tbuckley/cabot-search huggingface dataset:
Inhibition of multiple MKK signaling pathway suppressed renal cell carcinoma growth and angiogenesis in vivo
Authors: Dan Huang, Yan Ding, Wangmei Luo, Stephanie Bender, Chao-Nan Qian, Bree Berghuis, Nicholas Duesbery, James Resau, Bin Teh
Journal: Cancer Research (2007)

5413   Advanced renal cell carcinoma (RCC) is refractory to current therapies. The MKKK/MKK/MAPK signaling pathway plays an essential role in cell proliferation and differentiation. Recent studies also show activation of MAPK signaling pathway in the tumorigenesis, metastasis and angiogenesis of multiple human malignancies including renal cell carcinoma. We evaluated whether targeting this pathway could be of therapeutic value against human renal cell carcinoma. The activation of MAPK signaling pathway and its role in renal cell carcinoma was accessed  in vitro  in two RCC cell lines by western blot, cell proliferation assay, cell counting, soft agar assay, and TUNEL staining, using anthrax lethal toxin (LeTx) which cleaves and inactivates multiple MKKs, as well as a specific MKK1/2 inhibitor, U0126, to block MKK signaling.  In vivo  xenograft studies were carried by intravenous or intraperitoneal injection of LeTx into nude mice bearing RCC tumors. Tumor growth was measured and tumors were subjected to immunohistochemical analysis. Western blot showed phosphorylation levels of ERK, JNK and p38 decreased after LeTx treatment. Exposure to LeTx or U0126 for 72h reduced cell growth by up to 40% without induction of apoptosis. Anchorage-independent growth of RCC cells was totally inhibited by LeTx. Importantly,  in vivo  tumor growth of RCC xenografts could be totally suppressed by LeTx, as well as tumor neovascularization was inhibited by LeTx. Because of the existence of autocrine and paracrine growth factors in tumors, we also tested the effect of LeTx on VEGF release using ELISA method. LeTx could reduce the serum level of mouse VEGF, but had no effect on human VEGF release by RCC cells. Our results suggest that multiple MKK signaling inhibitors may be a potentially useful treatment for patients with renal cell carcinoma.
MLN8237: an orally active small molecule inhibitor of Aurora A kinase in phase I clinical trials
Authors: Todd Sells, Jeffrey Ecsedy, Stephen Stroud, David Janowick, Kara Hoar, Patrick LeRoy, Deborah Wysong, Mengkun Zhang, Jessica Huck, Lee Silverman, Wei Chen, Michael Bembenek, Christopher Claiborne, Mark Manfredi
Journal: Cancer Research (2008)

237  Aurora A kinase regulates the activity of a number of proteins essential to the proper execution of mitosis. Perturbation of Aurora A results in aberrant mitoses leading to cell death. We have developed a selective Aurora A kinase inhibitor, MLN8237; to be used for the therapeutic intervention of human cancers. MLN8237 displays potent activity against Aurora A in both enzymes and cell assays. In cells, MLN8237 proved to be more than 200 fold more selective for Aurora A than the structurally related kinase Aurora B. Treatment of cultured human tumor cells with MLN8237 results in mitotic spindle abnormalities, mitotic accumulation, inhibition of cell proliferation and apoptosis. MLN8237 is orally bioavailable and has a favorable pharmacokinetic profile. A single oral administration of MLN8237 to nude mice bearing subcutaneous human tumor xenografts resulted in a time dependent accumulation of mitotic cells, consistent with the pharmacological effect being mediated through Aurora A inhibition. Repeat oral administration of MLN8237 at well tolerated doses to nude mice bearing subcutaneous human tumor xenografts resulted in dramatic tumor growth inhibition in all models evaluated. In these models, MLN8237 induced mitotic accumulation and apoptosis. MLN8237 did not appreciably inhibit Aurora B at efficacious concentrations, as indicated by measuring phosphorylated histone H3 Ser10 staining. MLN8237 is currently in Phase I clinical trials in patients with advanced malignancies.
Abstract 48: Reduction of Histological Damage with Mild Therapeutic Hypothermia after Prolonged Cardiac Arrest
Authors: Gregor Springler, Andreas Janata, Wolfgang Weihs, Keywan Bayegan, Alexandra Schratter, Oliver Robak, Michael Holzer, Martin Frossard, Wilhelm Behringer, Robert B Schock, Marc Coté, Robert J Freedman, Udo M Losert, Peter Schmidt, Anton N Laggner, Fritz Sterz
Journal: Circulation (2007)

Purpose: The aim of our study was to assess the effect of hypothermia on histological damage in 19 brain regions after prolonged cardiac arrest in pigs. Methods: Pigs were anaesthetized and mechanically ventilated. After stabilisation of pulmonary artery temperature (Tpa) at 38.5±0.2 °C, ventricular fibrillation (VF) was induced and 10 min of untreated VF were followed by 8 min of cardiopulmonary resuscitation (mechanical chest compressions, two doses of vasopressin 0.4 IE/kg). At 8 min of CPR, up to 3 countershocks were delivered. Pigs that had return of spontaneous circulation (ROSC) were randomized to one of 2 groups (control, hypothermia). Pigs in the hypothermia group were cooled to Tpa 33.0±1.0 °C with a surface cooling device (LRS Thermosuit™) circulating ice water over most of the skin surface. Pigs in the control group were kept at 38.5±1.0 °C throughout the experiment. After 14 hours of hypothermia, pigs were rewarmed, weaned and brought to the stable. At day 9 of the experiment, final neurologic examination was performed. After that the animals were sacrificed and perfused with 4 liters of saline, followed by 1 liter of paraformaldehyde (3%, pH 7.4). The brain was removed and 19 different regions of the brain were examined by means of lightmicroscopy using a histopathologic damage score that was used in previous studies. Following damage qualities were considered: edema, eosinophilic necrosis (oncosis), vacuolar degeneration and malacia. The total numeric histological damage score (HDS) was the sum of all area scores. Data are presented as median and interquartile range, group comparison was done with a Mann-Whitney-U test. Results: 16 (29 –35 kg) pigs were randomized. The time to reach target temperature in the hypothermia group (n = 8) was 9.0 (5.3; 11.9) min. Total HDS in the hypothermia group was 71 (61; 84), in the control group 132 (124; 174; p&lt;0.001). Significant (p&lt;0.05) improvements in damage were found in hippocampus, temporal, parietal, frontal and occipital cortex. Conclusions: Histological damage after prolonged cardiac arrest was improved significantly in cooled animals compared to control animals. Not all brain regions could benefit to the same extent.
Clarification
Authors: Peter Simmons
Journal: BMJ (2008)

Nicholson et al say in their article that, except when a court of protection order—a consequence of which is the deprivation of liberty—is in place, the Mental Capacity Act cannot be used to give care involving deprivation of liberty (see code of practice for details).1

This is not necessarily correct, and following this advice may make readers believe that they may not give life saving treatment entailing deprivation of liberty for physical illness to a person without mental capacity and without an existing court order when it is lawful and necessary to do so. Section 6.52 of the code of practice of the Mental Capacity Act 2005 explains the interpretation of “deprivation of liberty” derived from European Court of Human Rights judgments.2 Section 50 paragraph (2) of part 2 chapter 2 of the Mental Health Act 2007 amends the Mental Capacity Act 2005 specifically to provide for situations where it is lawful and necessary for deprivation of liberty necessary for life sustaining treatment,3 including while a court decision is being sought.

The authors say that the current Mental Health Act (1983) is due to be replaced by a new one (2007) in 2008. The Mental Health Act 2007 will amend rather than replace the Mental Health Act 1983.
Abstract 9398: Upregulation of iNOS in Mesenchymal Stem Cells Mediates Cardioprotection against Hypoxia via Activating HIF-1{alpha}
Authors: Zhisong He, Yigang Wang, Meifeng Xu
Journal: Circulation (2010)

Nitric oxide (NO), a highly reactive free radical, plays an important role in the regulation of vascular and immune function, antiapoptosis, and neurotransmission. Nitric oxide synthase (NOS) catal...
Suicidal behavior in schizophrenia and its relationship to awareness of illness
Authors: X F Amador, J H Friedman, C Kasapis, S A Yale, M Flaum, J M Gorman
Journal: American Journal of Psychiatry (1996)

Suicidal behavior is prevalent in individuals with schizophrenia. Although a relationship between greater awareness of illness and suicidal behavior has been posited, the question has not been systematically studied. The purpose of this study was to examine the relationship between suicidal behavior and various aspects of insight in 218 patients with schizophrenia.Patients who were participating in the DSM-IV field trial for schizophrenia were assessed with the Scale to Assess Unawareness of Mental Disorder and an instrument that was developed for the field trial study that measured multiple aspects of psychopathology, including suicidal behavior.The prevalence of suicidal thoughts and behavior found in this study was consistent with previous published reports. Schizophrenia patients with recurrent suicidal thoughts and behavior were generally more aware of their negative symptoms and delusions than were nonsuicidal patients. Contrary to expectations, general awareness of having a mental disorder did not predict suicidal behavior.The notion that insight may be associated with greater suicidality was partially supported.
Abstract 15001: Fusion of Echocardiographic Hemodynamic Data and Computed Tomographic Anatomical Data of the Aortic Valve Determine Severity of Low-Gradient Aortic Stenosis with Preserved Ejection Fraction
Authors: Vasileios Kamperidis, Philippe J van Rosendael, Spyridon Katsanos, Frank van der Kley, Madelien Regeer, Ibtihal Al Amri, Georgios Sianos, Nina Ajmone Marsan, Jeroen J Bax, Victoria Delgado
Journal: Circulation (2014)

Introduction: Severe aortic stenosis with preserved left ventricular ejection fraction is classified into 4 groups, according to flow and gradient, with still debatable underlying pathophysiology. Hypothesis: The use of multi-detector computed tomography (MDCT) and Doppler echocardiography refines the differential characteristics and true severity of each aortic stenosis group. Methods: Patients with severe aortic stenosis [aortic valve area index (AVAi) &lt;0.6cm2/m2] and ejection fraction ≥50% (n=191, age 80±7 years, 48.2% male) with echocardiography and MDCT prior to transcatheter aortic valve replacement were included. Patients were classified into 4 groups based on stroke volume index (≤35 or &gt;35 ml/m2) and mean pressure gradient (≤40 or &gt;40mmHg): 1. Normal-flow, high-gradient, 2. Low-flow, high-gradient, 3. Normal-flow, low-gradient, 4. Low-flow, low-gradient. Aortic valve calcium was evaluated on MDCT. Fusion AVAi was estimated by continuity equation using Doppler hemodynamics and MDCT left ventricular outflow tract (LVOT) area. Results: AVAi and LVOT area index were both significantly different among the 4 groups when evaluated by echocardiography. On MDCT, although LVOT area index was comparable among groups, fusion AVAi remained significantly different (Figure): normal-flow, low-gradient had the largest area (0.62±0.11cm2/m2), resulting in reclassification into moderate stenosis in 52% of these patients, while low-flow, low-gradient group had comparable fusion AVAi to normal-flow, high-gradient group. Aortic valve calcium load was largest among patients with high-gradient (median 3412AU for normal-flow and 3181AU for low-flow) and was comparable between patients with low-gradient (2143AU for normal-flow and 2310AU for low-flow). Conclusion: MDCT refines the hemodynamic characterization of low gradient AS patients by providing more accurate AVAi estimation and calcium load.
Evaluation of Epidemiology and Immunogenetics of IDDM in Spanish- and Portuguese-Heritage Registries: A Key to Understanding the Etiology of IDDM?
Journal: Diabetes Care (1989)

There appears to be extraordinary international variation in the incidence of insulin-dependent diabetes mellitus (IDDM), the reasons for which are not known. By evaluating the incidence of IDDM in Spanish- and Portuguese-heritage populations, important insight into reasons for the major worldwide differences in IDDM risk may be gained. The limited data that are available for Hispanic populations suggest that there is at least a 10-fold difference in risk between individuals of Hispanic ancestry in Colorado and Mexicans in Mexico City. Standard methods for assessing IDDM incidence are needed to further elucidate the patterns of risk among populations of Iberian heritage. Therefore, we propose that comparable IDDM registries be established in the Spanish- and Portuguese-speaking world. Once registries are established, further investigation of the characteristics of IDDM among various populations (including seasonal distributions, sex differences, age at onset, and changing trends over time) may help explain the large international incidence differences among not only Spanish- and Portuguese-heritage populations but also among all children.
QUANTITATIVE ASPECTS OF IRON DEFICIENCY IN HYPOCHROMIC ANEMIA
Authors: Clark W. Heath, Maurice B. Strauss, William B. Castle
Journal: Journal of Clinical Investigation (1932)

these factors.Complications which significantly inhibit blood formation were absent, such as severe sepsis, severe damage to organs, and car- cinoma.Adequate control periods before therapy was instituted were regarded as essential in such a study, and were made in each case. METHODSBlood was taken daily from the ear for reticulocyte counts during the period of close observation.As a rule, every second or third day venous blood was taken for complete blood studies.The blood counts were made with pipettes and counting chambers certified by the U. S. Bureau of Standards.The hemoglobin was determined with the Sahli Haemometer, which had been standardized by determinations of the oxygen capacity of the blood using the Van Slyke apparatus.One hundred per cent hemoglobin was taken as the equivalent of 15.6 grams per 100 cc. of blood, or 21 volumes per cent oxygen capacity.Blood volumes were determined upon five cases by the vital red dye method of Rowntree, Brown and Roth (4).Except in two instances which will be indicated, iron citrate green (N.N.R.) in various dilutions, usually in 10 per cent solution, was used for daily intra- muscular or subcutaneous injection.This is a neutralized solution of iron and ammonium citrate with 0.5 per cent quinine and urea hydrochloride as a local anesthetic.The iron and ammonium citrate in this preparation contains approximately 16 per cent of metallic iron.Solutions containing 10 per cent iron and ammonium citrate were used as a rule, but sometimes more dilute solutions were administered.It was given usually in a dose corresponding to from 8 to 32 mgm.metallic iron at each injection.Iron and ammonium citrate (brown scales 2) was used orally, usually in a dose of 6 grams daily, corresponding to approximately 1 gram of metallic iron.
Capsaicin induces apoptosis in human pancreatic cancer cells by activating mitochondrial death pathway
Authors: Ian Humphreys, Sivakumar Loganathan, Sanjay K. Srivastava
Journal: Cancer Research (2005)

2469   Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. It is one of the most aggressive human malignancies with an extremely poor prognosis and is highly resistant to radiation and chemotherapy. Recently, considerable efforts have been made to evaluate the chemotherapeutic potential of dietary agents against human malignancies. Moreover, epidemiological and experimental studies have demonstrated that several dietary agents are effective against breast, prostate, lung and colon cancers. Capsaicin, an active ingredient of red chili pepper (∼0.1-1%), is one such dietary agent that has been shown to exhibit significant chemopreventive activity against experimentally induced mutagenesis and tumorigenesis. Accordingly, current studies revealed that capsaicin inhibits proliferation and induces apoptosis in various cancer cells, however, its therapeutic effects against pancreatic cancer has never been investigated. In the present study, we demonstrate that capsaicin is antiproliferative and induces apoptosis in AsPC-1 human pancreatic cancer cells. Treatment of AsPC-1 cells with capsaicin increased both the expression of pro-apoptotic protein bax and cytochrome c release into the cytosol, in a dose-dependent manner. In addition, we observed the generation of reactive oxygen species (measured by the oxidation of DCFDA by flow cytometery) and disruption of mitochondrial membrane potential (determined by flow cytometery using JC-1) in AsPC-1 cells following exposure to capsaicin for 24h. Our results also demonstrate that exposure of AsPC-1 cells to capsaicin causes activation of caspase-3 and its downstream target PARP, thus resulting in apoptosis. Interestingly, all of these effects were significantly attenuated upon pretreatment of cells with the antioxidant, N-acetyl cysteine (NAC). This strongly suggest that capsaicin induces apoptosis in AsPC-1 cells by altering redox homeostasis and targeting the mitochondrial death pathway. Taken together, our results demonstrate for the first time, the anticancer activity of capsaicin against human pancreatic cancer cells and its potential use as a novel chemotherapeutic agent. [Supported in part by RO1 grant CA 106953 (to S.K.S.) awarded by the National Cancer Institute].
Recombinant Tumor Necrosis Factor Enhances the Locomotion of Memory and Naive B Lymphocytes From Human Tonsils Through the Selective Engagement of the Type II Receptor
Authors: Anna Corcione, Luciano Ottonello, Giuseppe Tortolina, Paola Tasso, Fabio Ghiotto, Irma Airoldi, Giuseppe Taborelli, Fabio Malavasi, Franco Dallegri, Vito Pistoia
Journal: Blood (1997)
Dopamine reuptake site densities in patients with social phobia
Authors: J Tiihonen, J Kuikka, K Bergström, U Lepola, H Koponen, E Leinonen
Journal: American Journal of Psychiatry (1997)

It has been suggested that social phobia is associated with dysfunction of the noradrenergic and dopaminergic systems, but there are no published anatomic data on the monoaminergic abnormalities found in the brains of phobic patients. The authors studied the density of dopamine reuptake sites in patients with social phobia.The study included 11 patients with social phobia and 28 healthy comparison subjects, 11 of whom were age- and gender-matched to the patients for the analyses. Measurement of the density of dopamine reuptake sites was performed by using a 123I-labeled cocaine analogue, [123I]beta-CIT, with single photon emission computed tomography (SPECT).Blind quantitative analysis revealed that striatal dopamine reuptake site densities were markedly lower in the patients with social phobia than in the age- and gender-matched comparison subjects.The results indicate that social phobia may be associated with a dysfunction of the striatal dopaminergic system.
Joint effects of serum triglycerides and LDL and HDL cholesterol.
Authors: A L Avins, S B Hulley
Journal: Circulation (1993)

Is QT Interval Prolongation a Strong or a Weak Predictor for Cardiac Death?In Ahnve's Editorial Comment in Circulation, ' based in part on our own papers,23 he discusses the prognostic value of QT, prolongation.We agree with his conclusion that QT, duration of >440 msec is associated with increased risk for cardiac death.However, we would like to draw attention to the observed difference between men and women.Among women, the prevalence of QT, prolongation is two to three times higher than among men.2-6However, we found that QT, of >440 msec is much less predictive of coronary heart disease mortality or sudden death in women than in men.In the 28-year follow-up study of >3,000 civil servants, men with QT, of 2440 msec had twice the risk of coronary heart disease mortality as men with QT, of <420 msec.Among women, the relative risk was only 1.1.2The risk for cardiovascular disease mortality was somewhat higher but not significant.Choosing a cut off of 450 or
The Hajj
Authors: A. R. Gatrad, A. Sheikh
Journal: BMJ (2011)

child with suspected egg allergy (BMJ 2011;343:d4536) O Osgood-Schlatter disease (BMJ 2011;343:d4534) O Sexual dysfunction in cardiovascular disease (BMJ 2011;343:d4437) O The watery eye (BMJ 2011;343:d4029) A 68 year old Muslim man with diabetes, which is reasonably well controlled on twice daily insulin, and who has a history of myocardial infarction 12 months previ ously wants advice on his fitness to go on pilgrimage (the Hajj) to Mecca.
Abstract 2581: Pancreatic cancer immunotherapy with chitosan/IL-12
Authors: Haley K. Perlow, Lirong Yang, David Zaharoff
Journal: Cancer Research (2014)

Abstract Pancreatic cancer is difficult to treat due to its late diagnoses and limited treatment options. Strategies capable of reducing tumor mass so that patients are eligible for tumor resection, i.e. the Whipple procedure, and strategies for reducing metastatic deposits with immunotherapy are needed. New immunotherapy techniques can provide an alternative to modern chemotherapy, radiation, or surgical options which have not been able to reduce pancreatic cancer mortality. IL-12 has been discovered to be a potent agent in the development of anti-tumor immunity through its ability to stimulate the activities of cytotoxic T lymphocytes, NK cells, and macrophages while promoting Th1 differentiation. We have previously discovered that a bioadhesive chitosan/IL-12 combination can aggressively eliminate implanted tumors in murine models. Chitosan is a non-toxic and degradable polysaccharide derived from crustacean shells that shows great potential for use in immunotherapy models due to its unique binding properties. Here, ability of chitosan/IL-12 vaccinations to slow the growth of a pancreatic adenocarcinoma cells in vivo was investigated. C57BL/6 mice received subcutaneous inoculations with Panc02 cells. After Panc02 tumors became visible, the mice received 4 weekly intratumoral immunotherapy treatments with either saline or chitosan/IL-12. There was a prominent delay in the tumor growth of the chitosan/IL-12 group at all stages of the treatment. Seven days after the second treatment, control mice had an average tumor volume of 180mm3 and treatment mice tumors became undetectable. Seven days after the fourth treatment, the control mice had an average tumor volume of 743mm3 and treatment mice had an average tumor volume of 221mm3. Cell proliferation assays showed that IL-12 had no direct effect on the Panc02 cell line. However, interferon-γ, a cytokine whose production is induced by IL-12, reduced the growth of Panc02 cells in vitro. These data shows that chitosan/IL-12 may be an effective immunotherapy for pancreatic cancer and also that IL-12 is not directly cytotoxic, but rather, it initiates an effector response capable of inhibiting pancreatic tumors. Citation Format: Haley K. Perlow, Lirong Yang, David Zaharoff. Pancreatic cancer immunotherapy with chitosan/IL-12. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2581. doi:10.1158/1538-7445.AM2014-2581