tbuckley/cabot-search huggingface dataset:
Nuclear Targeting of Akt Enhances Ventricular Function and Myocyte Contractility
Authors: Marcello Rota, Alessandro Boni, Konrad Urbanek, Maria Elena Padin-Iruegas, Tymoteusz J. Kajstura, Giuseppe Fiore, Hajime Kubo, Edmund H. Sonnenblick, Ezio Musso, Steve R. Houser, Annarosa Leri, Mark A. Sussman, Piero Anversa
Journal: Circulation Research (2005)

Cytoplasmic overexpression of Akt in the heart results in a myopathy characterized by organ and myocyte hypertrophy. Conversely, nuclear-targeted Akt does not lead to cardiac hypertrophy, but the cellular basis of this distinct heart phenotype remains to be determined. Similarly, whether nuclear-targeted Akt affects ventricular performance and mechanics, calcium metabolism, and electrical properties of myocytes is unknown. Moreover, whether the expression and state of phosphorylation of regulatory proteins implicated in calcium cycling and myocyte contractility are altered in nuclear-targeted Akt has not been established. We report that nuclear overexpression of Akt does not modify cardiac size and shape but results in an increased number of cardiomyocytes, which are smaller in volume. Additionally, the heart possesses enhanced systolic and diastolic function, which is paralleled by increased myocyte performance. Myocyte shortening and velocity of shortening and relengthening are increased in transgenic mice and are coupled with a more efficient reuptake of calcium by the sarcoplasmic reticulum (SR). This process increases calcium loading of the SR during relengthening. The enhanced SR function appears to be mediated by an increase in SR Ca 2+ -ATPase2a activity sustained by a higher degree of phosphorylation of phospholamban. This posttranslational modification was associated with an increase in phospho–protein kinase A and a decrease in protein phosphatase-1. Together, these observations provide a plausible biochemical mechanism for the potentiation of myocyte and ventricular function in Akt transgenic mice. Therefore, nuclear-targeted Akt in myocytes may have important implications for the diseased heart.
Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) Classification of Renal Tumours in Patients who are Candidates for Nephron-Sparing Surgery
Authors: Vincenzo Ficarra, Giacomo Novara, Silvia Secco, Veronica Macchi, Andrea Porzionato, Raffaele De Caro, Walter Artibani
Journal: European Urology (2009)
Search activity: A key to resolving contradictions in sleep/dream investigation
Authors: V. S. Rotenberg
Journal: Behavioral and Brain Sciences (2000)

The target articles on sleep and dreaming are discussed in terms of the concept of search activity integrating different types of behavior, body resistance, REM sleep/dream functions, and the brain catecholamine system. REM sleep may be functionally sufficient or insufficient, depending on the dream scenario, the latter being more important than the physiological manifestation of REM sleep. REM sleep contributes to memory consolidation in the indirect way. [Nielsen; Revonsuo; Solms; Vertes &amp; Eastman]
Potent Antitumor Activity of an Auristatin-Conjugated, Fully Human Monoclonal Antibody to Prostate-Specific Membrane Antigen
Authors: Dangshe Ma, Christine E. Hopf, Andrew D. Malewicz, Gerald P. Donovan, Peter D. Senter, William F. Goeckeler, Paul J. Maddon, William C. Olson
Journal: Clinical Cancer Research (2006)

Abstract Prostate-specific membrane antigen (PSMA) is the prototypic cell-surface marker of prostate cancer and provides an attractive target for monoclonal antibody (mAb) targeted therapies. In this study, a novel antibody-drug conjugate (ADC) was generated by linking a fully human PSMA mAb to monomethylauristatin E (MMAE), a potent inhibitor of tubulin polymerization. The PSMA ADC was evaluated for antitumor activity in vitro and in a mouse xenograft model of androgen-independent human prostate cancer. The PSMA ADC eliminated PSMA-expressing cells with picomolar potency and &amp;gt;700-fold selectivity in culture. When used to treat mice with established human C4-2 tumors, the PSMA ADC significantly improved median survival 9-fold relative to vehicle or isotype-matched ADC (P = 0.0018) without toxicity. Treatment effects were also manifest as significant (P = 0.0068) reduction in serum levels of prostate-specific antigen (PSA). Importantly, 40% of treated animals had no detectable tumor or measurable PSA at day 500 and could be considered cured. The findings support development of PSMA antibody-auristatin conjugates for therapy of prostate cancer.
Randomized Comparison of the Stanford V Regimen and ABVD in the Treatment of Advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244
Authors: Peter J. Hoskin, Lisa Lowry, Alan Horwich, Andrew Jack, Ben Mead, Barry W. Hancock, Paul Smith, Wendi Qian, Philippa Patrick, Bilyana Popova, Andrew Pettitt, David Cunningham, Ruth Pettengell, John Sweetenham, David Linch, Peter W.M. Johnson
Journal: Journal of Clinical Oncology (2009)

This multicenter, prospective, randomized controlled trial compared the efficacy and toxicity of two chemotherapy regimens in advanced Hodgkin's lymphoma (HL): the weekly alternating Stanford V and the standard, twice-weekly regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).Patients had stage IIB, III, or IV disease or had stages I to IIA disease with bulky disease or other adverse features. Radiotherapy was administered in both arms to sites of previous bulk (> 5 cm) and to splenic deposits, although this was omitted in the latter part of the trial for patients achieving complete remission (CR) in the ABVD arm. A total of 520 patients were randomly assigned and were assessed for the primary outcome measure of progression-free survival (PFS). Five hundred patients received protocol treatment, and radiotherapy was administered to 73% in the Stanford V arm and to 53% in the ABVD arm.The overall response rates after completion of all treatment were 91% for Stanford V and 92% for ABVD. During a median follow-up of 4.3 years, there was no evidence of a difference in projected 5-year PFS and overall survival (OS) rates (76% and 90%, respectively, for ABVD; 74% and 92%, respectively, for Stanford V). More pulmonary toxicity was reported for ABVD, whereas other toxicities were more frequent with Stanford V.In a large, randomized trial, the efficacies of Stanford V and ABVD were comparable when given in combination with appropriate radiotherapy.
Clonal Genetic Alterations in the Lungs of Current and Former Smokers
Authors: L. Mao, J. S. Lee, J. M. Kurie, Y. H. Fan, S. M. Lippman, A. Broxson, F. R. Khuri, W. K. Hong, J. J. Lee, R. Yu, J. Y. Ro, B. L. Kemp, R. C. Morice, G. L. Walsh, W. N. Hittelman
Journal: JNCI Journal of the National Cancer Institute (1997)

Genetic damage has been identified at multiple chromosomal sites (i.e., loci) in lung cancer cells. We questioned whether similar damage could be detected in the bronchial epithelial cells of chronic smokers who do not have this disease.Biopsy specimens from six different bronchial regions were obtained from 54 chronic smokers (40 current smokers and 14 former smokers). The presence of squamous metaplasia and dysplasia (abnormal histologic changes) in the specimens was documented by examination of hematoxylin-eosin-stained sections, and a metaplasia index ([number of biopsy specimens with metaplasia/total number of biopsy specimens] x 100%) was calculated for each subject. Loss of heterozygosity (i.e., loss of DNA sequences from one member of a chromosome pair) involving microsatellite DNA at three specific loci-chromosome 3p14, chromosome 9p21, and chromosome 17p13-was evaluated by means of the polymerase chain reaction. Fisher's exact test and logistic regression analysis were used to assess the data. Reported P values are two-sided.Data on microsatellite DNA status at chromosomes 3p14, 9p21, and 17p13 were available for 54, 50, and 44 subjects, respectively. The numbers of individuals who were actually informative (i.e., able to be evaluated for a loss of heterozygosity) at the three loci were 36 (67%), 37 (74%), and 34 (77%), respectively. DNA losses were detected in 27 (75%), 21 (57%), and six (18%) of the informative subjects at chromosomes 3p14, 9p21, and 17p13, respectively. Fifty-one subjects were informative for at least one of the three loci, and 39 (76%) exhibited a loss of heterozygosity. Forty-two subjects were informative for at least two of the loci, and 13 (31%) exhibited losses at a minimum of two loci. Loss of heterozygosity at chromosome 3p14 was more frequent in current smokers (22 [88%] of 25 informative) than in former smokers (five [45%] of 11 informative) (P = .01) and in subjects with a metaplasia index greater than or equal to 15% (21 [91%] of 23 informative) than in subjects with a metaplasia index of less than 15% (six [46%] of 13 informative) (P = .003). In five informative individuals among nine tested nonsmokers, a loss of heterozygosity was detected in only one subject at chromosome 3p14 (P = .03), and no losses were detected at chromosome 9p21 (P = .05).Genetic alterations at chromosomal sites containing putative tumor-suppressor genes (i.e., 3p14 and the FHIT gene, 9p21 and the p16 gene [also known as CDKN2], and 17p13 and the p53 gene [also known as TP53]) occur frequently in the histologically normal or minimally altered bronchial epithelium of chronic smokers.
Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma
Authors: Henry S. Friedman, Michael D. Prados, Patrick Y. Wen, Tom Mikkelsen, David Schiff, Lauren E. Abrey, W.K. Alfred Yung, Nina Paleologos, Martin K. Nicholas, Randy Jensen, James Vredenburgh, Jane Huang, Maoxia Zheng, Timothy Cloughesy
Journal: Journal of Clinical Oncology (2009)

We evaluated the efficacy of bevacizumab, alone and in combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial.
Mortality and Morbidity Remain High Despite Captopril and/or Valsartan Therapy in Elderly Patients With Left Ventricular Systolic Dysfunction, Heart Failure, or Both After Acute Myocardial Infarction
Authors: Harvey D. White, Philip E.G. Aylward, Zhen Huang, Anthony J. Dalby, W. Douglas Weaver, Ståle Barvik, José Antonio Marin-Neto, Jan Murin, Rolf O. Nordlander, Wiek H. van Gilst, Faiez Zannad, John J.V. McMurray, Robert M. Califf, Marc A. Pfeffer
Journal: Circulation (2005)

The elderly constitute an increasing proportion of acute myocardial infarction patients and have disproportionately high mortality and morbidity. Those with heart failure or impaired left ventricular left ventricular function after acute myocardial infarction have high complication and mortality rates. Little is known about outcomes with contemporary therapies in these patients.The Valsartan in Acute Myocardial Infarction Trial (VALIANT) randomized 14,703 patients with heart failure and/or left ventricular ejection fraction <40% to receive captopril, valsartan, or both. Mortality and a composite end point, including cardiovascular mortality, readmission for heart failure, reinfarction, stroke, and resuscitated cardiac arrest, were compared for the age groups of <65 (n=6988), 65 to 74 (n=4555), 75 to 84 (n=2777), and > or =85 (n=383) years. With increasing age, 3-year mortality almost quadrupled (13.4%, 26.3%, 36.0%, and 52.1%, respectively), composite end-point events more than doubled (25.2%, 41.0%, 52.3%, and 66.8%), and hospital admissions for heart failure almost tripled (12.0%, 23.1%, 31.3%, and 35.4%). Outcomes did not differ between the 3 study treatments in any age group. Adverse events associated with captopril and valsartan were more common in the elderly and in patients receiving combination therapy. With increasing age, use of aspirin, beta-blockers, and statins declined, and use of digoxin, calcium-channel blockers, and non-potassium-sparing diuretics increased. On 3-year multivariable analysis, each 10-year age increase was associated with a hazard ratio of 1.49 (95% CI, 1.426 to 1.557; P<0.0001) for mortality and an odds ratio of 1.38 (95% CI, 1.31 to 1.46; P<0.0001) for readmission with heart failure.Outcomes remained poor in elderly patients with heart failure and/or impaired left ventricular systolic function after acute myocardial infarction, although most received beta-blockers and all received an ACE inhibitor and/or an angiotensin receptor blocker. Better therapies and increased use of aspirin, beta-blockers, and statins are needed in this important and increasing patient group.
Dual conductance mode of the TREK-1 channel: A hidden track to mechanoelectric regulation in the heart?
Authors: S JOONKIM, Y EARM
Journal: Cardiovascular Research (2005)

See article by Li et al. [12] (pages 86–97) in this issue. 

Two-pore-domain K+ channels (K2P channels) form a novel class of K+ channels identified in various types of cells. K2P channels display constitutive activity at around the resting membrane potential and are sensitively regulated by various physical and chemical factors [1,2]. Among the members of K2P channels, TREK and TRAAK families respond to the widest variety of stimuli including pH, temperature, unsaturated fatty acids, phospholipids, volatile anesthetics, and membrane stretch [1,2]. The mechanical gating of TREK seems to arise from the direct interaction between the membrane phospholipid and the sensor domain of the channel without involvement of the actin cytoskeleton [3].

The heart undergoes incessant cyclic stretch and sudden changes in volume loading. Such mechanical stress provokes electrical responses termed “mechanoelectric feedback” [4]. To elucidate the mechanism, the role of stretch-activated signal transduction and mechanosensitive nonselective cation channels (NSCMS) have been persistently investigated [5–7]. Besides the more widely recognized NSCMS at the level of whole-cell or tissue experiments, the stretch of local membranes via the patch pipette technique showed mechanosensitive K+ channels in rat atrial myocytes that are also activated by intracellular acidification and arachidonic acids [8,9]. After the … 

*Corresponding author. Tel.: +82 2 740 8224; fax: +82 2 763 9667. Email address: earmye{at}snu.ac.kr
HIGH-ALTITUDE PULMONARY EDEMA: Current Concepts
Authors: Herbert N. Hultgren, M.D
Journal: Annual Review of Medicine (1996)

High-altitude pulmonary edema (HAPE) occurs in unacclimatized individuals who are rapidly exposed to altitudes in excess of 2450 m. It is commonly seen in climbers and skiers who ascend to high altitude without previous acclimatization. Initial symptoms of dyspnea, cough, weakness, and chest tightness appear, usually within 1-3 days after arrival. Common physical signs are tachypnea, tachycardia, rales, and cyanosis. Descent to a lower altitude, nifedipine, and oxygen administration result in rapid clinical improvement. Physiologic studies during the acute stage have revealed a normal pulmonary artery wedge pressure, marked elevation of pulmonary artery pressure, severe arterial unsaturation, and usually a low cardiac output. Pulmonary arteriolar (precapillary) resistance is elevated. A working hypothesis of the etiology of HAPE suggests that hypoxic pulmonary vasoconstriction is extensive but not uniform. The result is overperfusion of the remaining patent vessels with transmission of the high pulmonary artery pressure to capillaries. Dilatation of the capillaries and high flow results in capillary injury, with leakage of protein and red cells into the alveoli and airways. HAPE represents one of the few varieties of pulmonary edema where left ventricular filling pressure is normal.
Return to sport following anterior cruciate ligament reconstruction surgery: a systematic review and meta-analysis of the state of play
Authors: Clare L Ardern, Kate E Webster, Nicholas F Taylor, Julian A Feller
Journal: British Journal of Sports Medicine (2011)

Background An athlete's intention to return to sport following anterior cruciate ligament (ACL) injury is a major indication for surgical intervention. Purpose The purpose of this review was to determine postoperative return-to-sport outcomes after ACL reconstruction surgery. Study design Meta-analysis and systematic review Methods Electronic databases including Medline, Embase, SPORTDiscus and CINAHL were searched from the earliest possible entry to April 2010. Studies were included that reported the number of patients returning to sports participation following ACL reconstruction surgery. The results were presented using the World Health Organization's International Classification of Functioning, Disability and Health as a framework and combined using proportion meta-analyses. Results Forty-eight studies evaluating 5770 participants at a mean follow-up of 41.5 months were included for review. Overall, 82% of participants had returned to some kind of sports participation, 63% had returned to their preinjury level of participation, and 44% had returned to competitive sport at final follow-up. Approximately 90% of participants achieved normal or nearly normal knee function when assessed postoperatively using impairment-based outcomes such as laxity and strength, and 85% when using activity-based outcomes such as the International Knee Documentation Committee knee evaluation form. Fear of reinjury was the most common reason cited for a postoperative reduction in or cessation of sports participation. Conclusion The relatively low rate of return to competitive sport despite the high rates of successful outcome in terms of knee impairment-based function suggests that other factors such as psychological factors may be contributing to return-to-sport outcomes.
Essential Role of a Ca <sup>2+</sup> -Selective, Store-Operated Current ( <i>I</i> <sub>SOC</sub> ) in Endothelial Cell Permeability
Authors: Songwei Wu, Eugene A. Cioffi, Diego Alvarez, Sarah L. Sayner, Hairu Chen, Donna L. Cioffi, Judy King, Judy R. Creighton, Mary Townsley, Steven R. Goodman, Troy Stevens
Journal: Circulation Research (2005)

Store-operated calcium (SOC) entry is sufficient to disrupt the extra-alveolar, but not the alveolar, endothelial cell barrier. Mechanism(s) underlying such insensitivity to transitions in cytosolic calcium ([Ca 2+ ] i ) in microvascular endothelial cells are unknown. Depletion of stored Ca 2+ activates a larger SOC entry response in extra-alveolar (pulmonary artery; PAECs) than alveolar (pulmonary microvascular; PMVECs) endothelial cells. In vivo permeation studies revealed that Ca 2+ store depletion activates similar nonselective cationic conductances in PAECs and PMVECs, while only PAECs possess the calcium-selective, store-operated Ca 2+ entry current, I SOC . Pretreatment with the type 4 phosphodiesterase inhibitor, rolipram, abolished thapsigargin-activated I SOC in PAECs, and revealed I SOC in PMVECs. Rolipram pretreatment shifted the thapsigargin-induced fluid leak site from extra-alveolar to alveolar vessels in the intact pulmonary circulation. Thus, our results indicate I SOC provides a [Ca 2+ ] i source that is needed to disrupt the endothelial cell barrier, and demonstrate that intracellular events controlling I SOC activation coordinate the site-specific vascular response to inflammation.
Diabetes and Idiopathic Cardiomyopathy
Authors: Alain G. Bertoni, Arthur Tsai, Edward K. Kasper, Frederick L. Brancati
Journal: Diabetes Care (2003)

OBJECTIVE—Controversy exists regarding the relation between diabetes and nonischemic idiopathic cardiomyopathy (ICM), and only limited data on the incidence of ICM in adults with diabetes are available. Therefore, we used the 1995 Nationwide Inpatient Sample (NIS) to determine discharge rates and test the hypothesis that diabetes is independently associated with ICM. RESEARCH DESIGN AND METHODS—The 1995 NIS includes demographic and diagnostic data on all discharges from &amp;gt;900 representative hospitals in 19 states. ICD-9 codes were used to identify ICM, defined as discharges with a diagnosis of primary cardiomyopathy but without established risk factors for cardiomyopathy. Control subjects were selected by stratified random sampling by age to yield 10 per ICM case. The analyzed covariates included age, race, median income, diabetes, and hypertension. Multivariate logistic regression was used to conduct case-control analyses. RESULTS—Using sampling weights, we estimated that in 1995, the rate of hospital discharge for ICM among individuals diagnosed with diabetes was 7.6 per 1,000. The prevalence of diabetes was substantially higher in the 44,837 ICM vs. 450,254 control subjects (26.6 vs. 17.2%), corresponding to a relative odds (RO) of 1.75 (95% CI 1.71–1.79). After adjusting for age, sex, race, hypertension, and median income using multiple logistic regression, diabetes remained significantly associated with ICM (RO 1.58, 95% CI 1.55–1.62). CONCLUSIONS—We concluded that diabetes is independently associated with ICM in the general U.S. population.
Biomechanical overload syndrome: defining a new diagnosis
Authors: Andrew Franklyn-Miller, Andrew Roberts, David Hulse, John Foster
Journal: British Journal of Sports Medicine (2012)

Chronic exertional compartment syndrome (CECS) was first described in 1956,1 but little research has been performed since then to confirm the pathological physiology. An assumption is made that elevated subfascial or intramuscular pressure during exercise causes tissue hypoxia and subsequent ischaemic pain due to decreased blood flow.2 To date, no conclusive evidence exists to demonstrate cellular hypoxic damage or decreased capillary perfusion.3 Further supposition is made regarding muscle hypertrophy, reduced compartment volume due to a decreased fascial compliance,4 and shorter periods of muscle relaxation as the underlying pathophysiology of CECS.

There are many questions over whether the technique of intracompartmental pressure measurement is reliable. Examination of the widely accepted diagnostic criteria published in the seminal paper by Pedowitz et al 5 reveals significant flaws, as the CECS and non-CECS groups were preselected by their differences in intramuscular pressure. We have also demonstrated significant overlap of the published diagnostic criteria for CECS with the published normative data.6 Furthermore, intramuscular pressure measurement varies considerably with the depth of the catheter tip, the means of measurement and the mode of exercise. It is also important that the criteria presented are only applicable to the anterior compartment. CECS is also reported as being diagnosed in the deep posterior and peroneal compartments of the leg,7 the foot8 and the forearm,9 despite diagnostic pressure criteria never having been established in these other myofascial compartments. What is undeniable however is that exertional lower-limb symptoms localised to the myofacial compartments are commonly reported in elite and recreational athletes,10 military personnel,11 ,12 and non-athletes alike,13 and that CECS is included in the differential diagnosis.

As a tertiary referral centre for exertional leg pain, we have conducted large numbers (c.100/year) of intracompartmental pressure measurements, often with subsequent referral …