tbuckley/cabot-search huggingface dataset:
Abstract 18540: Heme Oxygenase 1 Activity and Expression Suppresses a Proinflammatory Phenotype in Monocytes and Correlates With Endothelial Function in Mice and Humans
Authors: Philip Wenzel, Heidi Rossmann, Christian Müller, Sabine Kossmann, Canan Simsek, Swenja Kröller-Schön, Eberhard Schulz, Matthias Oelze, Andreas Daiber, Karl Lackner, Renate Schnabel, Stefan Blankenberg, Tanja Zeller, Philipp Wild, Thomas Münzel
Journal: Circulation (2014)

Background: Heme oxygenase-1 (HO-1) confers protection to the vasculature and suppresses inflammatory properties of monocytes and macrophages. It is unclear how HO-1 activity and expression determine the extent of vascular dysfunction in mice and humans. Methods and results: Decreasing HO activity was parallelled by decreasing aortic HO-1, eNOS and phospho-eNOS (ser1177) protein expression in HO-1 deficient mice, whereas aortic expression of nox2 showed a stepwise increase in HO-1+/- and HO-1-/- mice as compared to HO-1+/+ controls. Aortic superoxide formation increased depending on the extent of HO-1 deficiency and was blunted by the PKC inhibitor chelerythrine, indicating activation of the NADPH oxidase. When subjected to disease models of vascular dysfunction - angiotensin II-infusion (ATII, 0.1mg/kg/d for 7d), streptozotocin-induced diabetes mellitus and aging - HO-1 deficient mice showed an increased vascular dysfunction (shown by isometric tension studies) that was inversely correlated with HO activity. In a primary prevention population based cohort (the Gutenberg Health Study, GHS), we assessed length polymorphisms of the HO-1 promoter region, established a bipolar frequency pattern of allele length (long vs short repeats) in 4937 individuals and found a moderately significant association with flow mediated dilation of the brachial artery (FMD) in individuals with arterial hypertension. Monocytic HO-1 mRNA expression was positively correlated with CD14 expression indicating proinflammatory monocytes (p&lt;0.001) and inversely with FMD in 733 hypertensive individuals of the GHS. ATII-infused HO-1+/+ mice had a significant infiltration of proinflammatory CD11b+Ly6Chi monocytes into the aortic wall, which was sharpely increased in HO-1+/- and HO-1-/- mice, providing a mechanistic link of the monocyte phenotype determined by HO-1 and vascular dysfunction in arterial hypertension. Conclusions: We here present evidence that HO activity and expression and inversely correlates with vascular dysfunction and NADPH oxidase mediated oxidative stress in mice and humans. We conclude, that HO-1 is a regulator of vascular function in hypertension via determining the phenotype of inflammatory circulating and infiltrating monocytes.
Mixed Culture Cytopathogenicity Induced by Virus Preparations Derived From Cultures Infected by Simian Sarcoma Virus&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: S R Rangan, M C Wong, P J Ueberhorst, D V Ablashi
Journal: JNCI Journal of the National Cancer Institute (1972)

The development of an XC cell mixed-culture cytopathogenic reaction in dog embryo Fibroblasts and a canine tumor cell line, M.132-1, infected with simian sarcoma virus preparations are described.
Abstract 111: Paradoxical Exacerbation of Arrhythmias by the Cardioprotective Mitochondrial K-ATP Channel Agonist Diazoxide in Type 2 Diabetes Mellitus
Authors: Chaoqin Xie, Basil S Karam, Fadi G Akar
Journal: Circulation Research (2014)

Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular complications including ischemia reperfusion injury (IR). Activation of mitochondrial KATP channels by Diazoxide (DZX) promotes beta cell rest and suppresses glucose production in patients. We hypothesized that DZX prevents IR arrhythmias in T2DM owing to its dual cardioprotective &amp; antidiabetic property. Methods: Obese Zucker Diabetic Fatty (ZDF) rats (n=17) with established T2DM were studied. Control groups consisted of lean ZDF (n=6) and normal Sprague Dawley (n=10) rats. High resolution optical action potential (AP) mapping was performed in hearts before and after challenge with no flow ischemia for 12min followed by reperfusion. Results: Basal properties including rate dependence of conduction velocity (CV) and AP duration (APD) were not significantly (p=NS) altered in T2DM. Remarkably, ischemia uncovered major differences between groups as APD in T2DM failed to adapt to the ischemic challenge. Unlike APD, CV was reduced in all groups. DZX paradoxically promoted arrhythmias as all DZX (30uM) treated T2DM hearts exhibited ischemia related VT. In contrast, untreated T2DM (0/5) and control (0/9) hearts did not exhibit VT during ischemia. Underlying arrhythmic vulnerability of DZX treated T2DM hearts was a pronounced reduction (by 75% p&lt;0.01) of the cardiac wavelength (WL) caused by accelerated APD shortening in response to ischemia. Upon reperfusion, T2DM and control groups exhibited a high (60% T2DM vs 44% control, p=NS) rate of VT, although the VT cycle length in T2DM was significantly longer (72 vs 44ms, p&lt;0.01) suggesting a more adverse substrate modification by IR injury. Blocking the inner membrane anion channel (IMAC) fully abrogated reperfusion VT in T2DM. Conclusion: Ischemia uncovers a paradoxical resistance of T2DM hearts to APD adaptation. DZX reverses this property resulting in accelerated APD &amp; WL shortening. This promotes reentrant VT during ischemia. Therefore, the anti-diabetic agent DZX should be avoided in T2DM patients at risk of ischemic events. Instead IMAC is an effective antiarrhythmic target for these patients.
Paper on suicidality and aggression during antidepressant treatment was flawed and the press release was misleading
Authors: Bernadka Dubicka, Alys Cole-King, Shirley Reynolds, Paul Ramchandani
Journal: BMJ (2016)

We have concerns about the editorial process involved in the publication of Sharma and colleagues’ article.1 The article is fundamentally flawed in presentation and logic, and the results were further misrepresented by The BMJ press release. The BMJ is highly regarded and anything it publishes will probably be taken as fact by journalists and the public. It is therefore crucial that The BMJ operates with the highest levels of peer review scrutiny and editorial comment.

Depression in young people is underdiagnosed and undertreated.2 Parents often feel conflicted or guilty. Suicide is a highly emotional topic and the claim that antidepressants increase suicide in young people is likely to …
RELATION OF BIOCHEMICAL EFFECTS OF EPINEPHRINE TO ITS MUSCULAR EFFECTS
Authors: Sydney Ellis
Journal: Pharmacological Reviews (1959)

The actions of epinephrine on muscles are not dependent on either oxidative metabolism or on the energy produced from carbohydrate through the Embden-Meyerhof glycolytic pathway.  Nonetheless, the activation of glycogenolysis may be important for the muscular effects of epinephrine.  The apparent discrepancies of the two statements relating to carbohydrate metabolism may be resolved by findings which implicate the hexosemonophosphates in the control of muscle contractility.  In their responses to epinephrine, muscles appear to fall into two groups: 1) excited smooth muscles which lose potassium, and 2) inhibited smooth muscle, skeletal muscle and cardiac muscle which retain or increase their potassium.  Changes in the ionic environment of various muscle cells modify the degree of response and, in some instances, the duration of the response to epinephrine.
The British Society of Gastroenterology
Authors: A M Tomkins, S Wright, W P James, B S Drasar
Journal: Gut (1975)

of Southampton on 10 to 12 April 1975.On the first morning scientific papers were read at a meeting of the Liver Club and the Council of the British Society of Gastro- enterology met in the afternoon.On Friday morning a symposium on 'Immunology of liver disease' was held jointly with the Liver Club with Professor Ralph Wright in the Chair, and there was a meeting of the Path- ologists' Group in the afternoon.The spring meeting banquet was held at Beaulieu Abbey on Friday evening.Also on Friday afternoon and on Saturday morning there were sessions devoted to scientific papers on 'Coeliac syndromes' (Chairman:
Successful treatment with minimal chemotherapy followed by low-dose involved field radiotherapy in children with Hodgkin's disease: A 20-year experience in a single institution in Greece
Authors: A. G. Pourtsidis, D. Doganis, M. Baka, D. Bouhoutsou, M. Varvoutsi, M. Servitzoglou, S. Kosmidis, M. Synodinou, C. Strantzia, H. Kosmidis
Journal: Journal of Clinical Oncology (2009)

10052 Background: The vast majority of children with Hodgkin's disease (HD) nowadays have an excellent chance of definite cure. The high curative rates as well as the prevention of late effects have to be among aims when managing children with HD. The purpose of our retrospective study was to report the outcome and prognostic factors of patients (pts) less than 15 years of age with HD treated with chemotherapy (CT) followed by low dose radiation from 1987 to 2006. Methods: We studied 58 children analyzing the following data: age, sex, stage, histology, therapy correlating these with the outcome of pts. Among 35 boys and 23 girls, age at diagnosis 4.5 - 15 years (median 12), all aged 7 years or less were boys (8/58). Nodurar sclerosis was the predominant histology subtype (69%) and 45% had advanced disease (stages III or IV). According the study period pts with early stage received 4 cycles of ABVD or VBVP and those with advanced stage disease alternating 3 cycles of MOPP/ABVD or 2 of MOPP/ABVP for stage III and alternating 3 cycles of MOPP/ABVD or 2 OPPA plus 4 COPP for stage IV. All pts had a good response (more than a 70% reduction) after initial CT and received 20 Gy of RT to initially involved fields. Results: Complete remission (CR) was achieved in all patients. Chemo- and radio-therapy were well tolerated. Fifty-three pts (DFS: 91.4%) live in their first complete remission. In 5 pts (8.6 %) relapse occurred, 20 -65 months from dx (median 25 mo). All received salvage treatment in combination with high dose CT and autologous stem-cell transplantation (SCT). Of the 5 relapsed all live 21 - 207 months (median 75 mo) from the dx of relapse and 41 - 232 mo (median 99) from the dx of disease. Second (thyroid cancer) plus third malignancy in one (osteosarcoma) was detected in 3 pts and all are alive. Finally for our group the overall survival is 100% and all children are alive 25 - 264 mo from dx (median 145 mo) and the event free survival is 86.2% (50/58). No factors related to the outcome were detected. Conclusions: In conclusion combined-modality therapy remains the standard of care for children with HD. However, there may be a significant number who can be cured with chemotherapy alone. At this moment the main question is: who can be cured without RT? No significant financial relationships to disclose.
Initial results from ASSURE (E2805): Adjuvant sorafenib or sunitinib for unfavorable renal carcinoma, an ECOG-ACRIN-led, NCTN phase III trial.
Authors: Naomi B. Haas, Judith Manola, Robert G. Uzzo, Michael B. Atkins, George Wilding, Michael Pins, Michael A. S. Jewett, Christopher J. Kane, David Cella, Lynne I. Wagner, Bob Coomes, Christopher G. Wood, Janice P. Dutcher, Keith Flaherty, Robert S. DiPaola
Journal: Journal of Clinical Oncology (2015)

403 Background: Patients (pts) with locally advanced renal cell carcinoma (RCC) are not uniformly cured by resection. The pursuit of tolerable and effective adjuvant therapies led to this investigation of two oral agents that are widely effective in the metastatic setting. Methods: 1,943 pts with completely resected RCC (pT1b high grade to pT4 any grade N any) were stratified on risk (intermediate-high or very high), clear/non-clear histology, ECOG PS, and resection approach, and randomized equally to sunitinib daily for 4 of 6 wk cycle, sorafenib daily, or placebo, then treated for up to 1 year. The primary endpoint was disease-free survival (DFS). The study was designed to detect a 25% reduction in the hazard rate, corresponding to an improvement from 5.8 to 7.7 years median DFS. After accrual of 1322 pts, the starting dose was reduced and then individually titrated to mitigate the effect of pt discontinuation from treatment intolerance. Results: At an interim analysis conducted with 62% information, although no efficacy or futility boundaries were crossed, the Data Safety Monitoring Committee recommended release of results. Using a stratified log-rank test, there were no significant differences in DFS or overall survival between either of the experimental arms and placebo. The redesign reduced the discontinuation rate on the experimental arms from about 26% in pts starting at full dose to about 14% in pts starting at reduced dose. Most common grade ≥3 adverse events were hypertension (16%/16%/4%), hand-foot reaction (15%/33%/1%), Rash (2%/15%/&lt;1%), and fatigue (17%/7%/3%) on sunitinib, sorafenib and placebo, respectively. (See Table.) Conclusions: In pts with locally advanced, resected RCC, adjuvant treatment with sorafenib or sunitinib should not be pursued. Dose titration reduced the treatment discontinuation rate; this finding may have relevance in other settings. Clinical trial information: NCT00326898. [Table: see text]
Contrast-enhanced harmonic endoscopic ultrasonography for differential diagnosis of pancreatic cysts
Authors: Ken Kamata, Masayuki Kitano, Shunsuke Omoto, Kumpei Kadosaka, Takeshi Miyata, Kentaro Yamao, Hajime Imai, Hiroki Sakamoto, Yogesh Harwani, Takaaki Chikugo, Yasutaka Chiba, Ippei Matsumoto, Yoshifumi Takeyama, Masatoshi Kudo
Journal: Endoscopy (2015)

<b>Background and study aim:</b> Comparison of fundamental B-mode endoscopic ultrasonography (FB-EUS) and contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) in the differential diagnosis of pancreatic cysts according to presence of mural nodules. <b>Patients and methods:</b> Between April 2007 and April 2012, FB-EUS and CH-EUS data were prospectively collected from 581 consecutive patients with pancreatic cysts, and were retrospectively analyzed from 70 with subsequent cyst resection. Presence and height of mural nodules as detected on FB-EUS and CH-EUS were evaluated, and thence accuracies of both methods for diagnosing mucinous versus nonmucinous and malignant versus benign cysts. <b>Results:</b> On pathological examination 48 cysts were mucinous and 22 were nonmucinous; 30 cysts were malignant (high grade dysplasia or invasive carcinoma) and 40 were benign. If presence of a mural nodule was considered to indicate a mucinous cyst, FB-EUS and CH-EUS accuracies did not differ significantly (respectively: sensitivity 85 % vs. 79 %; specificity 46 % vs. 96 %; accuracy 73 % vs. 84 %, <i>P</i> = 0.057). If presence of mural nodule was considered to indicate malignancy, CH-EUS was significantly more accurate than FB-EUS (respectively: sensitivity 97 % vs. 97 %; specificity 75 % vs. 40 %; accuracy 84 % vs. 64 %, <i>P</i> = 0.0001). For diagnosing malignancy by evaluating mural nodule height, the area under the receiver operating characteristic (AUROC) was 0.84 and 0.93 for FB-EUS and CH-EUS, respectively (<i>P</i> = 0.028). Presence of a mural nodule of height ≥ 4 mm on CH-EUS was a sign of malignancy (false-positive fraction 0.2; true-positive fraction 0.93; odds ratio 56.0). <b>Conclusions:</b> CH-EUS is more accurate than FB-EUS for diagnosing malignant pancreatic cysts.
LKB1 deletion causes early changes in atrial channel expression and electrophysiology prior to atrial fibrillation
Authors: Grace E. Kim, Jenna L. Ross, Chaoqin Xie, Kevin N. Su, Vlad G. Zaha, Xiaohong Wu, Monica Palmeri, Mohammed Ashraf, Joseph G. Akar, Kerry S. Russell, Fadi G. Akar, Lawrence H. Young
Journal: Cardiovascular Research (2015)

Liver kinase B1 (LKB1) is a protein kinase that activates the metabolic regulator AMP-activated protein kinase (AMPK) and other related kinases. Deletion of LKB1 in mice leads to cardiomyopathy and atrial fibrillation (AF). However, the specific role of the LKB1 pathway in early atrial biology remains unknown. Thus, we investigated whether LKB1 deletion altered atrial channel expression and electrophysiological function in a cardiomyocyte-specific knockout mouse model.We performed a systematic comparison of αMHC-Cre LKB1(fl/fl) and littermate LKB1(fl/fl) male mice. This included analysis of gene expression, histology, and echocardiography, as well as cellular and tissue-level electrophysiology using patch-clamp recordings in vitro, optical mapping ex vivo, and ECG recordings in vivo. At postnatal day 1, atrial depolarization was prolonged, and Nav1.5 and Cx40 expression were markedly down-regulated in MHC-Cre LKB1(fl/fl) mice. Inward sodium current density was significantly decreased in MHC-Cre LKB1(fl/fl) neonatal atrial myocytes. Subsequently, additional alterations in atrial channel expression, atrial fibrosis, and spontaneous onset of AF developed by 2 weeks of age. In adult mice, abnormalities of interatrial conduction and bi-atrial electrical coupling were observed, likely promoting the perpetuation of AF. Mice with AMPK-inactivated hearts demonstrated modest overlap in channel expression with MHC-Cre LKB1(fl/fl) hearts, but retained normal structure, electrophysiological function and contractility.Deletion of LKB1 causes early defects in atrial channel expression, action potential generation and conduction, which precede widespread atrial remodelling, fibrosis and AF. LKB1 is critical for normal atrial growth and electrophysiological function.
Time trends in the epidemiology of newly diagnosed stage IV prostate cancer in the United States: An analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Program (1988 - 2003)
Authors: M. A. Carducci, K. Cetin, R. Markus, J. P. Fryzek
Journal: Journal of Clinical Oncology (2008)

5059 Background: Despite the addition of prostate specific antigen (PSA) screening in the 1990s, a significant proportion of patients still present with late-stage prostate cancer. To better understand this group of patients, we examined recent time trends in the epidemiology of prostate cancer initially diagnosed at stage IV. Methods: Data from SEER were used to calculate annual incidence rates of stage IV prostate cancer from 1988 to 2003 and to describe the patient characteristics and survival for three time periods (1988–1992, 1993–1997, and 1998–2003). Regression analysis (joinpoint) was used to identify significant changes in trends over time with respect to stage IV prostate cancer incidence and patient characteristics. Results: The age-adjusted incidence rate of stage IV prostate cancer was 28 per 100,000 men in 1988 and steadily declined to 12 per 100,000 men in 2003 (an average decrease of 6.4% per year, p<0.05). The proportion of men diagnosed at age 18–65 years significantly increased across the study period (23% during 1988–1992 to 39% during 1998- 2003). Additionally, more unmarried men were diagnosed with stage IV tumors over time. Overall, 5-year survival for stage IV cancer increased across the study period. Of those diagnosed at age ≤ 50 years during 1998–2003, 65% survived at least five years compared to a five- year survival of 37% for those diagnosed during 1988–1992. A similar pattern was seen for those aged 51 to 70 years. In contrast, 5-year survival among those aged 71 to 80 years remained relatively constant over time (approximately 48%) and actually decreased in those aged ≥ 80 years (40% during 1988–1992 to 24% during 1998–2003). Conclusions: The age-adjusted incidence of stage IV prostate cancer declined over the past two decades. The proportion of men diagnosed at younger ages (65 years or less) continues to increase, and 5- year survival among this group appears to be improving. As younger men may expect to live longer with stage IV disease, we must consider long term management of their disease. Increased public awareness of these trends as well as the development of clinical trials for men presenting with advanced disease are needed. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Inc. Amgen Inc. Amgen Inc. Amgen Inc. Amgen Inc.
Efficacy and safety of bevacizumab in the treatment of advanced, non-squamous non-small cell lung cancer (NSCLC).
Authors: D. Tassinari, F. Drudi, F. Carloni, S. Nicoletti, C. Possenti, C. Santelmo, L. Lazzari
Journal: Journal of Clinical Oncology (2010)

7578 Background: To assess the efficacy and safety of bevacizumab-containing regimens in the treatment of advanced, chemotherapy-naive, non-squamous NSCLC on the basis of the two registrative trials (ECOG E4599 trial and BO17704 [AVAiL] trial). Methods: A pooled analysis of the two trials was performed using a random effect model, and the results were summarized as number-needed-to-treat (NNT) and number-needed-to-harm (NNH). The 1-year survival and 6-month progression free rates were assumed as indexes of efficacy, and grade III-IV side effects were assumed as index of safety. Results: One thousand nine hundred twenty two patients were potentially eligible for the pooled analysis, and 1576 patients were included in the final analysis. A large heterogeneity was documented for both 6-month progression free interval (I2 = 88.164%, p = 0.004) and overall survival (I2=73.541, p = 0.052). The absolute risk reduction of 1-year death and 6-month progression were 3.3% (CI-95% = [-6.5]%-13.2%, p = 0.507), with a NNT = 30; and 15.2% (CI-95% = 0.07%-29.6%, p = 0.04), with a NNT = 6 (both in favor of the bevacizumab-containing regimens), respectively. The absolute risk of treatment-related death was 2.4% (CI-95% = 0.8%-3.9%, p = 0.003), with a NNH = 41 against the bevacizumab-containing regimens; that of bleeding was 3.3% (CI-95% = 1.6%-4.9%, p < 0.001), with a NNH = 30; that of hypertension was 6.6% (CI-95% = 4.6%-8.6%, p < 0.001), with a NNH = 15; that of proteinuria was 2.1% (CI-95% = 0.3%-3.8%, p = 0.024), with a NNH = 47; that of neutropenia was 7.3% (CI-95% = 3.2%-11.4%, p < 0.001), with a NNH = 13; that of thrombocytopenia was 1.5% (CI-95% = 0.2%-2.7%, p = 0.021), with a NNH = 66. Conclusions: Adding bevacizumab to standard chemotherapy in the treatment of advanced, chemotherapy-naive, non-squamous NSCLC seems to favor a modest improvement in the main outcomes, with a significant worsening of the safety profile. These data suggest caution in the generalized use of bevacizumab-containing regimens in the treatment of advanced, chemotherapy-naive, non-squamous NSCLC. No significant financial relationships to disclose.