tbuckley/cabot-search huggingface dataset:
Applying Synthetic Lethality for the Selective Targeting of Cancer
Authors: Donal P. McLornan, Alan List, Ghulam J. Mufti
Journal: New England Journal of Medicine (2014)

Synthetic lethality refers to the requirement that two defects be present for cell death to occur. When an agent damages DNA, its effects on the cell can be amplified if the efforts of the cell to repair the damage are inhibited. Clinical application of this idea is just beginning.
A Meta-Analysis of Aortic Root Size in Elite Athletes
Authors: Aline Iskandar, Paul D. Thompson
Journal: Circulation (2013)

The aorta is exposed to hemodynamic stress during exercise, but whether or not the aorta is larger in athletes is not clear. We performed a systematic literature review and meta-analysis to examine whethere athletes demonstrate increased aortic root dimensions compared with nonathlete controls.We searched MEDLINE and Scopus from inception through August 12, 2012, for English-language studies reporting the aortic root size in elite athletes. Two investigators independently extracted athlete and study characteristics. A multivariate linear mixed model was used to conduct meta-regression analyses. We identified 71 studies reporting aortic root dimensions in 8564 unique athletes, but only 23 of these studies met our criteria by reporting aortic root dimensions at the aortic valve annulus or sinus of Valsalva in elite athletes (n=5580). Athletes were compared directly with controls (n=727) in 13 studies. On meta-regression, the weighted mean aortic root diameter measured at the sinuses of Valsalva was 3.2 mm (P=0.02) larger in athletes than in the nonathletic controls, whereas aortic root size at the aortic valve annulus was 1.6 mm (P=0.04) greater in athletes than in controls.Elite athletes have a small but significantly larger aortic root diameter at the sinuses of Valsalva and aortic valve annulus, but this difference is minor and clinically insignificant. Clinicians evaluating athletes should know that marked aortic root dilatation likely represents a pathological process and not a physiological adaptation to exercise.
Intestinal excretion of oxalate in chronic renal failure.
Authors: M Hatch, R W Freel, N D Vaziri
Journal: Journal of the American Society of Nephrology (1994)

The extrarenal elimination of oxalate via the intestine was studied in rats with chronic renal failure by measuring the magnitude and direction of oxalate fluxes across the small and large intestine. Oxalate transport was determined in vitro across short-circuited sheets of jejunum, ileum, and colon that were placed in Ussing chambers. The concentration of oxalate in plasma and urine was measured immediately before the transport studies. The results show that, 6 wk after 5/6 nephrectomy, rats with chronic renal failure have lower (decreases 50%) renal clearance of oxalate and a higher mean plasma oxalate concentration (increases 80%) than controls. The basal absorption of oxalate across the colon was changed to secretion in animals with chronic renal failure (from 12.81 +/- 2.22 (N = 9) to -14.96 +/- 2.57 (N = 11) pmol/cm2 per hour). Both the jejunum and the ileum supported a basal net secretory flux of oxalate (-19.71 +/- 2.39 (N = 13) and -30.06 +/- 2.80 (N = 16) pmol/cm2 per hour) that was unaffected by renal insufficiency. These studies demonstrate that intestinal transport systems for oxalate are altered in experimental chronic renal failure, and the distal colon is identified as the primary site for this adaptive response. In chronic renal failure, the entire intestinal tract can potentially excrete oxalate.
Left atrial pressure reduction for mitral stenosis reverses left atrial direction-dependent conduction abnormalities
Authors: R. Coronel, J. Langerveld, L. V.A. Boersma, E. F.D. Wever, L. Bon, P. F.H.M. van Dessel, A. C. Linnenbank, W. H. van Gilst, S. M.P.G. Ernst, T. Opthof, N. M. van Hemel
Journal: Cardiovascular Research (2009)

Left atrial (LA) stretch-associated electrophysiological changes in patients with mitral stenosis (MS) predispose to atrial fibrillation. We hypothesized that the normalization of the pressure gradient by percutaneous transvenous mitral balloon valvotomy (PTMV) affects LA but not right atrial (RA) conduction, depending on the site of stimulation. Because direction-dependent (asymmetric) changes of conduction may contribute to arrhythmogenesis, we assessed conduction symmetry in MS patients and tested whether it is restored by PTMV. In nine patients with MS, atrial effective refractory period and local activation times (ATs) were determined during stimulation before and after PTMV, with up to four decapolar catheters (LA and RA). Eight patients with ventricular pre-excitation served as controls. ATs at basic cycle length were similar before and after PTMV. With stimulation from either atrium, they were about 45 ms in the ipsilateral atrium and about 115 ms in the contralateral atrium. With premature stimulation, ATs increased dramatically. The shortest ATs were found in the RA with RA stimulation (78 ± 9 and 80 ± 6 ns, before and after PTMV). PTMV caused a shortening in LA-ATs (following LA stimulation) from 118 ± 14 to 82 ± 5 ms (before and after; P < 0.05). Asymmetry in conduction properties was therefore normalized by PTMV. PTMV led to a decrease in RA-ATs (following LA stimulation) from 196 ± 11 to 174 ± 13 ms (P < 0.02). In addition, following RA stimulation, the dispersion in ATs in the LA decreased significantly by PTMV (from 66 ± 10 to 34 ± 7 ms; P < 0.02). MS is associated with LA conduction delay, increased LA dispersion of conduction, and conduction asymmetry. These changes are immediately reversible by PTMV.
Global Calorie Counting: A Fitting Exercise for Obese Societies
Authors: Shiriki K. Kumanyika
Journal: Annual Review of Public Health (2008)

Implementation of strategies to address obesity on a global scale has not yet begun in earnest. One key issue is uncertainty about the relative importance of taking aggressive action on the food vs. physical activity side of the energy balance equation, recognizing that interventions in both areas are critical. Using data on obesity prevalence, food availability, and selected economic and sociodemographic indicators from member countries of the Organization for Economic Cooperation and Development, an article in this volume of the Annual Review of Public Health provides estimates and projections to help resolve this uncertainty. The analyses presented support the authors' hypothesis that most of the recent rise in obesity is attributable to excess caloric intake. The implication that policies to curb overconsumption might include deliberate changes in the price structure of the food supply should stimulate debate about our current agricultural and trade paradigms, particularly because any such global policies would also affect the developing world.
Users' guides to the medical literature
Authors: G. H. Guyatt
Journal: JAMA (1993)

Medical practice is constantly changing. The rate of change is accelerating, and physicians can be forgiven if they often find it dizzying. How can physicians learn about new information and innovations, and decide how (if at all) they should modify their practice? Possible sources include summaries from the medical literature (review articles, practice guidelines, consensus statements, editorials, and summary articles in "throwaway" journals); consultation with colleagues who have special expertise; lectures; seminars; advertisements in medical journals; conversations with representatives from pharmaceutical companies; and original articles in journals and journal supplements. Each of these sources of information might be valuable, though each is subject to its own particular biases.<sup>1,2</sup>Problems arise when, as is often the case, these sources of information provide different suggestions about patient care. See also p 2093. Without a way of critically appraising the information they receive, clinicians are relatively helpless in deciding what new information
Retinoic Acid and the Histone Deacetylase Inhibitor Trichostatin A Inhibit the Proliferation of Human Renal Cell Carcinoma in a Xenograft Tumor Model
Authors: Sue Ellen Touma, Jonathan S. Goldberg, Paul Moench, Xiaojia Guo, Satish K. Tickoo, Lorraine J. Gudas, David M. Nanus
Journal: Clinical Cancer Research (2005)

Therapy for advanced renal cell carcinoma (RCC) is ineffective in the majority of patients. We have previously reported that retinoid-induced up-regulation of retinoic acid receptor beta (RARbeta) correlated with antitumor effects in RCCs. Recent studies show that there is a reduction in the level of RARbeta2 expression in cancer cells due in part to histone hypoacetylation. Therefore, we tested whether combining histone deacetylase inhibitors with retinoic acid (RA) would restore RARbeta2 receptor expression, leading to increased growth inhibition in RCC cells.Cell proliferation, Western blot, and reverse transcription-PCR analyses of two RA-resistant RCC cell lines, SK-RC-39 and SK-RC-45, were assessed in the presence of all-trans retinoic acid (ATRA), trichostatin A (TSA), or the combination of ATRA and TSA. Analysis of apoptosis was also done on SK-RC-39 cells treated with these combinations. Additionally, a xenograft tumor model (SK-RC-39) was used in this study to investigate the efficacy of a liposome-encapsulated, i.v. form of ATRA (ATRA-IV) plus TSA combination therapy.Enhanced inhibition of the proliferation of RCC cell lines and of tumor growth in a xenograft model was observed with the combination of ATRA plus TSA. Reactivation of RARbeta2 mRNA expression was observed in SK-RC-39 and SK-RC-45 cells treated with TSA alone or TSA in combination with ATRA. A partial G0-G1 arrest and increased apoptosis were observed with SK-RC-39 cells on treatment with ATRA and TSA.The combination of ATRA and the histone deacetylase inhibitor TSA elicits an additive inhibition of cell proliferation in RCC cell lines. These results indicate that ATRA and histone deacetylase inhibitor therapies should be explored for the treatment of advanced RCC.
Polymorphonuclear neutrophils and cancer: Intense and sustained neutrophilia as a treatment against solid tumors
Authors: Juan Carlos Souto, Luis Vila, Antonio Brú
Journal: Medicinal Research Reviews (2009)

Abstract Polymorphonuclear neutrophils (PMN) are the most abundant circulating immune cells and represent the first line of immune defense against infection. This review of the biomedical literature of the last 40 years shows that they also have a powerful antitumoral effect under certain circumstances. Typically, the microenvironment surrounding a solid tumor possesses many of the characteristics of chronic inflammation, a condition considered very favorable for tumor growth and spread. However, there are many circumstances that shift the chronic inflammatory state toward an acute inflammatory response around a tumor. This shift seems to convert PMN into very efficient anticancer effector cells. Clinical reports of unexpected antitumoral effects linked to the prolonged use of granulocyte colony‐stimulating factor, which stimulates an intense and sustained neutrophilia, suggest that an easy way to fight solid tumors would be to encourage the development of intense peritumoral PMN infiltrates. Specifically designed clinical trials are urgently needed to evaluate the safety and efficacy of such drug‐induced neutrophilia in patients with solid tumors. This antitumoral role of neutrophils may provide new avenues for the clinical treatment of cancer. © 2009 Wiley Periodicals, Inc. Med Res Rev, 31, No. 3, 311–363, 2011
Statistical Issues in the Design of HIV Vaccine Trials
Authors: Carl Schaper, Thomas R. Fleming, Steven G. Self, Wasima N. Rida
Journal: Annual Review of Public Health (1995)

HIV vaccine trials present significant challenges related to trial endpoints, vaccine efficacy measurement, and the role of nonvaccine interventions. Infection is a valid endpoint for detecting sterilizing immunity. But if the vaccine prevents AIDS without preventing infection, infection may be a misleading surrogate. Appropriate endpoints must be defined for other mechanisms of vaccine action. Direct, indirect, behavioral, and biological effects all determine vaccine efficacy. False security among HIV-vaccine recipients may make negative behavioral effects an important component of vaccine performance. Both biological potency and a more comprehensive program effectiveness should be measured. These goals may require unblinded designs or community randomization. Nonvaccine interventions are currently the only HIV-prevention strategy. Support for larger scale implementation requires more rigorous evaluation that is less dependent on self-reported behavioral changes. The vaccine trial cohorts provide a unique opportunity to cost-effectively evaluate behavioral interventions.
Contributions of High Mobility Group Box Protein in Experimental and Clinical Acute Lung Injury
Authors: Hiroshi Ueno, Tomoyuki Matsuda, Satoru Hashimoto, Fumimasa Amaya, Yoshihiro Kitamura, Masaki Tanaka, Atsuko Kobayashi, Ikuro Maruyama, Shingo Yamada, Naoki Hasegawa, Junko Soejima, Hidefumi Koh, Akitoshi Ishizaka
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

This study was performed to examine the putative role of high mobility group box (HMGB) protein in the pathogenesis of acute lung injury (ALI). Observations were made (1) in 21 patients who were septic with ALI and 15 patients with normal lung function and (2) in a mouse model 24 hours after intratracheal instillation of lipopolysaccharide (LPS). The concentrations of HMGB1 were increased in plasma and lung epithelial lining fluid of patients with ALI and mice instilled with LPS. LPS-induced ALI was mitigated by anti-HMGB1 antibody. Although this protein was not detected in the plasma of control humans or mice, the concentrations of HMGB1 in lung epithelial lining fluid or in bronchoalveolar lavage fluid were unexpectedly high. The nuclear expression of HMGB1 was apparent in epithelial cells surrounding terminal bronchioles in normal mice, whereas its nuclear and cytoplasmic expression was observed in alveolar macrophages in LPS-instilled mice. Lung instillation of HMGB2 did not cause as much inflammation as HMGB1. Extracellular HMGB1 may play a key role in the pathogenesis of clinical and experimental ALI. However, its expression in normal airways is noteworthy and suggests that it also plays a physiologic role in the lung.
Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data
Authors: Kunihiro Matsushita, Josef Coresh, Yingying Sang, John Chalmers, Caroline Fox, Eliseo Guallar, Tazeen Jafar, Simerjot K Jassal, Gijs W D Landman, Paul Muntner, Paul Roderick, Toshimi Sairenchi, Ben Schöttker, Anoop Shankar, Michael Shlipak, Marcello Tonelli, Jonathan Townend, Arjan van Zuilen, Kazumasa Yamagishi, Kentaro Yamashita, Ron Gansevoort, Mark Sarnak, David G Warnock, Mark Woodward, Johan Ärnlöv
Journal: The Lancet Diabetes & Endocrinology (2015)
Suggested Minimal Effective Dose of Risperidone Based on PET-Measured D<sub>2</sub> and 5-HT<sub>2A</sub> Receptor Occupancy in Schizophrenic Patients
Authors: S Nyberg, B Eriksson, G Oxenstierna, C Halldin, L Farde
Journal: American Journal of Psychiatry (1999)

OBJECTIVE: Multicenter trials with the novel antipsychotic risperidone have suggested a standard dose of 6 mg/day. However, a dose producing the highest response rate in fixed-dose studies is likely to exceed the minimal effective dose in most patients. The aim of this positron emission tomography (PET) study was to suggest a minimal effective dose of risperidone based on measurements of dopamine D2 and serotonin 5-HT2A receptor occupancy. METHOD: Eight first-episode or drug-free schizophrenic patients were treated with risperidone, 6 mg/day, for 4 weeks and then 3 mg/day for 2 weeks. PET was performed after 4 and 6 weeks, with [11C]raclopride to measure D2 receptor occupancy and [11C]N-methyl­spiperone to measure 5-HT2A receptor occupancy. RESULTS: Seven patients completed the study and responded to treatment with risperidone. No patient had extrapyramidal side effects at the time of inclusion in the study. At the 6-mg/day dose, mean D2 receptor occupancy was 82% (range=79%–85%), 5-HT2A receptor occupancy was 95% (range=86%–109%), and six patients had developed extrapyramidal side effects. After dose reduction to 3 mg/day, D2 receptor occupancy was 72% (range=53%–78%), and 5-HT2A receptor occupancy was 83% (range=65%–112%). Three patients had extrapyramidal side effects at this time. CONCLUSIONS: Treatment with risperidone, 6 mg/day, is likely to induce unnecessarily high D2 receptor occupancy, with a consequent risk of extrapyramidal side effects. High 5-HT2A receptor occupancy did not prevent extrapyramidal side effects completely. The authors previously suggested an optimal interval for D2 receptor occupancy of 70%–80%. To achieve this, risperidone, 4 mg/day, should be a suitable initial dose for antipsychotic effect with a minimal risk of extrapyramidal side effects in most patients.
A Molecular Genetic and Statistical Approach for the Diagnosis of Dual-Site Cancers
Authors: D. Brinkmann, A. Ryan, A. Ayhan, W. G. McCluggage, R. Feakins, M. F. Santibanez-Koref, C. A. Mein, S. A. Gayther, I. J. Jacobs
Journal: JNCI Journal of the National Cancer Institute (2004)

Concurrent tumors can be synchronous, independently derived, non-metastatic tumors or metastatic tumors. The prognosis and clinical management of patients with these different concurrent tumor types are different.DNA from normal and tumor tissues of 62 patients with synchronous endometrial and ovarian, bilateral ovarian, or endometrial and bilateral ovarian tumors was analyzed for loss of heterozygosity and microsatellite instability using eight polymorphic microsatellite markers at loci frequently deleted in ovarian and/or endometrial cancers. A statistical algorithm was designed to assess the clonal relationship between the tumors.The original histopathology reports classified 26 (42%) case patients with single primary tumors and related metastatic lesions and 21 (34%) with independent primary tumors; 15 (24%) were unclassified. Genetic data identified 35 (56%) case patients with single primary tumors and related metastatic lesions, 18 (29%) with independent primary tumors, and nine (15%) that could not be typed. Excluding case patients with histopathology reports for which a clonal relationship was uncertain or was not reported, there was 53% concordance between genetic and histopathology diagnoses. Increasing the stringency of the statistical analysis increased the number of uncertain diagnoses but did not affect the proportion of discordant genetic and histologic diagnoses.We have developed a rapid and robust combined genetic and statistical method to establish whether multiple tumors from the same patient represent distinct primary tumors or whether they are clonally related and therefore metastatic. For the majority of case patients, histopathology reports and genetic analyses were in agreement and diagnostic confidence was improved. Importantly, in approximately one-fourth of all case patients, genetic and histopathologic analyses suggested alternative diagnoses. The results suggest that genetic analysis has implications for clinical management and can be performed rapidly as a diagnostic test with paraffin-embedded tissues.
Human Autologous Tumor-Specific T-Cell Responses Induced by Liposomal Delivery of a Lymphoma Antigen
Authors: Sattva S. Neelapu, Sivasubramanian Baskar, Barry L. Gause, Carol B. Kobrin, Thelma M. Watson, Andrea Robin Frye, Robin Pennington, Linda Harvey, Elaine S. Jaffe, Richard J. Robb, Mircea C. Popescu, Larry W. Kwak
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The idiotype (Id) of the immunoglobulin on a given B-cell malignancy is a clonal marker that can serve as a tumor-specific antigen. We developed a novel vaccine formulation by incorporating Id protein with liposomal lymphokine that was more potent than a prototype, carrier-conjugated Id protein vaccine in preclinical studies. In the present study, we evaluated the safety and immunogenicity of this vaccine in follicular lymphoma patients. Experimental Design: Ten patients with advanced-stage follicular lymphoma were treated with five doses of this second generation vaccine after chemotherapy-induced clinical remission. All patients were evaluated for cellular and humoral immune responses. Results: Autologous tumor and Id-specific type I cytokine responses were induced by vaccination in 10 and 9 patients, respectively. Antitumor immune responses were mediated by both CD4+ and CD8+ T cells, were human lymphocyte antigen class I and II associated, and persisted 18 months beyond the completion of vaccination. Specific anti-Id antibody responses were detected in four patients. After a median follow-up of 50 months, 6 of the 10 patients remain in continuous first complete remission. Conclusions: This first clinical report of a liposomal cancer vaccine demonstrates that liposomal delivery is safe, induces sustained tumor-specific CD4+ and CD8+ T-cell responses in lymphoma patients, and may serve as a model for vaccine development against other human cancers and infectious pathogens.
Intracellular calcium as a second messenger following growth stimulation of human keratinocytes
Authors: U.B. MCGOVERN, K.T. JONES, G.R. SHIARPE
Journal: British Journal of Dermatology (2010)

The mitogenic effect of the neuropeptide substance P and bombesin was investigated in normal human keratinocytes in serum-free culture, both with and without the presence of epidermal growth factor (EGF). Although both neuropeptides induced a small increase in cell numbers in the presence of EGF, the response was much greater in its absence, and cell numbers increased to 200% of controls at 5 days. Changes in intracellular free calcium are frequently seen following mitogenic stimulation of cells, and this phenomenon was studied in individual keratinocytes. Epidermal growth factor (10 ng/ml) induced calcium transients in 57% (n = 21) of cells. The mean intracellular free calcium was 97 +/- 11 nM (mean +/- SEM) in quiescent cells, and the calcium transients reached approximately 250 nM for 3-4 min. In the presence of EGF, calcium transients were never observed with the addition of either substance P or bombesin. For EGF-deprived cultures, 20% of keratinocytes (n = 10) showed a large calcium transient following the addition of 500 nM bombesin, and 63% (n = 12) of cells gave calcium transients following the addition of 700 nM of substance P. Studies in calcium-free medium, and following depletion of intracellular calcium stores with thapsigargin, showed that all of the calcium transients were dependent on the presence of intracellular stores, but also partially mediated by an influx of extracellular calcium. These studies demonstrate the mitogenic effect of substance P and bombesin on human keratinocytes in the absence of EGF. The ability of the neuropeptides to increase keratinocyte growth in culture suggests a possible in wound healing.
Regression of atheroma seen with intravascular ultrasound: A placebo controlled study of the effect of gemfibrozil on peripheral atherosclerosis
Authors: Andrew N. Deaner, Jeff Ball, Arzu A. Cubukcu, Simon Megary, Peter J. Scott, Paul Brooksby, Mohan Lal, Mohan Sivanathan, Gordon J. Williams
Journal: Journal of the American College of Cardiology (1996)