tbuckley/cabot-search huggingface dataset:
Selective BRAF Inhibitors Induce Marked T-cell Infiltration into Human Metastatic Melanoma
Authors: James S. Wilmott, Georgina V. Long, Julie R. Howle, Lauren E. Haydu, Raghwa N. Sharma, John F. Thompson, Richard F. Kefford, Peter Hersey, Richard A. Scolyer
Journal: Clinical Cancer Research (2011)

To evaluate the effects of treatment with the potent mutant BRAF inhibitors GSK2118436 or vemurafenib (PLX4720) on immune responses to metastatic melanoma in tissues taken before and after treatment.Thirty-seven tumor biopsies were collected from 15 patients with unresectable American Joint Committee on Cancer stage III or IV melanoma immediately before and approximately 7 days after the commencement of BRAF inhibitor treatment and at the time of tumor progression. Immunohistochemical staining was carried out on the biopsies using specific antibodies for CD8, CD4, CD20, CD1a, and Granzyme B.Tumor infiltration by CD4(+) and CD8(+) lymphocytes increased markedly following BRAF inhibitor treatment (both ρ = 0.015). There was a correlation between the degree of tumor infiltration by CD8(+) and Granzyme B-expressing lymphocytes in post-BRAF inhibitor-treated biopsies (r = 0.690 and ρ = 0.013). Increased intratumoral CD8(+) lymphocyte expression was correlated with a reduction in tumor size and an increase in necrosis in posttreatment biopsies (r = -0.793, ρ = 0.011; and r = 0.761, ρ = 0.004, respectively).The increase in tumor-infiltrating lymphocytes induced by treatment with BRAF inhibitors provides strong support for conducting trials that combine BRAF inhibitors with immunotherapy in the hope of prolonging clinical responses.
Innate immune activation in neutrophilic asthma and bronchiectasis
Authors: J. L Simpson, T. V Grissell, J. Douwes, R. J Scott, M. J Boyle, P. G Gibson
Journal: Thorax (2006)

<b>Background:</b> The role of the innate immune system in the pathogenesis of asthma is unclear. Activation of innate immune receptors in response to bacterial lipopolysaccharide, viral infection and particulate matter triggers a pre-programmed inflammatory response, which involves interleukin (IL)8 and neutrophil influx. The inflammatory response in asthma is heterogeneous. <b>Aim:</b> To test the hypothesis that innate immune activation may be a relevant inflammatory mechanism in neutrophilic asthma where IL8 levels are increased. <b>Methods:</b> Induced sputum was obtained from non-smoking adults with asthma (n = 49), healthy controls (n = 13) and a positive reference group with bronchiectasis (n = 9). Subjects with asthma were classified into inflammatory subtypes using induced sputum cell counts. Sputum was examined for mRNA expression of the innate immune receptors toll-like receptor (TLR)2, TLR4 and CD14, and inflammatory cytokines. A separate sputum portion was dispersed and the supernatant assayed for surfactant protein A, IL8, soluble CD14 and endotoxin. <b>Results:</b> Expression of innate immune receptors was increased in subjects with bronchiectasis and neutrophilic asthma compared with other asthma subtypes and controls. Increased expression of the receptors TLR2, TLR4 and CD14, as well as the pro-inflammatory cytokines IL8 and IL1β, was observed. Subjects with neutrophilic asthma had higher airway levels of endotoxin than the other groups studied. <b>Conclusion:</b> There is evidence of activation of the innate immune system in asthma which results in the production of pro-inflammatory cytokines and may contribute to the pathogenesis of neutrophilic asthma.
Recycling side-effects into clinical markers for drug repositioning
Authors: Miquel Duran-Frigola, Patrick Aloy
Journal: Genome Medicine (2012)

Side-effects are the unintended consequence of therapeutic treatments, but they can also be seen as valuable read-outs of drug effects in humans; these effects are difficult to infer or predict from pre-clinical models. Indeed, some studies suggest that drugs with similar side-effect profiles may also share therapeutic properties through related mechanisms of action. A recent publication exploits this concept to systematically investigate new indications for already marketed drugs, and presents a strategy to get the most out of the tiny portion of chemicals that have proved to be effective and safe.
Cartilage destruction and bone erosion in arthritis: the role of tumour necrosis factor alpha
Authors: R. O Williams
Journal: Annals of the Rheumatic Diseases (2000)

Rheumatoid arthritis (RA) is a chronic disabling disease characterised by synovitis, destruction of cartilage and bone and, ultimately, loss of joint function. A great deal of research in rheumatology over the past two decades has focused on identifying cytokines and other mediators responsible for the inflammatory and degenerative processes in RA, with the aim of developing specific inhibitors or antagonists of therapeutic value. A key question in this research has been whether there is a degree of hierarchy in proinflammatory cytokine expression in RA, such that inhibiting the activity of a cytokine high up in the inflammatory cascade has an impact on the expression of downstream mediators of inflammation and joint damage.

Of the many cytokines thought to contribute to the inflammatory and degenerative changes that occur in RA, tumour necrosis factor α (TNFα) has emerged as being of major pathological significance. For example, TNFα was identified in the synovial membrane, and particularly at the cartilage-pannus junction, of patients with RA,1 and was found to be spontaneously produced by cultured synovial cells derived from RA patients.2 The in vitro properties of TNFα were also found to be consistent with a pathogenic role. Thus, TNFα promoted cartilage and bone resorption3 4 and induced the release of prostaglandin E2 and collagenase by synovial cells.5 In addition, TNFα was reported to play a part in fibrosis6and to facilitate inflammatory cell infiltration by promoting the adhesion of neutrophils and lymphocytes to endothelial cells.7 8 Evidence was also provided to suggest that TNFα induces the production of interleukin 1 (IL1), another potential mediator of joint damage in RA,9 as antibodies to TNFα were shown to diminish the production of IL1 by rheumatoid synovium derived mononuclear cells.2 Using a similar experimental system, it was subsequently shown …
RING Domain–Mediated Interaction Is a Requirement for MDM2's E3 Ligase Activity
Authors: Hidehiko Kawai, Vanessa Lopez-Pajares, Mihee M. Kim, Dmitri Wiederschain, Zhi-Min Yuan
Journal: Cancer Research (2007)

Abstract The RING domain of MDM2 that is essential for its E3 ligase activity mediates binding to itself and its structural homologue MDMX. Whereas it has been reported that RING domain interactions are critical, it is not well understood how they affect the E3 ligase activity of MDM2. We report that the E3 ligase activity requires the RING domain–dependent complex formation. In vivo, MDM2 and MDMX hetero-RING complexes are the predominant form versus the MDM2 homo-RING complex. Importantly, the MDM2/MDMX hetero-RING complexes exhibit a greater E3 ligase activity than the MDM2 homo-RING complexes. Disruption of the binding between MDM2 and MDMX resulted in a marked increase in both abundance and activity of p53, emphasizing the functional importance of this heterocomplex in p53 control. [Cancer Res 2007;67(13):6026–30]
Isolated knee monoarthritis heralding resectable non-small-cell lung cancer. A paraneoplastic syndrome not previously described
Authors: F. Cantini, L. Niccoli, C. Nannini, D. Chindamo, M. Bertoni, E. Cassara, C. Salvarani
Journal: Annals of the Rheumatic Diseases (2007)

To describe isolated knee monoarthritis as a paraneoplastic syndrome heralding non-small cell lung cancer (NSCLC), and to discuss its clinical characteristics.Clinical records of all consecutive, new outpatients with isolated knee monoarthritis observed from January 2000 to December 2005 were reviewed. A systematic review of Medline and Cochrane Library databases was performed to identify English-language articles related to rheumatological paraneoplastic syndromes associated with NSCLC.Over 6 years, 6654 new outpatients with different rheumatic disorders were observed. Of these, 296 (4.4%) presented with isolated monoarthritis of the knee. In five out of 296 patients (1.7%) this feature represented the initial manifestation of NSCLC. All five patients were middle-aged men, with a long history of heavy cigarette smoking, who had a non-erosive, isolated knee monoarthritis, with mild articular fluid collection of non-inflammatory type. NSCLC was resectable in all patients, and knee monoarthritis remitted with no relapse confirming its paraneoplastic nature. All five patients are in good condition after a median follow up of 41 months. The literature review revealed that paraneoplastic knee monoarthritis has not previously been reported.Knee monoarthritis may in some cases represent a paraneoplastic syndrome heralding NSCLC at an early stage.
Association of bone attrition with knee pain, stiffness and disability: a cross-sectional study
Authors: S. Reichenbach, P. A. Dieppe, E. Nuesch, S. Williams, P. M. Villiger, P. Juni
Journal: Annals of the Rheumatic Diseases (2010)

Bone pathologies as detected on MRI are associated with the presence of pain in knee osteoarthritis (OA). The authors examined whether bone attrition assessed on x-rays was associated with pain, stiffness and disability.The authors analysed x-rays of 1326 knees with OA from 783 individuals participating in the cross-sectional population-based Somerset and Avon Survey of Health. The diagnosis of OA was defined by the presence of osteophytes in anteroposterior (AP) or lateral views. Bone attrition was graded from 0 (no attrition) to 3 (severe attrition >10 mm) and Kellgren and Lawrence (K/L) scores were assigned on AP views. Logistic regression models adjusted for gender, age, body mass index, effusion and K/L scores were used to determine whether bone attrition was associated with pain, stiffness and disability.Pain was reported in 84 knees (74%) with radiographic bone attrition compared with 505 (42%) without bone attrition (adjusted OR 2.22, 95% CI 1.29 to 3.80). The adjusted OR was increased for day pain but not for night pain (p for interaction <0.001). Stiffness was reported for 85 knees with bone attrition (75%) and 437 knees without (36%) (adjusted OR 3.23, 95% CI 1.85 to 5.64). Disability was reported by 40 individuals with bone attrition (50%) and 140 individuals without (24%) (adjusted OR 2.09, 95% CI 1.19 to 3.68).Bone attrition detected on conventional x-rays using a simple cheap technique is strongly associated with the presence of day pain, stiffness and disability in knee OA.
Heterogeneous control of blood flow amongst different vascular beds
Authors: Caryl E. Hill, Jacqueline K. Phillips, Shaun L. Sandow
Journal: Medicinal Research Reviews (2000)

The control and maintenance of vascular tone is due to a balance between vasoconstrictor and vasodilator pathways. Vasomotor responses to neural, metabolic and physical factors vary between vessels in different vascular beds, as well as along the same bed, particularly as vessels become smaller. These differences result from variation in the composition of neurotransmitters released by perivascular nerves, variation in the array and activation of receptor subtypes expressed in different vascular beds and variation in the signal transduction pathways activated in either the vascular smooth muscle or endothelial cells. As the study of vasomotor responses often requires pre-existing tone, some of the reported heterogeneity in the relative contributions of different vasodilator mechanisms may be compounded by different experimental conditions. Biochemical variations, such as the expression of ion channels, connexin subtypes and other important components of second messenger cascades, have been documented in the smooth muscle and endothelial cells in different parts of the body. Anatomical variations, in the presence and prevalence of gap junctions between smooth muscle cells, between endothelial cells and at myoendothelial gap junctions, between the two cell layers, have also been described. These factors will contribute further to the heterogeneity in local and conducted responses. © 2000 John Wiley & Sons, Inc. Med Res Rev, 21, No. 1, 1–60, 2001
Diabetes Distress but Not Clinical Depression or Depressive Symptoms Is Associated With Glycemic Control in Both Cross-Sectional and Longitudinal Analyses
Authors: Lawrence Fisher, Joseph T. Mullan, Patricia Arean, Russell E. Glasgow, Danielle Hessler, Umesh Masharani
Journal: Diabetes Care (2009)

OBJECTIVE To determine the concurrent, prospective, and time-concordant relationships among major depressive disorder (MDD), depressive symptoms, and diabetes distress with glycemic control. RESEARCH DESIGN AND METHODS In a noninterventional study, we assessed 506 type 2 diabetic patients for MDD (Composite International Diagnostic Interview), for depressive symptoms (Center for Epidemiological Studies-Depression), and for diabetes distress (Diabetes Distress Scale), along with self-management, stress, demographics, and diabetes status, at baseline and 9 and 18 months later. Using multilevel modeling (MLM), we explored the cross-sectional relationships of the three affective variables with A1C, the prospective relationships of baseline variables with change in A1C over time, and the time-concordant relationships with A1C. RESULTS All three affective variables were moderately intercorrelated, although the relationship between depressive symptoms and diabetes distress was greater than the relationship of either with MDD. In the cross-sectional MLM, only diabetes distress but not MDD or depressive symptoms was significantly associated with A1C. None of the three affective variables were linked with A1C in prospective analyses. Only diabetes distress displayed significant time-concordant relationships with A1C. CONCLUSIONS We found no concurrent or longitudinal association between MDD or depressive symptoms with A1C, whereas both concurrent and time-concordant relationships were found between diabetes distress and A1C. What has been called “depression” among type 2 diabetic patients may really be two conditions, MDD and diabetes distress, with only the latter displaying significant associations with A1C. Ongoing evaluation of both diabetes distress and MDD may be helpful in clinical settings.
The Seattle Heart Failure Model
Authors: Wayne C. Levy, Dariush Mozaffarian, David T. Linker, Santosh C. Sutradhar, Stefan D. Anker, Anne B. Cropp, Inder Anand, Aldo Maggioni, Paul Burton, Mark D. Sullivan, Bertram Pitt, Philip A. Poole-Wilson, Douglas L. Mann, Milton Packer
Journal: Circulation (2006)

Background— Heart failure has an annual mortality rate ranging from 5% to 75%. The purpose of the study was to develop and validate a multivariate risk model to predict 1-, 2-, and 3-year survival in heart failure patients with the use of easily obtainable characteristics relating to clinical status, therapy (pharmacological as well as devices), and laboratory parameters. Methods and Results— The Seattle Heart Failure Model was derived in a cohort of 1125 heart failure patients with the use of a multivariate Cox model. For medications and devices not available in the derivation database, hazard ratios were estimated from published literature. The model was prospectively validated in 5 additional cohorts totaling 9942 heart failure patients and 17 307 person-years of follow-up. The accuracy of the model was excellent, with predicted versus actual 1-year survival rates of 73.4% versus 74.3% in the derivation cohort and 90.5% versus 88.5%, 86.5% versus 86.5%, 83.8% versus 83.3%, 90.9% versus 91.0%, and 89.6% versus 86.7% in the 5 validation cohorts. For the lowest score, the 2-year survival was 92.8% compared with 88.7%, 77.8%, 58.1%, 29.5%, and 10.8% for scores of 0, 1, 2, 3, and 4, respectively. The overall receiver operating characteristic area under the curve was 0.729 (95% CI, 0.714 to 0.744). The model also allowed estimation of the benefit of adding medications or devices to an individual patient’s therapeutic regimen. Conclusions— The Seattle Heart Failure Model provides an accurate estimate of 1-, 2-, and 3-year survival with the use of easily obtained clinical, pharmacological, device, and laboratory characteristics.
Effects of atrial pacing on atrio-sinus conduction and overdrive suppression in the isolated rabbit sinus node.
Authors: G Steinbeck, R Haberl, B Lüderitz
Journal: Circulation Research (1980)

We evaluated the effects of atrial pacing on atrio-sinus conduction and overdrive suppression in 15 isolated rabbit sinus node preparations.Decreasing the pacing cycle length from 400 to 200 msec increased atrio-sinus conduction time from 35 ± 10 msec (± SD) to 72 ± 25 msec, and various degrees of atrio-sinus block developed.Increase of conduction time was associated with a decrease of maximum diastolic potential and a marked decrease in action potential amplitude of the sinus node fibers, which gradually returned to control values after cessation of drive; both the changes in conduction times and transmembrane potentials were most pronounced in dominant pacemaker fibers of the sinus node and gradually diminished toward the atrium.An increase in pacing rate decreased the slope of phase 4 depolarization of dominant pacemaker cells after drive (overdrive suppression), until atrio-sinus block ensued; the latter accounted for both the shortening and increasing variation of sinus node recovery time following rapid drive.We conclude that neither pacing-induced release of acetylcholine nor stimulation of an electrogenic sodium pump provide a major contribution to overdrive suppression of sinus node pacemaker cells as the latter likely does in Purkinje fibers.Depression of phase 4 depolarization depended on the prior rate of beats propagated to the sinus node.Sinus node recovery time cannot be interpreted only in terms of overdrive suppression of the automatic process but is the result of a complex interaction between conduction and impulse formation in the sinus node.
Obstructive Sleep Apnea during REM Sleep and Hypertension. Results of the Wisconsin Sleep Cohort
Authors: Babak Mokhlesi, Laurel A. Finn, Erika W. Hagen, Terry Young, Khin Mae Hla, Eve Van Cauter, Paul E. Peppard
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Obstructive sleep apnea (OSA) is associated with hypertension.We aimed to quantify the independent association of OSA during REM sleep with prevalent and incident hypertension.We included adults enrolled in the longitudinal community-based Wisconsin Sleep Cohort Study with at least 30 minutes of REM sleep obtained from overnight in-laboratory polysomnography. Studies were repeated at 4-year intervals to quantify OSA. Repeated measures logistic regression models were fitted to explore the association between REM sleep OSA and prevalent hypertension in the entire cohort (n = 4,385 sleep studies on 1,451 individuals) and additionally in a subset with ambulatory blood pressure data (n = 1,085 sleep studies on 742 individuals). Conditional logistic regression models were fitted to longitudinally explore the association between REM OSA and development of hypertension. All models controlled for OSA events during non-REM sleep, either by statistical adjustment or by stratification.Fully adjusted models demonstrated significant dose-relationships between REM apnea-hypopnea index (AHI) and prevalent hypertension. The higher relative odds of prevalent hypertension were most evident with REM AHI greater than or equal to 15. In individuals with non-REM AHI less than or equal to 5, a twofold increase in REM AHI was associated with 24% higher odds of hypertension (odds ratio, 1.24; 95% confidence interval, 1.08-1.41). Longitudinal analysis revealed a significant association between REM AHI categories and the development of hypertension (P trend = 0.017). Non-REM AHI was not a significant predictor of hypertension in any of the models.Our findings indicate that REM OSA is cross-sectionally and longitudinally associated with hypertension. This is clinically relevant because treatment of OSA is often limited to the first half of the sleep period leaving most of REM sleep untreated.
Tendons – time to revisit inflammation
Authors: Jonathan D Rees, Matthew Stride, Alex Scott
Journal: British Journal of Sports Medicine (2013)

It is currently widely accepted among clinicians that chronic tendinopathy is caused by a degenerative process devoid of inflammation. Current treatment strategies are focused on physical treatments, peritendinous or intratendinous injections of blood or blood products and interruption of painful stimuli. Results have been at best, moderately good and at worst a failure. The evidence for non-infammatory degenerative processes alone as the cause of tendinopathy is surprisingly weak. There is convincing evidence that the inflammatory response is a key component of chronic tendinopathy. Newer anti-inflammatory modalities may provide alternative potential opportunities in treating chronic tendinopathies and should be explored further.
Exercise during pregnancy
Authors: K. Duckitt
Journal: BMJ (2011)

Eat for one, exercise for two

With the start of the London 2012 Olympics less than a year away, athletes such as Paula Radcliffe and the Canadian heptathlete, Jessica Zelinka, remind us that it is possible not only to return to world class competition after having a baby but also to continue training—albeit with some modifications—throughout pregnancy. The prevalence of obesity is increasing: in 2007, 24% of women in the United Kingdom aged 16 and over were obese compared with only 16% in 1993. One of the aims of the London 2012 Olympic bid was to encourage the whole population to become more physically active. This should include pregnant women too.

Recognising the beneficial effects of exercise during pregnancy is not new. In 1900, J M Ballantyne, who helped pioneer antenatal care—or as he put it pre-maternity care—in Edinburgh, designed a card to make sure essential advice during pregnancy was remembered and recorded by his pre-maternity nurses. This included a tick box regarding exercise and rest.1 In 1945, the textbook Williams Obstetrics advised …
The reinterpretation hypothesis: Explanation or redescription?
Authors: José Luis Bermúdez
Journal: Behavioral and Brain Sciences (2008)

Abstract Penn et al. propose the relational reinterpretation hypothesis as an explanation of the profound discontinuities that they identify between human and nonhuman cognition. This hypothesis is not a genuine replacement for the explanations that they reject, however, because as it stands, it simply redescribes the phenomena it is trying to explain.