tbuckley/cabot-search huggingface dataset:
Genetic Profiling to Determine Risk of Relapse-Free Survival in High-Risk Localized Prostate Cancer
Authors: Christine M. Barnett, Michael C. Heinrich, Jeong Lim, Dylan Nelson, Carol Beadling, Andrea Warrick, Tanaya Neff, Celestia S. Higano, Mark Garzotto, David Qian, Christopher L. Corless, George V. Thomas, Tomasz M. Beer
Journal: Clinical Cancer Research (2013)

The characterization of actionable mutations in human tumors is a prerequisite for the development of individualized, targeted therapy. We examined the prevalence of potentially therapeutically actionable mutations in patients with high-risk clinically localized prostate cancer.Forty-eight samples of formalin-fixed paraffin-embedded prostatectomy tissue from a neoadjuvant chemotherapy trial were analyzed. DNA extracted from microdissected tumor was analyzed for 643 common solid tumor mutations in 53 genes using mass spectroscopy-based sequencing. In addition, PTEN loss and erythroblast transformation-specific-related gene (ERC) translocations were examined using immunohistochemistry (IHC) in associated tissue microarrays. Association with relapse during 5 years of follow-up was examined in exploratory analyses of the potential clinical relevance of the genetic alterations.Of the 40 tumors evaluable for mutations, 10% had point mutations in potentially actionable cancer genes. Of the 47 tumors evaluable for IHC, 36% had PTEN loss and 40% had ERG rearrangement. Individual mutations were not frequent enough to determine associations with relapse. Using Kaplan-Meier analysis with a log-rank test, the 16 patients who had PTEN loss had a significantly shorter median relapse-free survival, 19 versus 106 months (P = 0.01).This study confirms that point mutations in the most common cancer regulatory genes in prostate cancer are rare. However, the PIK3CA/AKT pathway was mutated in 10% of our samples. Although point mutations alone did not have a statistically significant association with relapse, PTEN loss was associated with an increased relapse in high-risk prostate cancer treated with chemotherapy followed by surgery.
Use-dependent effects of lidocaine on conduction in canine myocardium: application of the modulated receptor hypothesis in vivo.
Authors: J Davis, T Matsubara, M M Scheinman, B Katzung, L H Hondeghem
Journal: Circulation (1986)

Lidocaine is a commonly used antiarrhythmic drug that causes use-dependent blockade of sodium channels in vitro and reduces conduction velocity in vitro and in vivo. According to the modulated receptor hypothesis of antiarrhythmic drug action, lidocaine has a low affinity for rested sodium channels but a high affinity for open and inactivated channels. In the present experiments, we characterized use-dependent conduction slowing and recovery from slowing by lidocaine in anesthetized dogs. The His-to-ventricular conduction interval was used as the indicator of conduction velocity. We found that prolongation of conduction time was greater as the stimulation frequency was increased. Moreover, on abruptly changing the stimulation frequency, a new steady-state conduction time was approached in two to three depolarizations. On discontinuation of stimulation, the conduction time of progressively less premature extrastimuli shortened exponentially with a terminal phase time constant of 152 +/- 115 msec. These effects by lidocaine were enhanced during acidosis and enhancement was reversed by correction of the acidosis. It is concluded that the effects in vivo of lidocaine on conduction under several conditions of rate, rhythm, and pH are similar to its effects on the maximum upstroke velocity of the action potential in vitro. Although these experiments were not designed to validate the modulated receptor hypothesis, it appears that the modulated receptor hypothesis can predict the effects of lidocaine on conduction in vivo.
The Department of Health's "two week standard" for bowel cancer: is it working?
Authors: K Flashman, D P O'Leary, A Senapati, M R Thompson
Journal: Gut (2004)

<b>Objective:</b> To determine the effectiveness and efficiency of the Department of Health's new general practitioner referral guidelines for bowel cancer. <b>Design:</b> One year prospective audit. <b>Setting:</b> District general hospital serving a population of 550 000. <b>Subjects:</b> All patients with bowel cancer; all patients referred on the basis of the two week standard and to a routine colorectal surgical outpatient clinic. <b>Main outcome measures:</b> Proportion of cancers referred on the basis of the two week standard and to other colorectal clinics; the proportion with the higher risk criteria and their diagnostic yields; stage of cancers diagnosed in outpatient clinics; and time to treatment. <b>Results:</b> A total of 249 cancers were diagnosed in the index year. Sixty five (26.1%) were referred to two week standard clinics, 40 (16.1%) to routine colorectal surgical outpatient clinics, 54 (22%) to other clinics, and 88 (35.3%) were emergencies. Thirteen patients per week were referred to the two week standard clinics and 85% (54/65) of cancers so referred were seen within two weeks. The diagnostic yield of cancer in the two week standard clinic was 9.4% (65/695) compared with 2.2% (40/1815) in the routine colorectal surgical outpatient clinic (p&lt;0.0001). Eighty five per cent of patients with cancer referred to outpatients matched the guidelines for the two week standard clinics. Only 46% of this group were so referred. Overall, delay to treatment and Dukes' stage were not improved in patients diagnosed in the two week standard clinics. <b>Conclusions:</b> Most patients with bowel cancer were not referred on the basis of the two week standard although most fulfilled the referral criteria, which had higher diagnostic yields. The two week standard clinics did not shorten the overall time to treatment or improve the stage of disease because the time lags before referral and after the outpatient appointment are the major causes of delay in the bowel cancer patient's journey.
Brain and behavior: Which way does the shaping go?
Authors: A. Charles Catania
Journal: Behavioral and Brain Sciences (2008)

Abstract Evolutionary contingencies select organisms based on what they can do; brains and other evolved structures serve their behavior. Arguments that brains drive language structure get the direction wrong; with functional issues unacknowledged, interactions between central structures and periphery are overlooked. Evidence supports a peripherally driven central organization. If language modules develop like other brain compartments, then environmental consistencies can engender both structural and functional language units (e.g., the different phonemic, semantic, and grammatical structures of different languages).
Effect of Ramipril on the Incidence of Diabetes
Authors: Jackie Bosch, Salim Yusuf, Hertzel C Gerstein, Janice Pogue, Patrick Sheridan, Gilles Dagenais, Rafael Diaz, Alvaro Avezum, Fernando Lanas, Jeffrey Probstfield, George Fodor, Rury R Holman
Journal: New England Journal of Medicine (2006)

Previous studies have suggested that blockade of the renin-angiotensin system may prevent diabetes in people with cardiovascular disease or hypertension.In a double-blind, randomized clinical trial with a 2-by-2 factorial design, we randomly assigned 5269 participants without cardiovascular disease but with impaired fasting glucose levels (after an 8-hour fast) or impaired glucose tolerance to receive ramipril (up to 15 mg per day) or placebo (and rosiglitazone or placebo) and followed them for a median of 3 years. We studied the effects of ramipril on the development of diabetes or death, whichever came first (the primary outcome), and on secondary outcomes, including regression to normoglycemia.The incidence of the primary outcome did not differ significantly between the ramipril group (18.1%) and the placebo group (19.5%; hazard ratio for the ramipril group, 0.91; 95% confidence interval [CI], 0.81 to 1.03; P=0.15). Participants receiving ramipril were more likely to have regression to normoglycemia than those receiving placebo (hazard ratio, 1.16; 95% CI, 1.07 to 1.27; P=0.001). At the end of the study, the median fasting plasma glucose level was not significantly lower in the ramipril group (102.7 mg per deciliter [5.70 mmol per liter]) than in the placebo group (103.4 mg per deciliter [5.74 mmol per liter], P=0.07), though plasma glucose levels 2 hours after an oral glucose load were significantly lower in the ramipril group (135.1 mg per deciliter [7.50 mmol per liter] vs. 140.5 mg per deciliter [7.80 mmol per liter], P=0.01).Among persons with impaired fasting glucose levels or impaired glucose tolerance, the use of ramipril for 3 years does not significantly reduce the incidence of diabetes or death but does significantly increase regression to normoglycemia. (ClinicalTrials.gov number, NCT00095654 [ClinicalTrials.gov].).
An Exploratory Study into the Effect of Group Psychotherapy on Cardiovascular and Immunoreactivity to Acute Stress in Breast Cancer Patients
Authors: Gieta van der Pompe, Michael H. Antoni, Hugo J. Duivenvoorden, Alexander de Graeff, R.F.A. Simonis, Sytze G.L. van der Vegt, Cobi J. Heijnen
Journal: Psychotherapy and Psychosomatics (2001)

&lt;i&gt;Background:&lt;/i&gt; Previous studies of cancer patients investigated the effect of psychological treatment on basal endocrine and immune values. Using a randomized experiment, we explored the effect of a 13-week experiential-existential group psychotherapy (EEGP) program on the reactivity to a speech task in breast cancer patients. We explored whether changes in cardiovascular and immune reactivity to a speech task over the 3-month period correlated with changes in psychological distress and emotional expression. &lt;i&gt;Methods:&lt;/i&gt; Patients who had been treated for early-stage breast cancer and who were diagnosed as having either positive axillary lymph nodes or distant metastases were randomly assigned to either EEGP or a waiting list control (WLC) condition. We continuously recorded heart rate (HR), diastolic (DBP) and systolic blood pressure (SBP) in response to the speech task before and after treatment. We also measured lymphocyte proliferation to pokeweed (PWM) and phytohemagglutinin (PHA), and natural killer cell activity (NKCA) as well as peripheral blood lymphocyte distributions in blood samples that were drawn before, during and after the speech task. &lt;i&gt;Results:&lt;/i&gt; Patients in EEGP had smaller increases in natural killer (NK) cells induced by the speech task after treatment versus task-induced values observed at study entry and greater than pre-/posttreatment changes seen in patients randomized to the WLC. A similar pattern emerged with respect to NKCA over the intervention period, which was independent of the changes in NK cells. There were no differences between patients assigned to EEGP and WLC in HR, DBP and SBP responses as well as in changes in PWM- and PHA-induced lymphocyte proliferation in response to the speech task measured before and after the 3-month intervention period. Individual differences in pre-/posttreatment increases in emotional expression but not in psychological distress were significantly associated with smaller changes in the number and function of NK cells over the 3-month period. &lt;i&gt;Conclusions:&lt;/i&gt; These findings may indicate that emotional expression during EEGP may render breast cancer patients more comfortable expressing their emotional responses to the speech challenge, which, in turn, results in smaller stress-induced changes in NK cells and function.
DISTRIBUTION OF ANTIBODY-FORMING CELLS OF DIFFERENT SPECIFICITIES IN THE LYMPH NODES AND SPLEENS OF GUINEA PIGS
Authors: Ira Green
Journal: The Journal of Experimental Medicine (1968)

The distribution of antibody-forming cells of different specificities in the lymph nodes and spleens of guinea pigs immunized with two separate antigens or with antigens bearing two determinants was studied. When animals were immunized with two soluble protein antigens or antigens in which the two antigenic determinants were on the same molecule, antibody-forming cells of different specificities were always randomly intermixed. However, when animals were immunized with two heat-aggregated particulate protein antigens and then boosted with soluble protein antigens, cells of different specificities were often seen to occur in groups. These results suggest that antibody-forming cells may not arise by the antigen-stimulated proliferation of precommitted antibody-forming cells, but rather antibody-forming cells arise by a transformation of uncommitted precursor cells as the result of their interactions with a locally produced material derived from the processing of antigen.
Diagnostic accuracy of a portable recording device (MESAM IV) in suspected obstructive sleep apnoea
Authors: S Esnaola, J Duran, C Infante-Rivard, R Rubio, A Fernandez
Journal: European Respiratory Journal (1996)

This study evaluated the accuracy of a portable recording device (MESAM IV) in identifying obstructive sleep apnoea (OSA). The MESAM IV system measures arterial oxygen saturation (Sa,O2), heart rate, snoring sounds and body position, and allows both automatic and manual scoring of the recordings. Nocturnal polysomnography and MESAM IV recordings were performed simultaneously in 150 patients with suspected OSA, and were analysed blindly by a different observer. Patients with an apnoea-hypopnoea index (AHI) greater than or equal to 10 were diagnosed as having OSA. In the evaluation of the discriminatory ability of MESAM IV scores, the cut-off point was set to minimize first the exclusion of truly diseased patients (i.e. false-negative interpretations), and then confirmation of nondiseased subjects (i.e. false-positives). When used as an exclusion test, the portable device reached a sensitivity of 0.98 and a specificity of 0.78; as a confirmation test, these values were 0.69 and 0.97, respectively. These results were achieved with manual scoring, which was superior to automatic scoring. Manual scoring was also better than automatic scoring when OSA was defined according to other threshold values (> or = 5, 15 and 20) for the AHI. The combination of MESAM IV manual scores could reduce the need for diagnostic polysomnography in three quarters of the patients clinically suspected of having obstructive sleep apnoea, substantially reducing costs associated with diagnostic procedures.
Serum leptin concentration is increased in patients with Behcet's syndrome and is correlated with disease activity
Authors: C. Evereklioglu, H.S. Inaloz, N. Kirtak, S. Doganay, M. Bulbul, B. Otlu, E. Ozerol, H. Er, E. Ozbek
Journal: British Journal of Dermatology (2002)

Summary Background Behçet's syndrome is a systemic, relapsing immuno‐inflammatory disease with a generalized vasculitis of the microvasculature endothelial dysfunction. Leptin, a recently discovered neuroendocrine hormone, is a metabolic peptide that appears to be involved. Serum proinflammatory cytokines upregulate leptin levels and leptin itself directly induces nitric oxide production from endothelial cells with its specific receptors. Objectives To detect changes of serum leptin concentrations in patients with Behçet's syndrome compared with age‐ and sex‐matched healthy volunteers by using enzyme‐linked immunosorbent assay. We also investigated whether disease activity or the duration of Behçet's syndrome correlates with leptin concentration. Methods Thirty‐five consecutive patients with Behçet's syndrome (41·2 ± 8·4 years, 16 male, 19 female) and 20 age‐ and sex‐matched healthy control subjects (40·4 ± 10·91 years, nine male, 11 female) were included in this study. The body mass index (BMI) [weight (kg) height−1 (m2)] was calculated for subjects at study enrolment. We measured serum leptin with a leptin enzyme immunoassay kit, and acute‐phase reactants, including erythrocyte sedimentation rate, α1‐antitrypsin, α2‐macroglobulin and neutrophil count. The Mann–Whitney U‐test was used for statistical analysis and P < 0·05 was considered significant. Values were expressed as mean ± SD. Results The gender ratio, age and BMI were not substantially different among Behçet's patients and controls. The mean serum leptin concentrations in patients with Behçet's syndrome (16·8 ± 7·49 ng mL−1) were significantly (P < 0·001) higher than in healthy control volunteers (7·5 ± 2·77 ng mL−1). Active Behçet's patients had significantly (P = 0·001) higher leptin concentrations (20·5 ± 7·99 ng mL−1) when compared with patients in inactive periods (12·8 ± 4·43 ng mL−1). In addition, patients with longer disease duration (mean, 20·1 ± 5·15 years) had also significantly (P = 0·013) higher leptin concentrations (20·2 ± 8·52 ng mL−1) than those with shorter disease duration (13·4 ± 4·52 ng mL−1) (mean, 7·4 ± 3·29 years). All acute‐phase reaction parameters were found to be significantly (for each, P < 0·01) increased in active disease. Conclusions Leptinmay have a role in modulating endothelial function and may be involved in mechanisms for vessel endothelium repair, during an exacerbation as well as in chronic disease.
PI3 kinase signalling blocks Foxp3 expression by sequestering Foxo factors
Authors: Matthias Merkenschlager, Harald von Boehmer
Journal: The Journal of Experimental Medicine (2010)

Expression of the regulatory T (T reg) cell–associated transcription factor Foxp3 can be induced by signals from the T cell receptor (TCR), interleukin-2 (IL-2), and transforming growth factor (TGF)-β. These signals are integrated by a network involving phosphatidylinositol 3 kinase (PI3K), protein kinase B (PKB; here referred to as Akt), and the mammalian target of rapamycin (mTOR). New studies show that the Foxo proteins Foxo1 and Foxo3a, which are inactivated by Akt, drive Foxp3 expression. These studies therefore explain the negative regulation of Foxp3 by PI3K signaling, and add Foxo proteins to the growing list of nuclear factors capable of modulating Foxp3 expression.
The epidemiology of primary biliary cirrhosis: A survey of mortality in England and Wales
Authors: A. N. Hamlyn, S. Sherlock
Journal: Gut (1974)

Primary biliary cirrhosis is a rare disease in the general population. Estimates of its true incidence are difficult but since survival time is unaffected by treatment, mortality may reflect important regional and other variations. One hundred and sixty-five death certificates collected in England and Wales over the five-year period 1967-1971 were inspected and confirmed an overwhelming predilection for females. Deaths rose sharply at ages 50-54 in the latter with a peak of 4·1 million<sup>−1</sup> year<sup>−1</sup>, with perhaps a secondary peak at ages 70-74. No relation of mortality with climate, altitude, soil type, annual temperature range, or occupation was found, although outside the UK a broad correlation exists with total cirrhosis deaths. There was a suggestive excess of deaths among married women. The greater frequency of deaths in the London area, a rise in mortality from country to urban areas, a fall-off in deaths from primary biliary cirrhosis in old age, and predominance for social class I suggest a simple relationship with standards of medical care or diagnosis. An `epidemic9 of deaths in 1971 is attributed to greater availability of the mitochondrial antibody test in the regions. The importance of familial primary biliary cirrhosis and various models of pathogenesis are discussed. Both constitutional and environmental factors producing the disease must be widely distributed in the population of this country.
Nonbenzodiazepine Sleep Medication Use and Hip Fractures in Nursing Home Residents
Authors: Sarah D. Berry, Yoojin Lee, Shubing Cai, David D. Dore
Journal: JAMA Internal Medicine (2013)

It is important to understand the relationship between sleep medication use and injurious falls in nursing home residents.To conduct a case-crossover study to estimate the association between nonbenzodiazepine hypnotic drug use (zolpidem tartrate, eszopiclone, or zaleplon) and the risk for hip fracture among a nationwide sample of long-stay nursing home residents, overall and stratified by individual and facility-level characteristics.Case-crossover study performed in an academic research setting.The study participants included 15,528 long-stay US nursing home residents 50 years or older with a hip fracture documented in Medicare Part A and Part D fee-for-service claims between July 1, 2007, and December 31, 2008.Odds ratios (ORs) of hip fracture were estimated using conditional logistic regression models by comparing the exposure to nonbenzodiazepine hypnotic drugs during the 0 to 29 days before the hip fracture (hazard period) with the exposure during the 60 to 89 and 120 to 149 days before the hip fracture (control periods). Analyses were stratified by individual and facility-level characteristics.Among the study participants, 1715 (11.0%) were dispensed a nonbenzodiazepine hypnotic drug before the hip fracture, with 927 exposure-discordant pairs included in the analyses. The mean (SD) age of participants was 81.0 (9.7) years, and 77.6% were female. The risk for hip fracture was elevated among users of a nonbenzodiazepine hypnotic drug (OR, 1.66; 95% CI, 1.45-1.90). The association between nonbenzodiazepine hypnotic drug use and hip fracture was somes greater in new users (OR, 2.20; 95% CI, 1.76-2.74) and in residents with mild vs moderate to severe impairment in cognition (OR, 1.86 vs 1.43; P = .06), with moderate vs total or severe functional impairment (OR, 1.71 vs 1.16; P = .11), with limited vs full assistance required with transfers (OR, 2.02 vs 1.43; P = .02), or in a facility with fewer Medicaid beds (OR, 1.90 vs 1.46; P = .05).The risk for hip fracture is elevated among nursing home residents using a nonbenzodiazepine hypnotic drug. New users and residents having mild to moderate cognitive impairment or requiring limited assistance with transfers may be most vulnerable to the use of these drugs. Caution should be exercised when prescribing sleep medications to nursing home residents.
Environment and women's reproductive health
Authors: D. Caserta, A. Mantovani, R. Marci, A. Fazi, F. Ciardo, C. La Rocca, F. Maranghi, M. Moscarini
Journal: Human Reproduction Update (2011)

There is significant evidence that continuous and prolonged exposure to several endocrine disrupting chemicals (EDC) is a risk factor for reduced fertility and fecundity in women. There is also evidence that ED exposure has trans-generational effects. In this systematic review, we evaluate the evidence for an association between EDC exposure and women's reproductive health. Studies were found by searching the PubMed database for articles published up to 2010. Associations between ED exposure and women's reproductive health reported in the PubMed database are summarized and classified as fertility and fecundity, pregnancy outcomes, transgenerational exposure and effects. Epidemiological studies on EDCs are not always consistent, in part due to limitations imposed by practical constraints. In order to make progress in this field, we recommend taking advantage of biomonitoring and biobanks, including the development of appropriate biomarkers, and taking into greater consideration modulating factors such as genetic polymorphisms and dietary habits. Further human studies are warranted with particular focus on impaired fertility/fecundity associated with currently widespread ED (e.g. bisphenol A, phthalates and polybrominated flame retardants). A detailed appraisal of compounds specifically related to adverse reproductive outcomes is very important for prevention and risk-communication strategies. Besides research needs, the current evidence is sufficient to prompt precautionary actions to protect women's reproductive health.