. On the day of operation the patients were given median 600 ml of either nutrition or placebo, 60 ml per hour. On the first postoperative day the patients received either 1000 ml (median) of nutrition or placebo, on day 2 1200 ml (median) nutrition, 1400 ml placebo, on day 3 1000 ml (median) nutrition, 1150 ml placebo, and on day 4 1000 ml (median) nutrition, 800 ml placebo. All patients were followed up for 30 days by the same investigator.The two groups were similar with regard to nutritional status and type of operation. The rate of postoperative infectious complications was significantly lower in the nutrition group, two of 30 compared with 14 of 30 in the placebo group (p = 0.0009).Early enteral nutrition given to patients after major abdominal surgery results in an important reduction in infectious complications.
Programmed Genetic Instability: A Tumor-Permissive Mechanism for Maintaining the Evolvability of Higher Species through Methylation-Dependent Mutation of DNA Repair Genes in the Male Germ Line
Authors: Y. Zhao, R. J. Epstein
Journal: Molecular Biology and Evolution (2008)

Tumor suppressor genes are classified by their somatic behavior either as caretakers (CTs) that maintain DNA integrity or as gatekeepers (GKs) that regulate cell survival, but the germ line role of these disease-related gene subgroups may differ. To test this hypothesis, we have used genomic data mining to compare the features of human CTs (n = 38), GKs (n = 36), DNA repair genes (n = 165), apoptosis genes (n = 622), and their orthologs. This analysis reveals that repair genes are numerically less common than apoptosis genes in the genomes of multicellular organisms (P < 0.01), whereas CT orthologs are commoner than GK orthologs in unicellular organisms (P < 0.05). Gene targeting data show that CTs are less essential than GKs for survival of multicellular organisms (P < 0.0005) and that CT knockouts often permit offspring viability at the cost of male sterility. Patterns of human familial oncogenic mutations confirm that isolated CT loss is commoner than is isolated GK loss (P < 0.00001). In sexually reproducing species, CTs appear subject to less efficient purifying selection (i.e., higher Ka/Ks) than GKs (P = 0.000003); the faster evolution of CTs seems likely to be mediated by gene methylation and reduced transcription-coupled repair, based on differences in dinucleotide patterns (P = 0.001). These data suggest that germ line CT/repair gene function is relatively dispensable for survival, and imply that milder (e.g., epimutational) male prezygotic repair defects could enhance sperm variation—and hence environmental adaptation and speciation—while sparing fertility. We submit that CTs and repair genes are general targets for epigenetically initiated adaptive evolution, and propose a model in which human cancers arise in part as an evolutionarily programmed side effect of age- and damage-inducible genetic instability affecting both somatic and germ line lineages.
cGMP-Dependent Protein Kinase I Mediates the Negative Inotropic Effect of cGMP in the Murine Myocardium
Authors: Jörg W. Wegener, Hermann Nawrath, Wiebke Wolfsgruber, Susanne Kühbandner, Claudia Werner, Franz Hofmann, Robert Feil
Journal: Circulation Research (2002)

To study the role of cGMP-dependent protein kinase I (cGKI) for cardiac contractility, force of contraction (F c ) was studied in electrically driven heart muscle from wild-type (WT) mice and from conventional and conditional cGKI knockout mice. Both 8-Br-cGMP and 8-pCPT-cGMP reduced Fc in cardiac muscle from juvenile WT but not from juvenile cGKI-null mutants. Similarly, the cGMP analogues reduced F c in forskolin-stimulated ventricular muscle from WT mice but not from cGKI-null mutants. In contrast, carbachol reduced F c in both groups of animals. 8-Br-cGMP reduced F c also in heart muscle from adult WT mice but not from adult cardiomyocyte-specific cGKI-knockout mice. These results demonstrate that cGKI mediates the negative inotropic effect of cGMP in the myocardium of juvenile and adult mice.
Mechanisms of Altered Ca <sup>2+</sup> Handling in Heart Failure
Authors: Min Luo, Mark E. Anderson
Journal: Circulation Research (2013)

Ca 2+ plays a crucial role in connecting membrane excitability with contraction in myocardium. The hallmark features of heart failure are mechanical dysfunction and arrhythmias; defective intracellular Ca 2+ homeostasis is a central cause of contractile dysfunction and arrhythmias in failing myocardium. Defective Ca 2+ homeostasis in heart failure can result from pathological alteration in the expression and activity of an increasingly understood collection of Ca 2+ homeostatic and structural proteins, ion channels, and enzymes. This review focuses on the molecular mechanisms of defective Ca 2+ cycling in heart failure and considers how fundamental understanding of these pathways may translate into novel and innovative therapies.
Continual Low-Level Activation of the Classical Complement Pathway
Authors: Anthony P. Manderson, Matthew C. Pickering, Marina Botto, Mark J. Walport, Christopher R. Parish
Journal: The Journal of Experimental Medicine (2001)

There is evidence that the classical complement pathway may be activated via a “C1-tickover” mechanism, analogous to the C3-tickover of the alternative pathway. We have quantitated and characterized this pathway of complement activation. Analysis of freshly collected mouse and human plasma revealed that spontaneous C3 activation rapidly occurred with the generation of C3 fragments in the plasma. By the use of complement- and Ig-deficient mice it was found that C1q, C4, C2, and plasma Ig were all required for this spontaneous C3 activation, with the alternative complement pathway further amplifying C3 fragment generation. Study of plasma from a human with C1q deficiency before and after therapeutic C1q infusion confirmed the existence of a similar pathway for complement activation in humans. Elevated levels of plasma C3 were detected in mice deficient in complement components required for activation of either the classical or alternative complement pathways, supporting the hypothesis that there is continuous complement activation and C3 consumption through both these pathways in vivo. Blood stasis was found to stimulate C3 activation by classical pathway tick-over. This antigen-independent mechanism for classical pathway activation may augment activation of the complement system at sites of inflammation and infarction.
Diagnostic and Predictive Accuracy of Blood Pressure Screening Methods With Consideration of Rescreening Intervals: A Systematic Review for the U.S. Preventive Services Task Force
Authors: Margaret A. Piper, Corinne V. Evans, Brittany U. Burda, Karen L. Margolis, Elizabeth O'Connor, Evelyn P. Whitlock
Journal: Annals of Internal Medicine (2014)

Background: Elevated blood pressure (BP) is the largest contributing risk factor to all-cause and cardiovascular mortality. Purpose: To update a systematic review on the benefits and harms of screening for high BP in adults and to summarize evidence on rescreening intervals and diagnostic and predictive accuracy of different BP methods for cardiovascular events. Data Sources: Selected databases searched through 24 February 2014. Study Selection: Fair- and good-quality trials and diagnostic accuracy and cohort studies conducted in adults and published in English. Data Extraction: One investigator abstracted data, and a second checked for accuracy. Study quality was dual-reviewed. Data Synthesis: Ambulatory BP monitoring (ABPM) predicted long-term cardiovascular outcomes independently of office BP (hazard ratio range, 1.28 to 1.40, in 11 studies). Across 27 studies, 35% to 95% of persons with an elevated BP at screening remained hypertensive after nonoffice confirmatory testing. Cardiovascular outcomes in persons who were normotensive after confirmatory testing (isolated clinic hypertension) were similar to outcomes in those who were normotensive at screening. In 40 studies, hypertension incidence after rescreening varied considerably at each yearly interval up to 6 years. Intrastudy comparisons showed at least 2-fold higher incidence in older adults, those with high-normal BP, overweight and obese persons, and African Americans. Limitation: Few diagnostic accuracy studies of office BP methods and protocols in untreated adults. Conclusion: Evidence supports ABPM as the reference standard for confirming elevated office BP screening results to avoid misdiagnosis and overtreatment of persons with isolated clinic hypertension. Persons with BP in the high-normal range, older persons, those with an above-normal body mass index, and African Americans are at higher risk for hypertension on rescreening within 6 years than are persons without these risk factors. Primary Funding Source: Agency for Healthcare Research and Quality.
Effects of Cognitive Training Interventions With Older Adults
Authors: Karlene Ball, Daniel B. Berch, Karin F. Helmers, Jared B. Jobe, Mary D. Leveck, Michael Marsiske, John N. Morris, George W. Rebok, David M. Smith, Sharon L. Tennstedt, Frederick W. Unverzagt, Sherry L. Willis, None for the ACTIVE Study Group
Journal: JAMA (2002)

ContextCognitive function in older adults is related to independent living and need for care. However, few studies have addressed whether improving cognitive functions might have short- or long-term effects on activities related to living independently.ObjectiveTo evaluate whether 3 cognitive training interventions improve mental abilities and daily functioning in older, independent-living adults.DesignRandomized, controlled, single-blind trial with recruitment conducted from March 1998 to October 1999 and 2-year follow-up through December 2001.Setting and ParticipantsVolunteer sample of 2832 persons aged 65 to 94 years recruited from senior housing, community centers, and hospital/clinics in 6 metropolitan areas in the United States.InterventionsParticipants were randomly assigned to 1 of 4 groups: 10-session group training for memory (verbal episodic memory; n = 711), or reasoning (ability to solve problems that follow a serial pattern; n = 705), or speed of processing (visual search and identification; n = 712); or a no-contact control group (n = 704). For the 3 treatment groups, 4-session booster training was offered to a 60% random sample 11 months later.Main Outcome MeasuresCognitive function and cognitively demanding everyday functioning.ResultsThirty participants were incorrectly randomized and were excluded from the analysis. Each intervention improved the targeted cognitive ability compared with baseline, durable to 2 years (P&lt;.001 for all). Eighty-seven percent of speed-, 74% of reasoning-, and 26% of memory-trained participants demonstrated reliable cognitive improvement immediately after the intervention period. Booster training enhanced training gains in speed (P&lt;.001) and reasoning (P&lt;.001) interventions (speed booster, 92%; no booster, 68%; reasoning booster, 72%; no booster, 49%), which were maintained at 2-year follow-up (P&lt;.001 for both). No training effects on everyday functioning were detected at 2 years.ConclusionsResults support the effectiveness and durability of the cognitive training interventions in improving targeted cognitive abilities. Training effects were of a magnitude equivalent to the amount of decline expected in elderly persons without dementia over 7- to 14-year intervals. Because of minimal functional decline across all groups, longer follow-up is likely required to observe training effects on everyday function.
Osteoarthritis development is induced by increased dietary cholesterol and can be inhibited by atorvastatin in APOE*3Leiden.CETP mice—a translational model for atherosclerosis
Authors: L M Gierman, S Kühnast, A Koudijs, E J Pieterman, M Kloppenburg, G J V M van Osch, V Stojanovic-Susulic, T W J Huizinga, H M G Princen, A-M Zuurmond
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> Hypercholesterolaemia, a risk factor for atherosclerosis (ATH), has been suggested to have a role in the development of osteoarthritis (OA). To test this hypothesis, the effect of cholesterol and different cholesterol-lowering treatments on OA was investigated in a mouse model resembling human lipoprotein metabolism. <h3>Methods</h3> Female ApolipoproteinE*3Leiden.human Cholesteryl Ester Transfer Protein mice received a western-type diet with 0.1% (w/w) cholesterol (LC), 0.3% (w/w) cholesterol alone (HC) or treated with 3 mg/kg/day atorvastatin or 0.3 mg/kg/day ezetimibe. One group remained on chow (control). After 39 weeks, OA grades of the knees and the extent of ATH were determined. Plasma cholesterol levels were measured throughout the study. <h3>Results</h3> LC and HC groups developed significantly more OA at the medial side than the control group in a dose-dependent manner. Atorvastatin but not ezetimibe treatment significantly suppressed OA development. As expected, features of ATH were significantly increased in the LC and HC groups compared with the control group and suppressed by atorvastatin (48%) and ezetimibe (55%) treatment. There were significant correlations between the development of OA on the medial side of the joint and cholesterol exposure (r=0.4) or ATH features (r=0.3). <h3>Conclusions</h3> Dietary cholesterol and accordingly increased plasma levels play a role in the development of OA. The correlation found between OA, cholesterol and ATH demonstrates that these variables are connected, but indicates the contribution of other ongoing processes in the development of OA. The suppressive effect on OA development of atorvastatin but not of ezetimibe, which had similar cholesterol exposure levels, corroborates these findings.
Prevention of respiratory complications after abdominal surgery: a randomised clinical trial
Authors: J. C Hall, R. A Tarala, J. Tapper, J. L Hall
Journal: BMJ (1996)

<h3>Abstract</h3> <b>Objective</b>: To evaluate the prevention of respiratory complications after abdominal surgery by a comparison of a global policy of incentive spirometry with a regimen consisting of deep breathing exercises for low risk patients and incentive spirometry plus physiotherapy for high risk patients. <b>Design</b>: Stratified randomised trial. <b>Setting</b>: General surgical service of an urban teaching hospital. <b>Patients</b>: 456 patients undergoing abdominal surgery. Patients less than 60 years of age with an American Society of Anesthesia classification of 1 were considered to be at low risk. <b>Outcome measures</b>: Respiratory complications were defined as clinical features consistent with collapse or consolidation, a temperature above 38°C, plus either confirmatory chest radiology or positive results on sputum microbiology. We also recorded the time that staff devoted to prophylactic respiratory therapy. <b>Results</b>: There was good baseline equivalence between the groups. The incidence of respiratory complications was 15% (35/231) for patients in the incentive spirometry group and 12% (28/225) for patients in the mixed therapy group (P=0.40; 95% confidence interval -3.6% to 9.0%). It required similar amounts of staff time to provide incentive spirometry and deep breathing exercises for low risk patients. The inclusion of physiotherapy for high risk patients, however, resulted in the utilisation of an extra 30 minutes of staff time per patient. <b>Conclusions</b>: When the use of resources is taken into account, the most efficient regimen of prophylaxis against respiratory complications after abdominal surgery is deep breathing exercises for low risk patients and incentive spirometry for high risk patients. <h3>Key messages</h3> Key messages Most postoperative respiratory complications were due to atelectasis: less than 1% of the patients developed pneumonia An American Society of Anesthesia classification &gt;1 and an age &gt;/=60 years is a simple way of defining patients at high risk of respiratory complications and other adverse events after abdominal surgery A regimen consisting of deep breathing exercises (low risk patients) and incentive spirometry (high risk patients) is an efficient way of providing prophylaxis against respiratory complications after abdominal surgery
Chronic myeloid leukaemia and tuberculosis in a patient with rheumatoid arthritis treated with infliximab
Authors: F Broussais
Journal: Annals of the Rheumatic Diseases (2004)

Cases of lymphoma and tuberculosis (TB) have been described in patients receiving tumour necrosis factor α (TNFα) inhibitors.1,2 We report a case of chronic myeloid leukaemia (CML) and TB, where molecular markers could be followed in a rheumatoid patient treated with infliximab.

A 56 year old white woman, with a 2 year history of refractory and destructive rheumatoid arthritis (RA), had been treated with methotrexate (MTX, 10 mg/week). As this was not effective, MTX was increased to 15 mg/week, and she received a total amount of about 1250 mg. Because of persistent active disease and high erythrocyte sedimentation rate (44 mm/1st h) with high platelet count at 0.6×1012/l, infliximab was combined with MTX (15 mg/week) in August 2001 at 3 mg/kg every 8 weeks.3 It should be noted that at that time TB prophylaxis before starting anti-TNFα treatment was not yet organised as it is today.

Although the disease improved, thrombocytosis, first considered as possibly related to inflammation, increased up to 1.1×1012/l in January 2002. Bone marrow aspiration demonstrated …
Cancer Cell Metabolism: One Hallmark, Many Faces
Authors: Jason R. Cantor, David M. Sabatini
Journal: Cancer Discovery (2012)

Abstract Cancer cells must rewire cellular metabolism to satisfy the demands of growth and proliferation. Although many of the metabolic alterations are largely similar to those in normal proliferating cells, they are aberrantly driven in cancer by a combination of genetic lesions and nongenetic factors such as the tumor microenvironment. However, a single model of altered tumor metabolism does not describe the sum of metabolic changes that can support cell growth. Instead, the diversity of such changes within the metabolic program of a cancer cell can dictate by what means proliferative rewiring is driven, and can also impart heterogeneity in the metabolic dependencies of the cell. A better understanding of this heterogeneity may enable the development and optimization of therapeutic strategies that target tumor metabolism. Significance: Altered tumor metabolism is now a generally regarded hallmark of cancer. Nevertheless, the recognition of metabolic heterogeneity in cancer is becoming clearer as a result of advancements in several tools used to interrogate metabolic rewiring and dependencies. Deciphering this context-dependent heterogeneity will supplement our current understanding of tumor metabolism and may yield promising therapeutic and diagnostic utilities. Cancer Discov; 2(10); 881–98. ©2012 AACR.
Diagnostic value of histology in non-erosive gastro-oesophageal reflux disease.
Authors: N E Schindlbeck, B Wiebecke, A G Klauser, W A Voderholzer, S A Muller-Lissner
Journal: Gut (1996)

BACKGROUND: In the absence of oesophageal erosions longterm pH monitoring is the present gold standard for diagnosing gastro-oesophageal reflux disease (GORD). This method, however, is invasive, time consuming, expensive, and not generally available. AIMS: As histological changes have been described in GORD, this study looked at the possibility of whether the diagnosis of non-erosive reflux disease could be made by histological examination routinely during endoscopy. SUBJECTS: A total of 24 prospectively selected patients with symptoms suggestive of GORD and seven healthy volunteers. METHODS: Oesophageal erosions and other peptic lesions were excluded by oesophago-gastroduodenoscopy. Oesophageal pinch biopsy specimens were taken 2 cm and 5 cm above the oesophagogastric junction and evaluated blindly for the histological parameters cellular infiltration, basal zone hyperplasia, and papillary length. Twenty four hour pH monitoring was used as gold standard for the definition of reflux disease. It was abnormal in 13 patients (reflux patients) and normal in 11 patients (symptomatic controls) and in seven healthy volunteers. RESULTS: Sparse infiltration of the epithelium with lymphocytes in at least one biopsy specimen was found in all patients and volunteers, with neutrophils in three reflux patients, and with eosinophils in two reflux patients and in two healthy volunteers. The basal zone thickness was increased in three reflux patients, in one symptomatic control, and in one healthy volunteer. The papillary length was greater than two thirds of total epithelium in six of 13 reflux patients in contrast with none in 11 symptomatic controls (p &lt; 0.05) and to one healthy volunteer. The sensitivity of the parameter papillary length hence was only 46%. CONCLUSIONS: Although gastro-oesophageal reflux produces slight histological changes apart from oesophageal erosions in a few subjects, none of the established histological parameters can fulfil the for the diagnosis of GORD in patients without visible oesophageal erosions.