tbuckley/cabot-search huggingface dataset:
A Role of Suppressor of Cytokine Signaling 3 (SOCS3/CIS3/SSI3) in CD28-mediated Interleukin 2 Production
Authors: Akira Matsumoto, Yoh-ichi Seki, Ryosuke Watanabe, Katsuhiko Hayashi, James A. Johnston, Yohsuke Harada, Ryo Abe, Akihiko Yoshimura, Masato Kubo
Journal: The Journal of Experimental Medicine (2003)

Suppressor of cytokine signaling (SOCS)3 has been characterized as a negative feedback regulator in cytokine-mediated Janus kinase signal transducer and activator of transcription signaling. However, this study shows that T cells from transgenic mice expressing SOCS3 exhibit a significant reduction in interleukin (IL)-2 production induced by T cell receptor cross-linking when T cells are costimulated with CD28. Decreased protein expression in SOCS3+/− mice enhanced CD28-mediated IL-2 production, clearly indicating the correlation between expression level of SOCS3 and IL-2 production ability. The SOCS3 protein interacted with phosphorylated CD28 through its SH2 domain but not the kinase inhibitory region. In addition, a point mutation in the SOCS3 SH2 domain attenuated the inhibition of CD28 function in IL-2 promoter activation. Committed T helper (Th)2 cells exclusively expressed SOCS3 and production of Th2 cytokines, such as IL-4 and IL-5, was much less dependent on CD28 costimulation compared with interferon γ and IL-2 production in Th1 cells. Consistent with this notion, the expression level of SOCS3 in early T cell activation influenced the ability of IL-2 production induced by CD28 costimulation. Therefore, the SOCS3 may play an alternative role in prohibiting excessive progression of CD28-mediated IL-2 production.
Protective antigenic determinant of streptococcal M protein shared with sarcolemmal membrane protein of human heart.
Authors: J B Dale, E H Beachey
Journal: The Journal of Experimental Medicine (1982)

We present definitive evidence that at least one protective antigenic determinant on type 5 M protein of group A streptococci evokes antibody that is cross-reactive with human heart tissue. One of nine rabbits immunized with a peptide fragment of type 5 M protein (pep M5) produced antibody that cross-reacted by immunofluorescence with sarcolemmal membranes of human heart. The cross-reactive antibody could be removed by absorbing the antiserum with sarcolemmal membranes, types 5 and 19 streptococci, or their pepsin-extracted M proteins, but with no other serotypes tested. Although each of the pep M5 immune sera was opsonic for type 5 streptococci, only the heart-reactive antiserum opsonized type 19 streptococci. The opsonization of type 19 streptococci was abolished by absorbing the antiserum with sarcolemmal membranes isolated from human heart tissue. Purified heart-reactive antibodies eluted from sarcolemmal membranes opsonized both types 5 and 19 streptococci, indicating that the heart cross-reactive determinant of type 5 M protein is cross-protective. The cross-reactive antigen was purified by affinity chromatography from detergent extracts of sarcolemmal membranes and determined to be a complex protein composed of four subunits apparently linked by disulfide bonds.
Altruistic punishment as an explanation of hunter-gatherer cooperation: How much has experimental economics achieved?
Authors: Robert Sugden
Journal: Behavioral and Brain Sciences (2012)

The discovery of the altruistic punishment mechanism as a replicable experimental result is a genuine achievement of behavioural economics. The hypothesis that cooperation in hunter-gatherer societies is sustained by altruistic punishment is a scientifically legitimate conjecture, but it must be tested against real-world observations. Guala's doubts about the evidential support for this hypothesis are well founded.
Survivin, a Member of the Inhibitor of Apoptosis Family, Is Induced by Photodynamic Therapy and Is a Target for Improving Treatment Response
Authors: Angela Ferrario, Natalie Rucker, Sam Wong, Marian Luna, Charles J. Gomer
Journal: Cancer Research (2007)

Abstract We observed that photodynamic therapy (PDT) induces the expression and phosphorylation of the inhibitor of apoptosis (IAP) protein survivin in murine and human cancer cells and tumors. Survivin inhibits caspase-9, blocks apoptosis, and is associated with resistance to chemotherapy and radiation. Survivin is a client protein for the 90-kDa heat shock protein (Hsp-90), and the binding of survivin to Hsp-90 assists in the maturation, proper folding, assembly, and transport of this IAP protein. A derivative of the antibiotic geldanamycin, 17-allylamino-17-demethoxygeldanamycin (17-AAG), interferes with proper binding of client proteins, such as survivin, to Hsp-90 and leads to misfolding of client proteins, ubiquination, and proteasome degradation. We hypothesized that PDT efficacy may be reduced by treatment-mediated expression and phosphorylation of survivin, and therefore, targeting the survivin pathway could increase PDT responsiveness. To address this hypothesis, we examined cellular and molecular responses following exposure to PDT, 17-AAG, and the combination of PDT plus 17-AAG in human BT-474 breast cancer cells using Photofrin and NPe6 as photosensitizers. Cells treated with the combination of PDT and 17-AAG exhibited decreased expression of the Hsp-90 client proteins phosphorylated survivin, phosphorylated Akt, and Bcl-2. The decreased expression of these client proteins was accompanied by higher apoptotic indexes and increased cytotoxicity. To confirm a specific role for survivin in modulating PDT, we used a human melanoma cell line, YUSAC2/T34A-C4, stably transfected with an inducible dominant-negative survivin gene under the control of a tetracycline-regulated (tet-off) promoter. PDT treatment of melanoma cells expressing the dominant-negative survivin resulted in increased cleavage of the caspase substrate poly(ADP-ribose) polymerase, apoptosis, and cytotoxicity when compared with results following PDT of the same melanoma cell line expressing wild-type survivin. These results show for the first time that targeting survivin and possibly other Hsp-90 client proteins improves in vitro PDT responsiveness and suggest that manipulation of the antiapoptotic pathway maintained by survivin may enhance PDT-mediated cancer therapy. [Cancer Res 2007;67(10):4989–95]
Lack of Telomerase Gene Expression in Alternative Lengthening of Telomere Cells Is Associated with Chromatin Remodeling of the <i>hTR</i> and <i>hTERT</i> Gene Promoters
Authors: Stuart P. Atkinson, Stacey F. Hoare, Rosalind M. Glasspool, W. Nicol Keith
Journal: Cancer Research (2005)

Abstract The presence of active telomere maintenance mechanisms in immortal cells allows the bypass of senescence by maintaining telomere length. In most immortal cell lines and tumors, telomere maintenance is attributable to telomerase reactivation. However, a number of immortal cell lines and tumors can achieve telomere maintenance in the absence of detectable telomerase activity by the alternative lengthening of telomere (ALT) mechanism. Epigenetic mechanisms have been implicated in the regulation of telomerase expression. We show that specific modifications within the chromatin environment of the hTR and hTERT promoters correlate with expression of hTR and hTERT in ALT, normal and telomerase-positive tumor cell lines. Lack of expression of hTR and hTERT in ALT cell lines is associated with histone H3 and H4 hypoacetylation and methylation of Lys9 histone H3. Conversely, hTR and hTERT expression in telomerase-positive cell lines is associated with hyperacetylation of H3 and H4 and methylation of Lys4 H3. Methylation of Lys20 H4 was not linked to gene expression but instead was specific to the hTR and hTERT promoters of ALT cells. This may provide an insight into the differences between ALT and telomerase-positive cells as well as a novel marker for the ALT phenotype. Treatment of normal and ALT cells with 5-azadeoxycytidine in combination with Trichostatin A caused chromatin remodeling of both promoters and reactivation of hTR and hTERT expression in ALT and normal cell lines. This data establishes a definite link between the chromatin environment of the telomerase gene promoters and transcriptional activity.
Neoadjuvant chemotherapy and radiotherapy followed by surgery in selected patients with stage IIIB non-small-cell lung cancer: a multicentre phase II trial
Authors: Roger Stupp, Michael Mayer, Roger Kann, Walter Weder, Abderahim Zouhair, Daniel C Betticher, Arnaud D Roth, Rolf A Stahel, Sabine Balmer Majno, Solange Peters, Lorenz Jost, Markus Furrer, Sandra Thierstein, Ralph A Schmid, Shu-Fang Hsu-Schmitz, René-Olivier Mirimanoff, Hans-Beat Ris, Miklos Pless
Journal: The Lancet Oncology (2009)
Cholesterol Reduction Yields Clinical Benefit
Authors: A. Lawrence Gould, Jacques E. Rossouw, Nancy C. Santanello, Joseph F. Heyse, Curt D. Furberg
Journal: Circulation (1998)

Background —We determined the effect of incorporating the results of eight recently published trials of Hmg CoA reductase inhibitors (“statins”) on the conclusions from our previously published meta-analysis regarding the clinical benefit of cholesterol lowering. Methods and Results —We used the same analytic approach as in our previous investigation, separating the specific effects of cholesterol lowering from the effects attributable to the different types of intervention studied. The reductions in coronary heart disease (CHD) and total mortality risk observed for the statins fell near the predictions from our earlier meta-analysis. Including the statin trial findings into the calculations led to a prediction that for every 10 percentage points of cholesterol lowering, CHD mortality risk would be reduced by 15% ( P &lt;.001), and total mortality risk would be reduced by 11% ( P &lt;.001), as opposed to the values of 13% and 10%, respectively, reported previously. Cholesterol lowering in general and by the statins in particular does not increase non-CHD mortality risk. Conclusions —Adding the results from the statin trials confirmed our original conclusion that lowering cholesterol is clinically beneficial. The relationships (slope) between cholesterol lowering and reduction in CHD and total mortality risk became stronger, and the standard error of the estimated slopes decreased by about half. Use of statins does not increase non-CHD mortality risk. The effect of the statins on CHD and total mortality risk can be explained by their lipid-lowering ability and appears to be directly proportional to the degree to which they lower lipids.
15(<i>S</i>)-Hydroxyeicosatetraenoic Acid–Induced Angiogenesis Requires STAT3-Dependent Expression of VEGF
Authors: Kalyan Srivastava, Venkatesh Kundumani-Sridharan, Baolin Zhang, Arun K. Bajpai, Gadiparthi N. Rao
Journal: Cancer Research (2007)

Abstract 15(S)-Hydroxyeicosatetraenoic acid [15(S)-HETE] activated signal transducer and activator of transcription 3 (STAT3) as measured by its tyrosine phosphorylation, translocation from the cytoplasm to the nucleus, DNA binding, and reporter gene activity in human dermal microvascular endothelial cells (HDMVEC). Inhibition of STAT3 activation via adenovirus-mediated expression of its dominant-negative mutant suppressed 15(S)-HETE–induced HDMVEC migration and tube formation in vitro and aortic ring and Matrigel plug angiogenesis in vivo. 15(S)-HETE induced the expression of vascular endothelial growth factor (VEGF) in a time- and STAT3-dependent manner in HDMVEC. In addition, neutralizing anti-VEGF antibodies blocked 15(S)-HETE–induced HDMVEC migration and tube formation in vitro and aortic ring and Matrigel plug angiogenesis in vivo. Together, these results show for the first time that 15(S)-HETE–induced angiogenesis requires STAT3-dependent expression of VEGF. In view of these findings, it is suggested that eicosanoids, particularly 15(S)-HETE, via its capacity to stimulate angiogenesis, may influence the progression of cancer and vascular disease. [Cancer Res 2007;67(9):4328–36]
The effect of heme oxygenase-1 complexed with collagen on MSC performance in the treatment of diabetic ischemic ulcer
Authors: Chunli Hou, Lei Shen, Qiang Huang, Jianhong Mi, Yangxiao Wu, Mingcan Yang, Wen Zeng, Li Li, Wen Chen, Chuhong Zhu
Journal: Biomaterials (2012)
Jet and ultrasonic nebuliser output: use of a new method for direct measurement of aerosol output.
Authors: J H Dennis, S C Stenton, J R Beach, A J Avery, E H Walters, D J Hendrick
Journal: Thorax (1990)

Output from jet nebulisers is calibrated traditionally by weighing them before and after nebulisation, but the assumption that the weight difference is a close measure of aerosol generation could be invalidated by the concomitant process of evaporation. A method has been developed for measuring aerosol output directly by using a solute (fluoride) tracer and aerosol impaction, and this has been compared with the traditional weight loss method for two Wright, six Turbo, and four Micro-Cirrus jet nebulisers and two Microinhaler ultrasonic nebulisers. The weight loss method overestimated true aerosol output for all jet nebulisers. The mean aerosol content, expressed as a percentage of the total weight loss, varied from as little as 15% for the Wright jet nebulisers to 54% (range 45-61%) for the Turbo and Micro-Cirrus jet nebulisers under the operating conditions used. In contrast, there was no discrepancy between weight loss and aerosol output for the ultrasonic nebulisers. These findings, along with evidence of both concentrating and cooling effects from jet nebulisation, confirm that total output from jet nebulisers contains two distinct fractions, vapour and aerosol. The vapour fraction, but not the aerosol fraction, was greatly influenced by reservoir temperature within the nebuliser; so the ratio of aerosol output to total weight loss varied considerably with temperature. It is concluded that weight loss is an inappropriate method of calibrating jet nebuliser aerosol output, and that this should be measured directly.
AMPK deficiency in cardiac muscle results in dilated cardiomyopathy in the absence of changes in energy metabolism
Authors: Miranda M. Sung, Beshay N. Zordoky, Adam L. Bujak, James S.V. Lally, David Fung, Martin E. Young, Sandrine Horman, Edward J. Miller, Peter E. Light, Bruce E. Kemp, Gregory R. Steinberg, Jason R.B. Dyck
Journal: Cardiovascular Research (2015)

AMP-activated protein kinase (AMPK) is thought to be a central player in regulating myocardial metabolism and its activation has been shown to inhibit cardiac hypertrophy. Recently, mice with muscle-specific deletion of AMPK β1/β2 subunits (AMPKβ1β2-deficient mice, β1β2M-KO) have been generated and possess <10% of normal AMPK activity in muscle. However, how/if dramatic AMPK deficiency alters cardiac metabolism, function, or morphology has not been investigated. Therefore, the aim of this study was to determine whether a significant loss of AMPK activity alters cardiac function, metabolism, and hypertrophy, and whether this may play a role in the pathogenesis of heart failure. β1β2M-KO mice exhibit an approximate 25% reduction in systolic and diastolic function compared with wild-type (WT) littermates. Despite the well-documented role of AMPK in controlling myocardial energy metabolism, there was no difference in basal glucose and fatty acid oxidation rates between β1β2M-KO and WT mice. However, there was reduced AMPK-mediated phosphorylation of troponin I in β1β2M-KO and reduced ventricular cell shortening in the presence of low Ca2+, which may explain the impaired cardiac function in these mice. Interestingly, β1β2M-KO mice did not display any signs of compensatory cardiac hypertrophy, which could be attributed to impaired activation of p38 MAPK. β1β2M-KO mice display evidence of dilated cardiomyopathy. This is the first mouse model of AMPK deficiency that demonstrates cardiac dysfunction in the absence of pathological stress and provides insights into the role of AMPK in regulating myocardial function, metabolism, hypertrophy, and the progression to heart failure.
A classic consultation
Authors: L. Farrell
Journal: BMJ (2011)

Give a dog a bad name, said Flashy, it’s far harder to live down a good one. So when the Greek heroes learnt that I had fixed Heracles’ bursitis, the waiting room was soon bursting with Homeric valour and girded loins. The testosterone was sky high, an equal temper of heroic hearts and body oil, and we had to give the Trojans a separate room.⇑

Some of it was predictable: Tithonus had dementia, and Polyphemus had glaucoma. But there was also the …
New Concepts Relating to the Preexcitation Syndrome
Authors: M. Irené Ferrer
Journal: JAMA (1967)

Since its original description in 1930, considerable controversy has centered on the basic explanation for the anomalous atrioventricular (AV) conduction seen in the preexcitation or Wolff-Parkinson-White (WPW) syndrome.<sup>1</sup>An abnormally short PR interval associated with a prolonged QRS containing a delta wave (an initial slurring or thickening of the first wave of the QRS complex, be this an R or an S) in the presence of sinus rhythm is the classic criteria for its electrocardiographic diagnosis.<sup>2</sup>The delta wave represents the early excitation of the ventricles. However, in addition to this form of anomalous AV conduction, several variants have come to be recognized.<sup>3-5</sup>These include a short PR interval (less than 0.12 seconds) with a normal QRS, ie, a QRS with normal duration and no delta wave and a normal or even prolonged PR interval coupled to a prolonged QRS containing a delta wave. Recent and very
Predictors of abnormal cardiovascular autonomic function measured by frequence domain analysis of heart rate variability and conventional tests in patients with type 1 diabetes.
Authors: S Mäkimattila, A Schlenzka, M Mäntysaari, R Bergholm, P Summanen, P Saar, H Erkkilä, H Yki-Järvinen
Journal: Diabetes Care (2000)

OBJECTIVE: Frequency domain analysis of heart rate variability (HRV) is used to assess cardiovascular autonomic function. There are no prospective data on the sensitivity of its various components to glycemia or other diabetes-related risk factors compared with conventional tests and with other complications of diabetes. RESEARCH DESIGN AND METHODS: In 1985, possible risk factors of future complications were determined in 115 children with type 1 diabetes. In 1996, the presence of complications (HRV analysis, conventional tests of autonomic function, urinary albumin excretion rate [UAER], and retinopathy) were assessed in 83 of these patients (age 32 +/- 1 years, duration of diabetes 22 +/- 1 years). RESULTS: Poor glycemic control (measured as lifetime glycemic exposure or HbA1c in 1985) was the most important independent predictor of decreases in all measures of absolute power of HRV (total power [TP] and very low frequency, low frequency [LF], and high frequency [HF] power) and square root of the mean square of R-R interval differences but not of changes of normalized measures or ratios (normalized HF and LF LF/HF). Other significant independent predictors of autonomic dysfunction were late age of onset of diabetes, female sex, and high BMI. To examine the sensitivity of the various tests to glycemia, the patients were divided into tertiles based on lifetime glycemic exposure (A1c months). Glycemic exposure in the tertiles averaged 194 +/- 25 A1c months (20 years of HbA1c 0.8% above normal), 556 +/- 19 A1c months(20 years of HbA1c 2.3% above normal), and 963 +/- 30 A1c months (20 years of HbA1c 4% above normal). Tests of complications that were significantly abnormal in patients already in the lowest tertile and were correlated with glycemia were TP and severity of retinopathy. Of conventional tests, only the ratio of length of R-R intervals during expiration to inspiration (E/I ratio) was significantly related to glycemic exposure, but it required high glycemic exposure (20 years of HbA1c 4% above normal) to be abnormal. UAER was significantly increased only in the highest tertile of glycemic exposure. CONCLUSIONS: TP and retinopathy score were much more sensitive to antecedent glycemia than conventional tests of autonomic function or UAER and were significantly abnormal in patients exposed to approximately 20 years' duration of an HbA1c 0.8% above normal.
Thiosulfate Reduces Calcium Phosphate Nephrolithiasis
Authors: John R. Asplin, Susan E. Donahue, Christina Lindeman, Anne Michalenka, Kelly Laplante Strutz, David A. Bushinsky
Journal: Journal of the American Society of Nephrology (2009)

An uncontrolled trial reported that sodium thiosulfate reduces formation of calcium kidney stones in humans, but this has not been established in a controlled human study or animal model. Using the genetic hypercalciuric rat, an animal model of calcium phosphate stone formation, we studied the effect of sodium thiosulfate on urine chemistries and stone formation. We fed genetic hypercalciuric rats normal food with or without sodium thiosulfate for 18 wk and measured urine chemistries, supersaturation, and the upper limit of metastability of urine. Eleven of 12 untreated rats formed stones compared with only three of 12 thiosulfate-treated rats (P < 0.002). Urine calcium and phosphorus were higher and urine citrate and volume were lower in the thiosulfate-treated rats, changes that would increase calcium phosphate supersaturation. Thiosulfate treatment lowered urine pH, which would lower calcium phosphate supersaturation. Overall, there were no statistically significant differences in calcium phosphate supersaturation or upper limit of metastability between thiosulfate-treated and control rats. In vitro, thiosulfate only minimally affected ionized calcium, suggesting a mechanism of action other than calcium chelation. In summary, sodium thiosulfate reduces calcium phosphate stone formation in the genetic hypercalciuric rat. Controlled trials testing the efficacy and safety of sodium thiosulfate for recurrent kidney stones in humans are needed.
Radiological hand involvement in systemic sclerosis
Authors: J Avouac, H Guerini, J Wipff, N Assous, A Chevrot, A Kahan, Y Allanore
Journal: Annals of the Rheumatic Diseases (2006)

<b>Background:</b> The osteoarticular and soft tissue structures of the hand may be involved in systemic sclerosis (SSc), causing functional disability. <b>Objective:</b> To assess radiological hand features in a cross sectional study of SSc patients and in controls. <b>Methods:</b> Hand radiology was done systematically in patients with SSc seen over a two year period and in unselected controls with rheumatoid arthritis or digital trauma. Two independent investigators blind to the diagnosis carried out the radiological assessment. <b>Results:</b> 120 consecutive SSc patients (median (range) age, 56.5 (20 to 90) years; disease duration, 6 (0 to 42) years) and 42 controls (22 with rheumatoid arthritis and 20 with digital trauma) were studied. Radiological abnormalities in SSc patients included erosion (21%), joint space narrowing (28%), arthritis (defined by concomitant erosion and joint space narrowing) (18%), radiological demineralisation (23%), acro-osteolysis (22%), flexion contracture (27%), and calcinosis (23%). In univariate and multivariate analysis, the resorption of distal phalanges was significantly associated with digital ulcers, extra-articular calcification, and pulmonary arterial hypertension; flexion contracture was associated with the diffuse cutaneous form and high HAQ (Health Assessment Questionnaire) disability score. Calcinosis was most often seen in patients with digital ulcers, but was similarly observed in patients with the diffuse or limited cutaneous subtypes. <b>Conclusions:</b> Flexion contracture was associated with disability and occurred in patients with the diffuse cutaneous subtype of SSc, consistent with the tendency towards fibrosis and functional impairment of this subtype. Calcinosis and acro-osteolysis were both associated with vascular complications, highlighting a potential role of vascular injury in such lesions.