tbuckley/cabot-search huggingface dataset:
Predialysis Health, Dialysis Timing, and Outcomes among Older United States Adults
Authors: Deidra C. Crews, Julia J. Scialla, Jiannong Liu, Haifeng Guo, Karen Bandeen-Roche, Patti L. Ephraim, Bernard G. Jaar, Stephen M. Sozio, Dana C. Miskulin, Navdeep Tangri, Tariq Shafi, Klemens B. Meyer, Albert W. Wu, Neil R. Powe, L. Ebony Boulware
Journal: Journal of the American Society of Nephrology (2013)

Studies of dialysis initiation timing have not accounted for predialysis clinical factors that could impact postdialysis outcomes. We examined the association of predialysis health with timing of dialysis initiation in older adult patients in the United States and contrasted morbidity and mortality outcomes among patients with early [estimated GFR (eGFR)≥10 ml/min per 1.73 m2] versus later (eGFR<10 ml/min per 1.73 m2) initiation. We included all patients from the US Renal Data System who initiated dialysis between 2006 and 2008, were ≥67 years old, and had ≥2 years of prior Medicare coverage (n=84,654). We calculated patients' propensity to initiate dialysis early and matched patients by propensity scores. Cox models were used to compare risks of mortality and hospitalization among initiation groups. The majority (58%) of patients initiated dialysis early. Early initiators were more likely to have had AKI, multiple congestive heart failure admissions, and other hospitalizations preceding initiation. Among propensity-matched patients (n=61,930), early initiation associated with greater all-cause (hazard ratio [HR], 1.11; 95% confidence interval [95% CI], 1.08 to 1.14), cardiovascular (CV; HR, 1.13; 95% CI, 1.09 to 1.17), and infectious (HR, 1.13; 95% CI, 1.06 to 1.22) mortality and greater all-cause (HR, 1.03; 95% CI, 1.01 to 1.05) and infectious (HR, 1.10; 95% CI, 1.07 to 1.13) hospitalizations. There was no difference in CV hospitalizations. Among these older adults, early dialysis initiation associates with greater mortality and hospitalizations, even after accounting for predialysis clinical factors. These findings do not support the common practice of early dialysis initiation in the United States.
A novel small molecule that selectively inhibits glioblastoma cells expressing EGFRvIII
Authors: Dimitri G Trembath, Anita Lal, David J Kroll, Nicholas H Oberlies, Gregory J Riggins
Journal: Molecular Cancer (2007)

Mutations of the epidermal growth factor receptor (EGFR) are a possible molecular target for cancer therapy. EGFR is frequently amplified in glioblastomas and 30 to 40% of glioblastomas also express the deletion mutation EGFRvIII. This frequent oncogenic mutation provides an opportunity for identifying new anti-glioblastoma therapies. In this study, we sought small molecule inhibitors specific for cancer cells expressing EGFRvIII, using isogenic parental cells without EGFRvIII as a control.A screen of the NCI small molecule diversity set identified one compound, NSC-154829, which consistently inhibited growth of different human glioblastoma cells expressing EGFRvIII, but permitted normal growth of matched control cells. NSC-154829 had no previously established medicinal use, but has a purine-like structural component. Further experiments showed this compound increased apoptosis in cells with EGFRvIII, and moderately affected the expression of p21, independent of any changes in p53 levels or in Akt phosphorylation.These initial results suggest that NSC-154829 or a closely related structure might be further investigated for its potential as an anti-glioblastoma drug, although its precise molecular mechanism is still undefined.
Persistent Cyclooxygenase-2 Inhibition Downregulates NF-κB, Resulting in Chronic Intestinal Inflammation in the Min/+ Mouse Model of Colon Tumorigenesis
Authors: Adelaide M. Carothers, Jennifer S. Davids, Beatrice C. Damas, Monica M. Bertagnolli
Journal: Cancer Research (2010)

Cyclooxygenase-2 (COX-2) inhibition prevents adenoma formation in humans and mouse models of colon cancer. The selective COX-2 inhibitor celecoxib reduces COX-2 and prostaglandin E(2) (PGE(2)) expression and adenomas in the intestine of Min/+ mice after treatment for several weeks, but prolonged treatment increases PGE(2) production, resulting in drug-resistant tumor formation and transforming growth factor beta (TGFbeta)-dependent intestinal fibrosis. In this study, we examined pathways that regulate COX-2 expression and suppress chronic intestinal inflammation. We show that NF-kappaB signaling was inhibited in the ileum of Min/+ mice receiving long-term treatment with celecoxib. This effect was associated with inhibition of TGFbeta-associated kinase-1 and IkappaB kinase alpha/beta activities and reduced expression of the Toll-like receptor (TLR) 2 and TLR4 that enhance colonic barrier function. Additionally, we observed reduced activities of protein kinases c-Jun NH(2)-terminal kinase 1 and protein kinase A and transcription factor cyclic AMP-responsive element binding protein, regulators of COX-2 expression, which cross-talk with NF-kappaB. In ileum subjected to long-term celecoxib treatment, we noted relatively higher expression of COX-2, vascular endothelial growth factor, and interleukin-1beta in Paneth cells, whereas NF-kappaB and COX-2 were more strongly expressed by an expanded population of stromal myofibroblasts. Our findings argue that celecoxib resistance is an acquired adaptation to changes in the crypt microenvironment that is associated with chronic intestinal inflammation and impaired acute wound-healing responsiveness.
Targeted Therapy in Older Patients With Solid Tumors
Authors: Ciara M. Kelly, Derek G. Power, Stuart M. Lichtman
Journal: Journal of Clinical Oncology (2014)

The introduction of targeted therapy has ushered in the era of personalized medicine in cancer therapy. The increased understanding of tumor heterogeneity has led to the determination of specific targets that can be exploited in treatment. This review highlights approved drugs in different therapeutic classes, including tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, drugs targeted to the human epidermal growth factor receptor 2, BRAF-mutation targeted drugs, anti-epidermal growth factor receptor inhibitors, and anti-vascular endothelial growth factor therapy. There have not been elderly patient-specific trials of these therapies. Most of the data are extrapolated from larger trials in which older patients generally were a fraction of the participants. Therapeutic recommendations are made on the basis of this analysis with the recognition that the older clinical trial participants may not be representative of patients seen in daily practice. Patient selection and geriatric evaluation are critical for appropriate drug selection, dosing, and monitoring. With care, these therapies are a major step forward in the safe and effective treatment of older patients with cancer.
Randomized Trial of Exercise Therapy in Women Treated for Breast Cancer
Authors: Amanda J. Daley, Helen Crank, John M. Saxton, Nanette Mutrie, Robert Coleman, Andrea Roalfe
Journal: Journal of Clinical Oncology (2007)

Purpose To examine the effects of aerobic exercise therapy on quality of life (QoL) and associated outcomes in women treated for breast cancer. Evidence suggests that exercise may be beneficial, but no trial has included an exercise-placebo and a usual-care group to control for the attention effects that might be associated with aerobic exercise interventions in cancer patients. Patients and Methods A total of 108 women who had been treated for breast cancer 12 to 36 months previously were randomly assigned to supervised aerobic exercise therapy (n = 34), exercise-placebo (body conditioning; n = 36), or usual care (n = 38). Exercise therapy and exercise-placebo sessions took place three times per week for 8 weeks. Outcomes included QoL, depression, exercise behavior, aerobic fitness; outcomes were assessed at baseline and at the 8- and 24-week follow-up. Results Analyses of covariance revealed a significant mean difference of 9.8 units in Functional Assessment of Cancer Therapy–General (primary outcome) favoring aerobic exercise therapy at 8 weeks, relative to usual care. Significant differences that favored aerobic exercise therapy relative to usual care were recorded for Functional Assessment of Cancer Therapy–Breast, social/family well-being, functional well-being, and breast cancer subscale scores at 8-week follow-up. Psychological health outcomes improved modestly for both intervention groups; these improvements were sustained for several end points. Conclusion Exercise therapy had large, clinically meaningful, short-term beneficial effects on QoL in women treated for breast cancer; this finding cannot be attributable to attention, given that the exercise-placebo group did not report similar effects relative to usual care.
Selective Targeting of Gene Transfer to Vascular Endothelial Cells by Use of Peptides Isolated by Phage Display
Authors: Stuart A. Nicklin, Steve J. White, Sarah J. Watkins, Robert E. Hawkins, Andrew H. Baker
Journal: Circulation (2000)

Background —Gene transfer to vascular cells is a highly inefficient and nonselective process, defined by the lack of specific cell-surface receptors for both nonviral and viral gene delivery vectors. Methods and Results —We used filamentous phage display to isolate a panel of peptides that have the ability to bind selectively and efficiently to quiescent human umbilical vein endothelial cells (HUVECs) with reduced or negligible binding to nonendothelial cells, including vascular smooth muscle cells and hepatocytes. By direct biopanning on HUVECs and a second approach involving preclearing steps before panning on HUVECs, we isolated and sequenced 140 individual phages and identified 59 peptides. We selected 7 candidates for further investigation by secondary screening of homogeneous phages on a panel of cell types. Using adenovirus-mediated gene transfer as a model gene delivery system, we cloned the peptide SIGYPLP and the positive control peptide KKKKKKK upstream of the S11e single-chain Fv (“adenobody”) directed against the knob domain of the adenovirus to create fusion proteins. Adenovirus-mediated gene transfer via fiber-dependent infection was blocked with S11e, whereas inclusion of the KKKKKKK peptide retargeted gene transfer. The peptide SIGYPLP, however, retargeted gene delivery specifically to endothelial cells with a significantly enhanced efficiency over nontargeted adenovirus and without transduction of nontarget cells. Conclusions —Our study demonstrates the feasibility of using small, novel peptides isolated via phage display to target gene delivery specifically and efficiently to HUVECs and highlights their use for retargeting both viral and nonviral gene transfer to vascular endothelial cells for future clinical applications.
Department of Health sets out plans for doctors to cut UK child death rates
Authors: A. O'Dowd
Journal: BMJ (2013)

The government has announced a new drive to reduce the rate of child mortality in the United Kingdom, which is currently one of the worst in Europe.1

Doctors will be able to look at colour coded maps showing local health trends for conditions such as asthma and diabetes, while GPs may be offered more training in children’s health, under proposals from the government.

The Department of Health published its official response2 on 19 February to the Children and Young People’s Health Outcomes Forum, a body set up by the government last year to identify health issues important to young people, which reported back in July3 4 that there was a pressing need for improvement.

The new “pledge” by the Department of Health to cut child deaths is being described as part of …
Cancer risks associated with external radiation from diagnostic imaging procedures
Authors: Martha S. Linet, Thomas L. Slovis, Donald L. Miller, Ruth Kleinerman, Choonsik Lee, Preetha Rajaraman, Amy Berrington de Gonzalez
Journal: CA A Cancer Journal for Clinicians (2012)

Abstract The 600% increase in medical radiation exposure to the US population since 1980 has provided immense benefit, but increased potential future cancer risks to patients. Most of the increase is from diagnostic radiologic procedures. The objectives of this review are to summarize epidemiologic data on cancer risks associated with diagnostic procedures, describe how exposures from recent diagnostic procedures relate to radiation levels linked with cancer occurrence, and propose a framework of strategies to reduce radiation from diagnostic imaging in patients. We briefly review radiation dose definitions, mechanisms of radiation carcinogenesis, key epidemiologic studies of medical and other radiation sources and cancer risks, and dose trends from diagnostic procedures. We describe cancer risks from experimental studies, future projected risks from current imaging procedures, and the potential for higher risks in genetically susceptible populations. To reduce future projected cancers from diagnostic procedures, we advocate the widespread use of evidence‐based appropriateness criteria for decisions about imaging procedures; oversight of equipment to deliver reliably the minimum radiation required to attain clinical objectives; development of electronic lifetime records of imaging procedures for patients and their physicians; and commitment by medical training programs, professional societies, and radiation protection organizations to educate all stakeholders in reducing radiation from diagnostic procedures. CA Cancer J Clin 2012. © 2012 American Cancer Society.
Thematic Series on the Pathobiology of Vascular Calcification
Authors: Dwight A. Towler, Linda L. Demer
Journal: Circulation Research (2011)

Vascular calcification increasingly afflicts our aging, dysmetabolic population. Once considered only a passive process of dead and dying cells, data from multiple laboratories worldwide have converged to demonstrate that vascular calcification is a highly regulated form of biomineralization. The goal of this thematic review series is to highlight what is known concerning the biological "players" and "game rules" with respect to vascular mineral metabolism. Armed with this understanding, it is hoped that novel therapeutic strategies can be crafted to prevent and treat vascular calcium accrual, to the benefit of our patients afflicted with arteriosclerotic valvular and vascular diseases.
Stability of Insulin Lispro in Insulin Infusion Systems
Authors: William D Lougheed, Bernard Zinman, Thomas R Strack, Linda J Janis, Alexandra B Weymouth, Elyse A Bernstein, Annette M Korbas, Bruce H Frank
Journal: Diabetes Care (1997)

OBJECTIVE To test stability of insulin lispro in two insulin infusion systems over 48 h. RESEARCH DESIGN AND METHODS We used reverse-phase and size-exclusion high-performance liquid chromatography (HPLC) to determine the purity, potency, and degree of polymerization of U100 insulin lispro (Humalog) after 24- and 48-h pump cycles conducted at 37°C in five Disetronic H-TRON V100 and five MiniMed 504 pumps. Pumps were set to deliver a basal rate of 0.5 U/h and 6-U boluses at t = 0, 4, 8, 24, 24.5, 28.5, 32.5, and 48 h during each cycle. The effluent was collected into 1-ml vials, pooled at 24 or 48 h, and stored at 4°C until assay. After each 48-h run period of insulin delivery, assays for potency, polymer, and purity were performed on the pooled samples from each individual cycle. m-cresol content and the pooled reservoir content were assayed in the 48-h pooled samples. RESULTS Insulin lispro retained full HPLC potency (Δ ≤ 4%) at 48 h, with no degradation of insulin lispro to des-amidoinsulin forms (24 or 48 h). No increase in pumped insulin polymer concentration was observed following 24 h of pump flow. Nonsignificant increases of ≤0.09% (Disetronic) and ≤0.15% (MiniMed) from initial concentrations of 0.18% (polymer divided by total insulin) were detected in three of five pump cycles at 48 h when compared with 37°C paired controls. Nonsignificant decreases (&amp;lt;5 and 10%, Disetronic and MiniMed, respectively) of m-cresol content occurred in both systems following 48 h storage in each device, but sterility was not compromised by this decrease (initial m-cresol concentration, 3.15 mg/ml). Pump performance was without mechanical or electrical fault throughout the study Basal and bolus insulin delivery was evaluated three times daily and remained as expected. Occlusion of catheters by insulin precipitation did not occur, and no change in pH was observed following delivery. CONCLUSIONS We conclude that insulin lispro is suitable for prolonged infusion in these two medical devices when syringes and catheters are replaced at 48-h intervals.
Modulation of Ras/Raf/Extracellular Signal–Regulated Kinase Pathway by Reactive Oxygen Species Is Involved in Cyclic Strain–Induced Early Growth Response-1 Gene Expression in Endothelial Cells
Authors: B. S. Wung, J. J. Cheng, Y. J. Chao, H. J. Hsieh, D. L. Wang
Journal: Circulation Research (1999)

Abstract —Endothelial cells (ECs) exposed to cyclic strain induce gene expression. To elucidate the signaling mechanisms involved, we studied the effects of cyclic strain on ECs by using early growth response-1 (Egr-1) as a target gene. Cyclic strain induced a transient increase of Egr-1 mRNA levels that resulted in an increase of binding of nuclear proteins to the Egr-1 binding sequences in the platelet-derived growth factor-A promoter region. ECs subjected to strain enhanced Egr-1 transcription as revealed by promoter activities. Catalase pretreatment inhibited this induction. ECs, transfected with a dominant positive mutant of Ras (RasL61), increased Egr-1 promoter activities. In contrast, transfection with a dominant negative mutant of Ras (RasN17) attenuated this strain inducibility. ECs transfected with a dominant negative mutant of Raf-1 (Raf301) or the catalytically inactive mutant of extracellular signal–regulated kinase (ERK)-2 (mERK2) diminished strain-induced promoter activities. However, little effect on strain inducibility was observed in ECs transfected with a dominant negative mutant of Rac (RacN17) or a catalytically inactive mutant of JNK (JNK[K-R]). Consistently, strain-induced Egr-1 expression was inhibited after ECs were treated with a specific inhibitor (PD98059) to mitogen-activated protein kinase kinase. Moreover, strain to ECs induced mitogen-activated protein kinase/ERK activity. The activation of the ERK pathway was further substantiated by an increase of strain-induced transcriptional activity of Elk1, an ERK substrate. This strain-induced ERK activity was attenuated after ECs were treated with N -acetylcysteine or catalase. Consequently, this Egr-1 gene induction was abolished after ECs were treated with N -acetylcysteine or catalase. Deletion analyses of the promoter region (–698 bp) indicated that cyclic strain and H 2 O 2 shared a common serum response element. Our data clearly indicate that cyclic strain–induced Egr-1 expression is mediated mainly via the Ras/Raf-1/ERK pathway and that strain-induced reactive oxygen species can modulate Egr-1 expression at least partially via this signaling pathway.
Platelet Activating Factor and Human Disease.
Authors: N. A FLORES
Journal: Cardiovascular Research (1993)

Journal Article Platelet Activating Factor and Human Disease. Get access NICHOLAS A FLORES NICHOLAS A FLORES London, UK Eds P J Barnes C P Page, P M Henson. (Pp 334; £55.) Oxford: Blackwell, 1989 (reprinted 1992). ISBN 0-632-02684-7. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 27, Issue 3, March 1993, Pages 539–540, https://doi.org/10.1093/cvr/27.3.539b Published: 01 March 1993
Guanine nucleotides modulate the binding affinity of the oligopeptide chemoattractant receptor on human polymorphonuclear leukocytes.
Authors: C Koo, R J Lefkowitz, R Snyderman
Journal: Journal of Clinical Investigation (1983)

The oligopeptide chemoattractant receptor on human polymorphonuclear leukocyte (PMN) membranes exists in two affinity states. Since guanine nucleotides regulate the binding affinity and transductional activity of several other types of receptors, we examined the effect of nucleotides on the binding of N-formyl-methionyl peptides to their receptors on human PMN membranes. The addition of guanylylimidodiphosphate (0.1 mM), a nonhydrolyzable derivative of guanosine triphosphate (GTP), to PMN membrane preparations reduced the fraction of high-affinity receptors detected in equilibrium binding studies from 21.3 +/- 0.13 to 11.8 +/- 0.05% (P less than 0.03), without altering the binding affinities. Since the total number of receptors remained unchanged, the effect of guanylylimidodiphosphate was to convert a portion of the receptors from the high-affinity state to the low-affinity state. At the maximal concentration of guanine nucleotide tested, approximately 50% of the high-affinity sites were converted to low-affinity sites. The findings obtained by equilibrium binding were supported by kinetic studies since the dissociation of the radiolabeled oligopeptide chemoattractant N-formyl-methionyl-leucyl-[3H]phenylalanine from PMN membranes was accelerated in the presence of guanine nucleotide. The effect of guanine nucleotides was reversed upon washing, indicating that affinity conversion is bidirectional. The guanine nucleotide effects were greatest with nonhydrolyzable derivatives of GTP followed by GTP then guanosine diphosphate. Neither guanosine monophosphate nor any adenine nucleotide tested had an effect on receptor binding. These data suggest a role for guanine nucleotides in the regulation of stimulus-receptor coupling of chemoattractant receptors on human PMN.
Epithelial microRNAs regulate gut mucosal immunity via epithelium–T cell crosstalk
Authors: Moshe Biton, Avi Levin, Michal Slyper, Irit Alkalay, Elad Horwitz, Hagar Mor, Sharon Kredo-Russo, Tali Avnit-Sagi, Gady Cojocaru, Farid Zreik, Zvi Bentwich, Matthew N Poy, David Artis, Michael D Walker, Eran Hornstein, Eli Pikarsky, Yinon Ben-Neriah
Journal: Nature Immunology (2011)
Childhood Correlates of Blood Lead Levels in Mumbai and Delhi
Authors: Nitin B. Jain, Howard Hu
Journal: Environmental Health Perspectives (2005)

Lead exposure has previously been associated with intellectual impairment in children in a number of international studies. In India, it has been reported that nearly half of the children have elevated blood lead levels (BLLs). However, little is known about risk factors for these elevated BLLs.We conducted a retrospective cross-sectional analysis of data from the Indian National Family Health Survey, a population-based study conducted in 1998-1999. We assessed potential correlates of BLLs in 1,081 children who were < 3 years of age and living in Mumbai or Delhi, India. We examined factors such as age, sex, religion, caste, mother's education, standard of living, breast-feeding, and weight/height percentile.Most children (76%) had BLLs between 5 and 20 microg/dL. Age, standard of living, weight/height percentile, and total number of children ever born to the mother were significantly associated with BLLs (log transformed) in multivariate regression models. Compared with children < or = 3 months of age, children 4-11 and 12-23 month of age had 84 and 146% higher BLLs, respectively (p < 0.001). A low standard of living correlated with a 32.3% increase in BLLs (p = 0.02). Children greater than the 95th percentile for their weight/height had 31% (p = 0.03) higher BLLs compared with those who were below the 5th percentile for their weight/height.Our study found various factors correlated with elevated BLLs in children. The correlation between greater than the 95th percentile weight/height and higher BLL may reflect an impact of lead exposure on body habitus. Our study may help in targeting susceptible populations and identifying correctable factors for elevated BLLs in Mumbai and Delhi.