tbuckley/cabot-search huggingface dataset:
Genetic and Pharmacological Inactivation of the Purinergic P2RX7 Receptor Dampens Inflammation but Increases Tumor Incidence in a Mouse Model of Colitis-Associated Cancer
Authors: Paul Hofman, Julien Cherfils-Vicini, Marie Bazin, Marius Ilie, Thierry Juhel, Xavier Hébuterne, Eric Gilson, Annie Schmid-Alliana, Olivier Boyer, Sahil Adriouch, Valérie Vouret-Craviari
Journal: Cancer Research (2015)

Colitis-associated cancer (CAC) is a complication of inflammatory bowel disease (IBD). Binding of extracellular ATP to the purinergic receptor P2RX7 has emerged as a critical event in controlling intestinal inflammation, acting to limit elevation of proinflammatory mast cells and cytokines and promote survival of regulatory T cells (Treg) and enteric neurons. In this study, we investigated the effect of P2RX7 blockade in an established mouse model of CAC. Using genetic and pharmacologic tools, we found unexpectedly that while P2RX7 mediated inflammatory responses, it also acted at an early time to suppress CAC development. P2RX7 blockade enhanced proliferation of intestinal epithelial cells and protected them from apoptosis. The proliferative effects of P2RX7 blockade were associated with an increased production of TGFβ1 that was sufficient to stimulate the proliferation of intestinal epithelial cells. Finally, P2RX7 blockade also altered immune cell infiltration and promoted Treg accumulation within lesions of the digestive system. Taken together, our findings reveal an unexpected role for P2RX7 in preventing CAC, suggesting cautions in the use of P2RX7 inhibitors to treat IBD given the possibility of increasing risks CAC as a result.
Calmodulin Kinase II and Arrhythmias in a Mouse Model of Cardiac Hypertrophy
Authors: Yuejin Wu, Joel Temple, Rong Zhang, Igor Dzhura, Wei Zhang, Robert Trimble, Dan M. Roden, Robert Passier, Eric N. Olson, Roger J. Colbran, Mark E. Anderson
Journal: Circulation (2002)

Calmodulin kinase (CaMK) II is linked to arrhythmia mechanisms in cellular models where repolarization is prolonged. CaMKII upregulation and prolonged repolarization are general features of cardiomyopathy, but the role of CaMKII in arrhythmias in cardiomyopathy is unknown.We studied a mouse model of cardiac hypertrophy attributable to transgenic (TG) overexpression of a constitutively active form of CaMKIV that also has increased endogenous CaMKII activity. ECG-telemetered TG mice had significantly more arrhythmias than wild-type (WT) littermate controls at baseline, and arrhythmias were additionally increased by isoproterenol. Arrhythmias were significantly suppressed by an inhibitory agent targeting endogenous CaMKII. TG mice had longer QT intervals and action potential durations than WT mice, and TG cardiomyocytes had frequent early afterdepolarizations (EADs), a hypothesized mechanism for triggering arrhythmias. EADs were absent in WT cells before and after isoproterenol, whereas EAD frequency was unaffected by isoproterenol in TG mice. L-type Ca2+ channels (LTTCs) can activate EADs, and LTCC opening probability (Po) was significantly higher in TG than WT cardiomyocytes before and after isoproterenol. A CaMKII inhibitory peptide equalized TG and WT LTCC Po and eliminated EADs, whereas a peptide antagonist of the Na+/Ca2+ exchanger current, also hypothesized to support EADs, was ineffective.These findings support the hypothesis that CaMKII is a proarrhythmic signaling molecule in cardiac hypertrophy in vivo. Cellular studies point to EADs as a triggering mechanism for arrhythmias but suggest that the increase in arrhythmias after beta-adrenergic stimulation is independent of enhanced EAD frequency.
Sulfation of acetaminophen by the perfused rat liver: The effect of red blood cell carriage
Authors: Sandy K. Pang, Ford Barker, Andre Simard, Andreas J. Schwab, Carl A. Goresky
Journal: Hepatology (1995)

Acetaminophen uptake and conversion in the perfused rat liver to acetaminophen sulfate was studied with the multiple indicator dilution technique (MID). Because acetaminophen is avidly bound to red blood cells and not albumin, a pre-equilibrated MID dose containing the noneliminated references (51Cr-labeled red blood cells [RBC, a vascular reference], [58Co]EDTA [a small molecular weight interstitial reference that does not enter cells], and D2O [a cellular reference]) and [3H]-acetaminophen was introduced into the portal vein of the single-pass perfused rat liver (1 mg/L acetaminophen) under varying conditions of hematocrit, with observation of timed outflow profiles in the hepatic venous blood. The [3H]acetaminophen curve exhibited an early high peak, paralleling that for red cells and varying with hematocrit, followed by a prolonged decline, with the late appearance of acetaminophen sulfate product; the early peak disappeared when red cells were absent from the dose and perfusate. Analysis demonstrated a slow release of acetaminophen from the red blood cells and rapid liver cell entry, so that red cell binding was displayed as a red cell carriage effect that reduced the rate of liver cell entry and hence of sulfation of [3H]-acetaminophen. The liver cells exhibited a concomitant very low permeability to product acetaminophen sulfate, leading to protracted product outflow curves. An inferred slow efflux-mediated storage phenomenon for product was found to evolve as a result.
Fecal Contamination of Drinking-Water in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis
Authors: Robert Bain, Ryan Cronk, Jim Wright, Hong Yang, Tom Slaymaker, Jamie Bartram
Journal: PLoS Medicine (2014)

Robert Bain and colleagues conduct a systematic review and meta-analysis to assess whether water from "improved" sources is less likely to contain fecal contamination than "unimproved" sources and find that access to an "improved source" provides a measure of sanitary protection but does not ensure water is free of fecal contamination. Please see later in the article for the Editors' Summary
An Evidence-Based Discussion of Heading the Ball and Concussions in High School Soccer
Authors: R. Dawn Comstock, Dustin W. Currie, Lauren A. Pierpoint, Joseph A. Grubenhoff, Sarah K. Fields
Journal: JAMA Pediatrics (2015)

<h3>Importance</h3> Soccer, originally introduced as a safer sport for children and adolescents, has seen a rapid increase in popularity in the United States over the past 3 decades. Recently, concerns have been raised regarding the safety of soccer ball heading (when an athlete attempts to play the ball in the air with his or her head) given the rise in concussion rates, with some calling for a ban on heading among soccer players younger than 14 years. <h3>Objectives</h3> To evaluate trends over time in boys' and girls' soccer concussions, to identify injury mechanisms commonly leading to concussions, to delineate soccer-specific activities during which most concussions occur, to detail heading-related soccer concussion mechanisms, and to compare concussion symptom patterns by injury mechanism. <h3>Design, Setting, and Participants</h3> Retrospective analysis of longitudinal surveillance data collected from 2005-2006 through 2013-2014 in a large, nationally representative sample of US high schools. Participants were boys and girls who were high school soccer players. <h3>Exposures</h3> Concussions sustained during high school–sanctioned soccer games and practices. <h3>Main Outcomes and Measures</h3> Mechanism and sport-specific activity of concussion. <h3>Results</h3> Overall, 627 concussions were sustained during 1 393 753 athlete exposures (AEs) among girls (4.50 concussions per 10 000 AEs), and 442 concussions were sustained during 1 592 238 AEs among boys (2.78 concussions per 10 000 AEs). For boys (68.8%) and girls (51.3%), contact with another player was the most common concussion mechanism. Heading was the most common soccer-specific activity, responsible for 30.6% of boys' concussions and 25.3% of girls' concussions. Contact with another player was the most common mechanism of injury in heading-related concussions among boys (78.1%) and girls (61.9%). There were few differences in concussion symptom patterns by injury mechanism. <h3>Conclusions and Relevance</h3> Although heading is the most common activity associated with concussions, the most frequent mechanism was athlete-athlete contact. Such information is needed to drive evidence-based, targeted prevention efforts to effectively reduce soccer-related concussions. Although banning heading from youth soccer would likely prevent some concussions, reducing athlete-athlete contact across all phases of play would likely be a more effective way to prevent concussions as well as other injuries.
A Functional Genomics Strategy Reveals Rora as a Component of the Mammalian Circadian Clock
Authors: Trey K. Sato, Satchidananda Panda, Loren J. Miraglia, Teresa M. Reyes, Radu D. Rudic, Peter McNamara, Kinnery A. Naik, Garret A. FitzGerald, Steve A. Kay, John B. Hogenesch
Journal: Neuron (2004)
Effect of Depression and Diabetes Mellitus on the Risk for Dementia
Authors: Wayne Katon, Henrik Sondergaard Pedersen, Anette Riisgaard Ribe, Morten Fenger-Grøn, Dimitry Davydow, Frans Boch Waldorff, Mogens Vestergaard
Journal: JAMA Psychiatry (2015)

Although depression and type 2 diabetes mellitus (DM) may independently increase the risk for dementia, no studies have examined whether the risk for dementia among people with comorbid depression and DM is higher than the sum of each exposure individually.To examine the risk for all-cause dementia among persons with depression, DM, or both compared with persons with neither exposure.We performed a national population-based cohort study of 2 454 532 adults, including 477 133 (19.4%) with depression, 223 174 (9.1%) with DM, and 95 691 (3.9%) with both. We included all living Danish citizens 50 years or older who were free of dementia from January 1, 2007, through December 31, 2013 (followed up through December 31, 2013). Dementia was ascertained by physician diagnosis from the Danish National Patient Register or the Danish Psychiatric Central Register and/or by prescription of a cholinesterase inhibitor or memantine hydrochloride from the Danish National Prescription Registry. Depression was ascertained by psychiatrist diagnosis from the Danish Psychiatric Central Research Register or by prescription of an antidepressant from the Danish National Prescription Registry. Diabetes mellitus was identified using the National Diabetes Register.We estimated the risk for all-cause dementia associated with DM, depression, or both using Cox proportional hazards regression models that adjusted for potential confounding factors (eg, demographics) and potential intermediates (eg, medical comorbidities).During 13 834 645 person-years of follow-up, 59 663 participants (2.4%) developed dementia; of these, 6466 (10.8%) had DM, 15 729 (26.4%) had depression, and 4022 (6.7%) had both. The adjusted hazard ratio for developing all-cause dementia was 1.83 (95% CI, 1.80-1.87) for persons with depression, 1.20 (95% CI, 1.17-1.23) for persons with DM, and 2.17 (95% CI, 2.10-2.24) for those with both compared with persons who had neither exposure. The excess risk for all-cause dementia observed for individuals with comorbid depression and DM surpassed the summed risk associated with each exposure individually, especially for persons younger than 65 years (hazard ratio, 4.84 [95% CI, 4.21-5.55]). The corresponding attributable proportion due to the interaction of comorbid depression and DM was 0.25 (95% CI, 0.13-0.36; P < .001) for those younger than 65 years and 0.06 (95% CI, 0.02-0.10; P = .001) for those 65 years or older.Depression and DM were independently associated with a greater risk for dementia, and the combined association of both exposures with the risk for all-cause dementia was stronger than the additive association.
Systematic Review of Barriers to the Recruitment of Older Patients With Cancer Onto Clinical Trials
Authors: Carol A. Townsley, Rita Selby, Lillian L. Siu
Journal: Journal of Clinical Oncology (2005)

Older patients are significantly underrepresented in cancer clinical trials. A literature review was undertaken to identify the barriers that impede the accrual of this vulnerable population onto clinical trials and to determine what specific strategies are needed to improve the representation of older patients in research studies.A systematic literature search was undertaken using several different strategies to identify relevant articles.Nine of 31 relevant papers from 159 citations were included. Age is a significant barrier to recruitment; only a quarter to one third of potentially eligible older patients are enrolled onto trials. Physicians' perceptions, protocol eligibility criteria with restrictions on comorbid conditions, and functional status to optimize treatment tolerability are the most important reasons resulting in the exclusion of older patients. Other barriers include the lack of social support and the need for extra time and resources to enroll these patients. Conversely, older patients do not view their age as an important reason for refusing trials.Specific clinical trials confined to older patients should be conducted to evaluate tumor biology, treatment tolerability, and the effect of comorbid conditions. Protocol designs need to stratify for age and be less restrictive with respect to exclusions on functional status, comorbidity, and previous cancers, such that results are generalizable to older patients. Physician education to dispel unfounded perceptions, improved access to available clinical trials, and provision of personnel and resources to accommodate the unique requirements of an older population are possible solutions to remove the barriers of ageism.
Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24
Authors: Brent W Zanke, Celia MT Greenwood, Jagadish Rangrej, Rafal Kustra, Albert Tenesa, Susan M Farrington, James Prendergast, Sylviane Olschwang, Theodore Chiang, Edgar Crowdy, Vincent Ferretti, Philippe Laflamme, Saravanan Sundararajan, Stéphanie Roumy, Jean-François Olivier, Frédérick Robidoux, Robert Sladek, Alexandre Montpetit, Peter Campbell, Stephane Bezieau, Anne Marie O'Shea, George Zogopoulos, Michelle Cotterchio, Polly Newcomb, John McLaughlin, Ban Younghusband, Roger Green, Jane Green, Mary E M Porteous, Harry Campbell, Helene Blanche, Mourad Sahbatou, Emmanuel Tubacher, Catherine Bonaiti-Pellié, Bruno Buecher, Elio Riboli, Sebastien Kury, Stephen J Chanock, John Potter, Gilles Thomas, Steven Gallinger, Thomas J Hudson, Malcolm G Dunlop
Journal: Nature Genetics (2007)
Radiation-Induced Leukemia at Doses Relevant to Radiation Therapy: Modeling Mechanisms and Estimating Risks
Authors: Igor Shuryak, Rainer K. Sachs, Lynn Hlatky, Mark P. Little, Philip Hahnfeldt, David J. Brenner
Journal: JNCI Journal of the National Cancer Institute (2006)

Because many cancer patients are diagnosed earlier and live longer than in the past, second cancers induced by radiation therapy have become a clinically significant issue. An earlier biologically based model that was designed to estimate risks of high-dose radiation-induced solid cancers included initiation of stem cells to a premalignant state, inactivation of stem cells at high radiation doses, and proliferation of stem cells during cellular repopulation after inactivation. This earlier model predicted the risks of solid tumors induced by radiation therapy but overestimated the corresponding leukemia risks.To extend the model to radiation-induced leukemias, we analyzed--in addition to cellular initiation, inactivation, and proliferation--a repopulation mechanism specific to the hematopoietic system: long-range migration through the blood stream of hematopoietic stem cells (HSCs) from distant locations. Parameters for the model were derived from HSC biologic data in the literature and from leukemia risks among atomic bomb survivors who were subjected to much lower radiation doses.Proliferating HSCs that migrate from sites distant from the high-dose region include few preleukemic HSCs, thus decreasing the high-dose leukemia risk. The extended model for leukemia provides risk estimates that are consistent with epidemiologic data for leukemia risk associated with radiation therapy over a wide dose range. For example, when applied to an earlier case-control study of 110,000 women undergoing radiotherapy for uterine cancer, the model predicted an excess relative risk (ERR) of 1.9 for leukemia among women who received a large inhomogeneous fractionated external beam dose to the bone marrow (mean = 14.9 Gy), consistent with the measured ERR (2.0, 95% confidence interval [CI] = 0.2 to 6.4; from 3.6 cases expected and 11 cases observed). As a corresponding example for brachytherapy, the predicted ERR of 0.80 among women who received an inhomogeneous low-dose-rate dose to the bone marrow (mean = 2.5 Gy) was consistent with the measured ERR (0.62, 95% CI = -0.2 to 1.9).An extended, biologically based model for leukemia that includes HSC initiation, inactivation, proliferation, and, uniquely for leukemia, long-range HSC migration predicts, with reasonable accuracy, risks for radiation-induced leukemia associated with exposure to therapeutic doses of radiation.
Genetic Manipulation of Tumor-specific Cytotoxic T Lymphocytes to Restore Responsiveness to IL-7
Authors: Juan F Vera, Valentina Hoyos, Barbara Savoldo, Concetta Quintarelli, Greta MP Giordano Attianese, Ann M Leen, Hao Liu, Aaron E Foster, Helen E Heslop, Cliona M Rooney, Malcolm K Brenner, Gianpietro Dotti
Journal: Molecular Therapy (2009)

Adoptive transfer of antigen-specific cytotoxic T lymphocytes (CTLs) can induce objective clinical responses in patients with malignant diseases. The option of providing a proliferative and survival advantage to adoptively transferred CTLs remains a challenge to improve their efficacy. Host lymphodepletion and administration of recombinant interleukin-2 (IL-2) are currently used to improve CTL survival and expansion after adoptive transfer, but these approaches are frequently associated with significant side effects and may increase proliferation of T regulatory cells. IL-7 is a crucial homeostatic cytokine that has been safely administered as a recombinant protein. However, while IL-7 induces robust expansion of naive and memory T lymphocytes, the lack of expression of the IL-7 receptor alpha chain (IL-7Ralpha) by CTLs precludes their response to this cytokine. We found that CTLs can be genetically modified to re-express IL-7Ralpha, and that this manipulation restores the response of these cells to IL-7 without apparent modification of their antigen specificity or dependency, and without changing their response to other common gamma (gammac) chain cytokines. This approach may allow selective expansion of CTLs without the unwanted effects associated with IL-2.
A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases
Authors: P.E. Beattie, M.S. Lewis-Jones
Journal: British Journal of Dermatology (2006)

Chronic disease can have physical and psychological effects which affect social functioning. These effects can be better understood from the perspective of parent and child by the use of health-related quality of life (HRQL) measures. Various HRQL measures are now available, of which generic health measures have been the most widely used. These permit comparison between different diseases and also the normal population.To cross-validate a new generic HRQL proxy measure for children, the Children's Life Quality Index (CLQI), with an established speciality-specific dermatological questionnaire, the Children's Dermatology Life Quality Index (CDLQI), in a group of children with chronic skin diseases. The impairment of HRQL in the same group of children with skin disease was then compared with that associated with other common chronic childhood diseases using the CLQI.The CDLQI was completed by 379 children aged 5-16 years with skin disease of more than 6 months' duration. Their parents (n=379) and parents of 161 children aged 5-16 years with other chronic diseases were also asked to complete a proxy measure, the CLQI.Using linear regression analysis, the CLQI and the CDLQI scores showed a strong linear association (rs=0.72, P<0.001) and on a Bland-Altman plot, reasonably good agreement (expressing scores out of 100, the 95% limits of agreement were from -25.5/100 to 26.7/100). In the child's opinion psoriasis and atopic dermatitis (AD) caused the greatest impairment (CDLQI scores of 30.6% and 30.5%), followed by urticaria (20%) and acne (18%). Using the generic CLQI (scored 0-36), from the parental perspective the highest score was for AD (33%), followed by urticaria (28%), psoriasis (27%) and alopecia (19%). Comparing this with children with other chronic diseases, those with cerebral palsy had the highest score (38%), followed in descending order by those with generalized AD (33%), renal disease (33%), cystic fibrosis (32%), urticaria (28%), asthma (28%) and psoriasis (27%). Diseases such as epilepsy (24%) and enuresis (24%) scored higher than diabetes (19%), localized eczema (19%), alopecia (19%) and acne (16%).Using the CLQI we have shown that HRQL impairment in children with chronic skin disease is at least equal to that experienced by children with many other chronic diseases of childhood, with AD and psoriasis having the greatest impact on HRQL among chronic skin disorders and only cerebral palsy scoring higher than AD. Cross-validation of the CLQI with the CDLQI in the group of children with skin disease demonstrates a strong linear association and good agreement between the two.
Multiple Aneurysms of the Abdominal Aorta
Authors: S. Osher Pais
Journal: JAMA (1968)

A patient had multiple aneurysms of the branches of the abdominal aorta. To our knowledge, this is the first case of this condition to be reported. This may be a different entity from most previously described aneurysms, or it may reflect the fact that angiograms are infrequently done on asymptomatic patients. The prognosis in this case may be better than that indicated in the literature.
Mutations in <i>BRAF</i> and <i>KRAS</i> Differentially Distinguish Serrated versus Non-Serrated Hyperplastic Aberrant Crypt Foci in Humans
Authors: Daniel W. Rosenberg, Shi Yang, Devon C. Pleau, Emily J. Greenspan, Richard G. Stevens, Thiruchandurai V. Rajan, Christopher D. Heinen, Joel Levine, Yijian Zhou, Michael J. O'Brien
Journal: Cancer Research (2007)

Abstract We previously reported that colon carcinomas, adenomas, and hyperplastic polyps exhibiting a serrated histology were very likely to possess BRAF mutations, whereas when these same advanced colonic lesions exhibited non-serrated histology, they were wild type for BRAF; among hyperplastic polyps, KRAS mutations were found mainly in a non-serrated variant. On this basis, we predicted that hyperplastic aberrant crypt foci (ACF), a putative precancerous lesion found in the colon, exhibiting a serrated phenotype would also harbor BRAF mutations and that non-serrated ACF would not. In contrast, KRAS mutations would be found more often in the non-serrated ACF. We examined 55 ACF collected during screening colonoscopy from a total of 28 patients. Following laser capture microdissection, DNA was isolated, and mutations in BRAF and KRAS were determined by direct PCR sequencing. When hyperplastic lesions were further classified into serrated and non-serrated histologies, there was a strong inverse relationship between BRAF and KRAS mutations: a BRAFV600E mutation was identified in 10 of 16 serrated compared with 1 of 33 non-serrated lesions (P = 0.001); conversely, KRAS mutations were present in 3 of 16 serrated compared with 14 of 33 non-serrated lesions. Our finding of a strong association between BRAF mutations and serrated histology in hyperplastic ACF supports the idea that these lesions are an early, sentinel, or a potentially initiating step on the serrated pathway to colorectal carcinoma. [Cancer Res 2007;67(8):3551–4]