tbuckley/cabot-search huggingface dataset:
Second Cancer Incidence and Cause-Specific Mortality Among 3104 Patients With Hairy Cell Leukemia: A Population-Based Study
Authors: Michie Hisada, Bingshu E. Chen, Elaine S. Jaffe, Lois B. Travis
Journal: JNCI Journal of the National Cancer Institute (2007)

The introduction of new treatments for hairy cell leukemia has resulted in improved patient survival but also engendered increasing concern about the possibility of excess second cancers. The available evidence is conflicting, with most risk estimates based on sparse numbers. To our knowledge, no study has evaluated cause-specific mortality in patients with hairy cell leukemia.We quantified second cancer incidence and cause-specific mortality among 3104 two-month survivors of hairy cell leukemia who were reported to 16 population-based registries in the Surveillance, Epidemiology and End Results (SEER) Program between 1973 and 2002. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were used to quantify the risk of second cancers and causes of death, respectively. The cumulative probability of a second cancer among survivors of hairy cell leukemia was calculated using a competing risk model. All statistical tests were two-sided.Mean follow-up of hairy cell leukemia survivors was 6.5 years (range, 2 months-29.3 years). Second cancer risk was statistically significantly elevated (SIR = 1.24, 95% confidence interval [CI] = 1.11 to 1.37) compared with the general population. Survivors had statistically significantly higher risks of Hodgkin lymphoma (SIR = 6.61, 95% CI = 2.13 to 15.42), non-Hodgkin lymphoma (SIR = 5.03, 95% CI = 3.77 to 6.58), and thyroid cancer (SIR = 3.56, 95% CI = 1.30 to 7.74) and a lower risk of lung cancer (SIR = 0.63, 95% CI = 0.42 to 0.90). The cumulative probability of all second cancers was estimated to be 31.9% (95% CI = 26.2 to 37.6) 25 years after hairy cell leukemia diagnosis. Among 10,000 hairy cell leukemia patients, a total excess of about 34 cancers, including 21 non-Hodgkin lymphomas, 2 Hodgkin lymphomas, and 7 solid tumors (including 2 thyroid cancers), might be observed per year. Deaths due to solid tumors were not elevated compared with the general population (SMR = 0.9), and there were statistically significant deficits in mortality due to both cardiovascular (SMR = 0.67, 95% CI = 0.56 to 0.80) and cerebrovascular (SMR = 0.61, 95% CI = 0.38 to 0.93) disease.Patients with hairy cell leukemia are at increased risk of Hodgkin lymphoma, non-Hodgkin lymphoma, and thyroid cancer. The decrease in lung cancer incidence and smoking-associated vascular mortality may reflect an inverse association of tobacco use with hairy cell leukemia. Future studies should address the roles of immunologic impairment inherent to hairy cell leukemia, treatment modalities, and other factors as codeterminants of morbidity and mortality in hairy cell leukemia survivors.
Monocyte tissue factor–dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin
Authors: A. Phillip Owens, Freda H. Passam, Silvio Antoniak, Stephanie M. Marshall, Allison L. McDaniel, Lawrence Rudel, Julie C. Williams, Brian K. Hubbard, Julie-Ann Dutton, Jianguo Wang, Peter S. Tobias, Linda K. Curtiss, Alan Daugherty, Daniel Kirchhofer, James P. Luyendyk, Patrick M. Moriarty, Shanmugam Nagarajan, Barbara C. Furie, Bruce Furie, Douglas G. Johns, Ryan E. Temel, Nigel Mackman
Journal: Journal of Clinical Investigation (2012)

Hypercholesterolemia is a major risk factor for atherosclerosis. It also is associated with platelet hyperactivity, which increases morbidity and mortality from cardiovascular disease. However, the mechanisms by which hypercholesterolemia produces a procoagulant state remain undefined. Atherosclerosis is associated with accumulation of oxidized lipoproteins within atherosclerotic lesions. Small quantities of oxidized lipoproteins are also present in the circulation of patients with coronary artery disease. We therefore hypothesized that hypercholesterolemia leads to elevated levels of oxidized LDL (oxLDL) in plasma and that this induces expression of the procoagulant protein tissue factor (TF) in monocytes. In support of this hypothesis, we report here that oxLDL induced TF expression in human monocytic cells and monocytes. In addition, patients with familial hypercholesterolemia had elevated levels of plasma microparticle (MP) TF activity. Furthermore, a high-fat diet induced a time-dependent increase in plasma MP TF activity and activation of coagulation in both LDL receptor–deficient mice and African green monkeys. Genetic deficiency of TF in bone marrow cells reduced coagulation in hypercholesterolemic mice, consistent with a major role for monocyte-derived TF in the activation of coagulation. Similarly, a deficiency of either TLR4 or TLR6 reduced levels of MP TF activity. Simvastatin treatment of hypercholesterolemic mice and monkeys reduced oxLDL, monocyte TF expression, MP TF activity, activation of coagulation, and inflammation, without affecting total cholesterol levels. Our results suggest that the prothrombotic state associated with hypercholesterolemia is caused by oxLDL-mediated induction of TF expression in monocytes via engagement of a TLR4/TLR6 complex.
Predicting the Development of Diabetes in Older Adults
Authors: Alka M. Kanaya, Christina L. Wassel Fyr, Nathalie de Rekeneire, Ronald I. Shorr, Ann V. Schwartz, Bret H. Goodpaster, Anne B. Newman, Tamara Harris, Elizabeth Barrett-Connor
Journal: Diabetes Care (2005)

OBJECTIVE— To create a simple prediction rule that could perform as well as the 2-h postchallenge plasma glucose (PCPG) test to predict those at risk for diabetes. We created a prediction rule in one sample and prospectively validated it for incident diabetes in a separate cohort. RESEARCH DESIGN AND METHODS— A cross-sectional analysis with data from the Rancho Bernardo Study (age 67 ± 11 years) to derive a rule predicting abnormal PCPG ≥140 mg/dl, using demographic, clinical, and laboratory data of nondiabetic participants with fasting plasma glucose (FPG) &amp;lt;126 mg/dl. Data from the Health, Aging and Body Composition study (age 74 ± 3 years) were used to prospectively validate this rule for incident diabetes and compare it with the predictive ability of the PCPG test. RESULTS— Of 1,549 RBS participants, 514 (33%) had PCPG ≥140 mg/dl. Female sex, age, triglycerides, and FPG were most significantly associated with abnormal PCPG. Based on standardized β-coefficients, we allotted 1 point for female sex, triglycerides ≥150 mg/dl, or FPG 95–104 mg/dl. Age ≥70 years or FPG 105–115 mg/dl were given 2 points, and FPG 116–125 mg/dl received 3 points. In the validation cohort, this simple prediction rule was as good as the 2-h PCPG test for predicting incident diabetes (C-statistic: 0.71 for both). CONCLUSIONS— Advanced age, female sex, FPG, and triglycerides were able to predict adults at risk for diabetes equally well as the 2-h PCPG test. Using this rule, clinicians may better identify older persons who should receive intensive lifestyle intervention to prevent type 2 diabetes.
Bleeding peptic ulcer--risk factors for rebleeding and sequential changes in endoscopic findings.
Authors: P I Hsu, X Z Lin, S H Chan, C Y Lin, T T Chang, J S Shin, L Y Hsu, C C Yang, K W Chen
Journal: Gut (1994)

From September 1991 to December 1992, a prospective study was conducted to determine the risk factors and residual risk of rebleeding, and the evolutionary endoscopic changes in peptic ulcers that rebled. Emergency endoscopies were performed on 452 patients with haematemesis or a melaena, or both within 24 hours of admission. If the lesions were actively bleeding, then the patients were treated with injection sclerotherapy. A multivariate analysis of clinical, laboratory, and endoscopic variables of 204 patients with ulcer bleeding showed that hypovolaemic shock, a non-bleeding visible vessel, and an adherent clot on the ulcer base were independently significant in predicting rebleeding (p < 0.05). Considering these three factors according to the estimates of their regression coefficients showed that a non-bleeding visible vessel was the strongest predictor of rebleeding. The study of the residual risk of rebleeding after admission showed that most rebleeding episodes (94.1%), including all associated with hypovolaemic shock, surgical treatment, and death, occurred within 96 hours of admission. After this time, the residual risk of rebleeding was less than 1%. Study of the changes in endoscopic findings before and after rebleeding illustrated that all ulcers with a visible vessel or adherent clot showed at follow up endoscopy were derived from ulcers with initial major stigmata. It is concluded that hypovolaemic shock, a non-bleeding visible vessel, and an adherent clot on an ulcer base are of independent significance in predicting rebleeding. Observation for 96 hours is sufficient to detect most rebleeding episodes after an initial bleed from peptic ulcer.
Progress Born From a Legacy of Collaboration
Authors: Melissa M. Hudson, William H. Meyer, Ching-Hon Pui
Journal: Journal of Clinical Oncology (2015)

This Special Series issue of Journal of Clinical Oncology highlights collaborative efforts that have contributed to the remarkable progress achieved in advancing survival for pediatric cancers. These efforts have involved collaborations across a variety of medical subspecialties, institutions, and national and international cooperative study groups and, most importantly, collaborations among clinicians, scientists, and patients and their families. Unique to the pediatric cancer experience is a high level of participation in clinical trials that has been instrumental in establishing effective therapies for virtually all types of pediatric cancers; characterizing acute, long-term, and late-onset toxicities of therapy; refining treatment approaches adapted to the biologic characteristics of the disease; and, in recent decades, modifying therapy to prevent treatment-related adverse effects. Particularly featured within this series are innovative and genomic discoveries that have guided risk-adapted stratification of therapy and use of targeted therapy providing real prospects for precision medicine.
ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction—Executive Summary
Authors: Elliott M. Antman, Daniel T. Anbe, Paul Wayne Armstrong, Eric R. Bates, Lee A. Green, Mary Hand, Judith S. Hochman, Harlan M. Krumholz, Frederick G. Kushner, Gervasio A. Lamas, Charles J. Mullany, Joseph P. Ornato, David L. Pearle, Michael A. Sloan, Sidney C. Smith, Elliott M. Antman, Sidney C. Smith, Joseph S. Alpert, Jeffrey L. Anderson, David P. Faxon, Valentin Fuster, Raymond J. Gibbons, Gabriel Gregoratos, Jonathan L. Halperin, Loren F. Hiratzka, Sharon Ann Hunt, Alice K. Jacobs, Joseph P. Ornato
Journal: Circulation (2004)
Metabolic peculiarities of Aspergillus niger disclosed by comparative metabolic genomics
Authors: Jibin Sun, Xin Lu, Ursula Rinas, An Zeng
Journal: Genome biology (2007)

Abstract Background Aspergillus niger is an important industrial microorganism for the production of both metabolites, such as citric acid, and proteins, such as fungal enzymes or heterologous proteins. Despite its extensive industrial applications, the genetic inventory of this fungus is only partially understood. The recently released genome sequence opens a new horizon for both scientific studies and biotechnological applications. Results Here, we present the first genome-scale metabolic network for A. niger and an in-depth genomic comparison of this species to seven other fungi to disclose its metabolic peculiarities. The raw genomic sequences of A. niger ATCC 9029 were first annotated. The reconstructed metabolic network is based on the annotation of two A. niger genomes, CBS 513.88 and ATCC 9029, including enzymes with 988 unique EC numbers, 2,443 reactions and 2,349 metabolites. More than 1,100 enzyme-coding genes are unique to A. niger in comparison to the other seven fungi. For example, we identified additional copies of genes such as those encoding alternative mitochondrial oxidoreductase and citrate synthase in A. niger , which might contribute to the high citric acid production efficiency of this species. Moreover, nine genes were identified as encoding enzymes with EC numbers exclusively found in A. niger , mostly involved in the biosynthesis of complex secondary metabolites and degradation of aromatic compounds. Conclusion The genome-level reconstruction of the metabolic network and genome-based metabolic comparison disclose peculiarities of A. niger highly relevant to its biotechnological applications and should contribute to future rational metabolic design and systems biology studies of this black mold and related species.
Laminar Shear Stress Upregulates the Complement-Inhibitory Protein Clusterin
Authors: Carmen Urbich, Michael Fritzenwanger, Andreas M. Zeiher, Stefanie Dimmeler
Journal: Circulation (2000)

Background —The complement system is implicated in the pathogenesis of atherosclerosis. Complement has been shown to activate endothelial cells (ECs) by inducing a proinflammatory response. Physiological levels of shear stress exert potent antiatherosclerotic effects. Therefore, we investigated whether shear stress antagonizes the effects of complement on ECs. Methods and Results —Incubation of ECs with nonlytic concentrations of complement serum (CS: 0.2 U/mL for 6 hours) resulted in an upregulation of interleukin-8 (IL-8) (165±12%) and monocyte chemoattractant protein-1 (MCP-1) mRNA expression (267±34%). Preexposure of ECs for 18 hours with laminar shear stress (15 dyne/cm 2 ) abrogated CS-induced IL-8 release to 106±10% ( P &lt;0.001) and reduced CS-induced MCP-1 expression (170±31%; P &lt;0.05). To examine the mechanism of the protective effect of shear stress, expression of the complement-inhibitory protein clusterin was analyzed under shear exposure. Shear stress increased clusterin mRNA (225±76%, 6 hours) and protein expression (164±22%, 18 hours). Specific inhibition of clusterin by transfection with antisense oligonucleotides reversed the protective effect of shear stress on CS-induced MCP-1 and IL-8 upregulation ( P &lt;0.05 versus sense-transfected cells). Moreover, clusterin overexpression inhibited CS-induced EC activation. Conclusions —Shear stress abrogates the complement-induced proinflammatory response of ECs by upregulation of the complement-inhibitory protein clusterin. Upregulation of clusterin may contribute to the potent antiatherosclerotic effects of shear stress by preventing endothelial activation through the complement cascade.
Notch3 Activation Promotes Invasive Glioma Formation in a Tissue Site-Specific Manner
Authors: Tarran J. Pierfelice, Karisa C. Schreck, Louis Dang, Laura Asnaghi, Nicholas Gaiano, Charles G. Eberhart
Journal: Cancer Research (2011)

Abstract Although Notch signaling has been widely implicated in neoplastic growth, direct evidence for in vivo initiation of neoplasia by the pathway in murine models has been limited to tumors of lymphoid, breast, and choroid plexus cells. To examine tumorigenic potential in the eye and brain, we injected retroviruses encoding activated forms of Notch1, Notch2, or Notch3 into embryonic mice. Interestingly, the majority of animals infected with active Notch3 developed proliferative lesions comprised of pigmented ocular choroid cells, retinal and optic nerve glia, and lens epithelium. Notch3-induced lesions in the choroid, retina, and optic nerve were capable of invading adjacent tissues, suggesting that they were malignant tumors. Although Notch3 activation induced choroidal tumors in up to 67% of eyes, Notch1 or Notch2 activation never resulted in such tumors. Active forms of Notch1 and Notch2 did generate a few small proliferative glial nodules in the retina and optic nerve, whereas Notch3 was 10-fold more efficient at generating growths, many of which were large invasive gliomas. Expression of active Notch1/Notch3 chimeric receptors implicated the RBPjk-association molecule and transactivation domains of Notch3 in generating choroidal and glial tumors, respectively. In contrast to our findings in the optic nerve and retina, introduction of active Notch receptors, including Notch3, into the brain never caused glial tumors. Our results highlight the differential ability of Notch receptor paralogs to initiate malignant tumor formation, and suggest that glial precursors of the optic nerve, but not the brain, are susceptible to transformation by Notch3. Cancer Res; 71(3); 1115–25. ©2011 AACR.
Mapping functional regions in the lumenal domain of the class II-associated invariant chain.
Authors: M J Bijlmakers, P Benaroch, H L Ploegh
Journal: The Journal of Experimental Medicine (1994)

The MHC class II-associated invariant chain interacts in trimeric form with class II molecules, inhibits peptide binding, and mediates targeting of class II molecules to endosomal compartments. To dissect the different functions of the invariant (Ii) chain, a set of cDNAs, encoding truncated forms of the Ii chain, was constructed. mRNAs, transcribed from these cDNAs were translated in vitro, together with mRNAs encoding class II HLA DR1 alpha and beta subunits. An Ii chain truncation that contains the 104 NH2-terminal amino acids was able to associate with class II molecules. This construct contains the region from which class II-associated Ii chain peptides (CLIP, amino acids 81-104) are derived. The absence of a further eight residues at the COOH terminus results in a construct of 96 amino acids that is unable to associate with class II molecules. Association of the truncated Ii chains with class II molecules showed a strict correlation with inhibition of peptide binding. Removal of the NH2-terminal cytoplasmic tail and transmembrane region of Ii chain and its replacement with a cleavable signal sequence led to aberrant folding and impaired association with class II molecules. The region between amino acids 163 and 183 was found to be essential for visualization of Ii chain homotrimers by covalent cross-linking.
Familial fundic gland polyposis with gastric cancer
Authors: Ritsuko Yanaru-Fujisawa, Shotaro Nakamura, Tomohiko Moriyama, Motohiro Esaki, Tadatoshi Tsuchigame, Masaki Gushima, Minako Hirahashi, Eishi Nagai, Takayuki Matsumoto, Takanari Kitazono
Journal: Gut (2011)

We read with interest the article by Worthley et al 1 regarding a new autosomal dominant syndrome characterised by fundic gland polyposis (FGP) and gastric cancer, which was not associated with familial adenomatous polyposis (FAP). We have experienced two similar cases of gastric adenocarcinoma occurring in pedigrees with familial FGP without FAP.

A 56-year-old woman was referred to our institution for further investigation of her multiple gastric polyps. On admission, serology and 13C urea breath test yielded negative results for Helicobacter pylori . Upper gastrointestinal endoscopy revealed numerous fundic gland polyps covering the …
Surgical Timing in Infectious Endocarditis
Authors: Ramin Farzaneh-Far, Ann F. Bolger
Journal: Circulation (2010)

ndocarditis is a rare and highly variable disease, with a dramatic mortality that has not improved significantly despite progress in diagnosis and treatment.Strategies for prevention and management have generally been based on relatively small, usually single-center, experiences or, in the case of prophylaxis guidelines, been extrapolated from animal models of disease.Randomized controlled studies are unavailable and seem unlikely to inform our practices any time soon.How can we hope to make better therapeutic choices and improve outcome in their absence?
Characterization of potential endocrine-related health effects at low-dose levels of exposure to PCBs.
Authors: A Brouwer, M P Longnecker, L S Birnbaum, J Cogliano, P Kostyniak, J Moore, S Schantz, G Winneke
Journal: Environmental Health Perspectives (1999)

This article addresses issues related to the characterization of endocrine-related health effects resulting from low-level exposures to polychlorinated biphenyls (PCBs). It is not intended to be a comprehensive review of the literature but reflects workshop discussions. "The Characterizing the Effects of Endocrine Disruptors on Human Health at Environmental Exposure Levels," workshop provided a forum to discuss the methods and data needed to improve risk assessments of endocrine disruptors. This article contains an overview of endocrine-related (estrogen and thyroid system) interactions and other low-dose effects of PCBs. The data set on endocrine effects includes results obtained from mechanistic methods/ and models (receptor based, metabolism based, and transport protein based), as well as from (italic)in vivo(/italic) models, including studies with experimental animals and wildlife species. Other low-dose effects induced by PCBs, such as neurodevelopmental and reproductive effects and endocrine-sensitive tumors, have been evaluated with respect to a possible causative linkage with PCB-induced alterations in endocrine systems. In addition, studies of low-dose exposure and effects in human populations are presented and critically evaluated. A list of conclusions and recommendations is included.
Islet dysfunction in insulin resistance involves impaired insulin secretion and increased glucagon secretion in postmenopausal women with impaired glucose tolerance.
Authors: H Larsson, B Ahrén
Journal: Diabetes Care (2000)

OBJECTIVE: To characterize in detail the association between insulin sensitivity and islet function in relation to glucose tolerance in nondiabetic subjects. RESEARCH DESIGN AND METHODS: The study included 108 postmenopausal women, aged 57-59 years, with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) and measured glucose tolerance (World Health Organization, 75 g glucose), insulin sensitivity (euglycemic-hyperinsulinemic clamp), and islet function (the 2-5 min insulin responses [AIR] and glucagon [AGR] responses to 5 g intravenous arginine at fasting, 14 and &amp;gt;25 mmol/l glucose levels). The product of insulin sensitivity and secretion was calculated (disposition index [DI]) and used to study the relationship between the two parameters. RESULTS: Insulin sensitivity and insulin secretion were highly inversely correlated in a hyperbolic manner (r &amp;gt; 0.64, P &amp;lt; 0.001) in women with NGT (n = 71). Women with IGT (n = 37) had reduced insulin sensitivity compared with women with NGT (P = 0.011). The AIRs were not appropriately increased in relation to the reduced insulin sensitivity in the IGT women, demonstrated as reduced DI in IGT compared with NGT (P &amp;lt; 0.001). Further, women with IGT had an increased AGR (P &amp;lt; 0.001) and a reduced glucose inhibition of glucagon secretion (slopeAGR, P = 0.014) compared with women with NGT. In a multivariate regression model including all of the 108 women, 2-h glucose was independently determined by the DI, the AGR, and the slopeAGR (r = 0.63, P &amp;lt; 0.001). CONCLUSIONS: We have shown that both the individual ability to adapt insulin secretion to the ambient insulin sensitivity and the level of glucagon secretion are important parameters for maintenance of NGT. Therefore, islet dysfunction in IGT involves low insulin and high glucagon secretion, which present potential targets for correcting impaired glycemia.