tbuckley/cabot-search huggingface dataset:
Role of neuronal nitric oxide synthase in lipopolysaccharide-induced tumor necrosis factor-alpha expression in neonatal mouse cardiomyocytes
Authors: N GEOGHEGANMORPHET, D BURGER, X LU, V SATHISH, T PENG, S SIMS, Q FENG
Journal: Cardiovascular Research (2007)

Neuronal nitric oxide synthase (nNOS) has been shown to regulate intracellular calcium in cardiomyocytes. Calcium in turn modulates extracellular signal-related kinase (ERK) signaling, which is important in tumor necrosis factor-alpha (TNF-alpha) expression during lipopolysaccharide (LPS) stimulation. However, the role of nNOS in LPS-induced TNF-alpha expression is not known. We hypothesized that nNOS suppresses LPS-induced TNF-alpha expression by inhibiting the calcium/ERK signaling pathway.Cultured neonatal mouse cardiomyocytes were challenged with LPS for 4 h. While there was no change in the basal Ca(2+) concentration, LPS increased peak Ca(2+) levels. LPS stimulation increased TNF-alpha mRNA and protein levels in wild-type cells however, the responses were enhanced in nNOS(-/-) cardiomyocytes. Treatment with an antisense oligonucleotide against nNOS also significantly enhanced TNF-alpha expression during LPS stimulation. Furthermore, LPS-induced ERK phosphorylation was significantly increased in the nNOS(-/-) compared to wild-type cardiomyocytes. The enhanced TNF-alpha expression in nNOS(-/-) cardiomyocytes was abrogated by an L-type calcium channel blocker verapamil or ERK1 siRNA. Finally, myocardial ERK phosphorylation and TNF-alpha expression were increased while cardiac function was decreased in endotoxemia in nNOS(-/-) compared to wild-type mice.nNOS inhibits LPS-induced TNF-alpha expression in cardiomyocytes and improves cardiac function in endotoxemia. The inhibitory role of nNOS is mediated by a reduction in L-type calcium channel-dependent ERK signaling in cardiomyocytes.
Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations
Authors: Christian Hartmann, Bettina Hentschel, Matthias Simon, Manfred Westphal, Gabriele Schackert, Jörg C. Tonn, Markus Loeffler, Guido Reifenberger, Torsten Pietsch, Andreas von Deimling, Michael Weller
Journal: Clinical Cancer Research (2013)

The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in World Health Organization (WHO) grades II and III gliomas, but rare in primary glioblastomas, and associated with longer survival.We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival >36 months (LTS-36), including 33 patients surviving >60 months (LTS-60), with 257 patients surviving <36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations, and IDH1/2 mutations were determined by standard techniques.The rate of IDH1/2 mutations in LTS-36 patients was 34% (23 of 67 patients) as opposed to 4.3% in controls (11 of 257 patients). Long-term survivors with IDH1/2-mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Long-term survivors with IDH1/2 wild-type showed no distinguishing features from other patients with IDH1/2 wild-type glioblastomas except for a higher rate of MGMT promoter methylation. Similarly, among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less-frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had less frequently TP53 mutations and radiotherapy alone as initial treatment.IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade II/III gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.
Upregulation of IGF1R by Mutant <i>RAS</i> in Leukemia and Potentiation of <i>RAS</i> Signaling Inhibitors by Small-Molecule Inhibition of IGF1R
Authors: Ellen Weisberg, Atsushi Nonami, Zhao Chen, Erik Nelson, Yongfei Chen, Feiyang Liu, HaeYeon Cho, Jianming Zhang, Martin Sattler, Constantine Mitsiades, Kwok-Kin Wong, Qingsong Liu, Nathanael S. Gray, James D. Griffin
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Activating mutations in the RAS oncogene occur frequently in human leukemias. Direct targeting of RAS has proven to be challenging, although targeting of downstream RAS mediators, such as MEK, is currently being tested clinically. Given the complexity of RAS signaling, it is likely that combinations of targeted agents will be more effective than single agents. Experimental Design: A chemical screen using RAS-dependent leukemia cells was developed to identify compounds with unanticipated activity in the presence of an MEK inhibitor and led to identification of inhibitors of IGF1R. Results were validated using cell-based proliferation, apoptosis, cell-cycle, and gene knockdown assays; immunoprecipitation and immunoblotting; and a noninvasive in vivo bioluminescence model of acute myeloid leukemia (AML). Results: Mechanistically, IGF1R protein expression/activity was substantially increased in mutant RAS-expressing cells, and suppression of RAS led to decreases in IGF1R. Synergy between MEK and IGF1R inhibitors correlated with induction of apoptosis, inhibition of cell-cycle progression, and decreased phospho-S6 and phospho-4E-BP1. In vivo, NSG mice tail veins injected with OCI-AML3-luc+ cells showed significantly lower tumor burden following 1 week of daily oral administration of 50 mg/kg NVP-AEW541 (IGF1R inhibitor) combined with 25 mg/kg AZD6244 (MEK inhibitor), as compared with mice treated with either agent alone. Drug combination effects observed in cell-based assays were generalized to additional mutant RAS-positive neoplasms. Conclusions: The finding that downstream inhibitors of RAS signaling and IGF1R inhibitors have synergistic activity warrants further clinical investigation of IGF1R and RAS signaling inhibition as a potential treatment strategy for RAS-driven malignancies. Clin Cancer Res; 20(21); 5483–95. ©2014 AACR.
Haemolysis with Bjork-Shiley and Starr-Edwards prosthetic heart valves: a comparative study
Authors: S. D. Slater, I. A. Sallam, W. H. Bain, M. A. Turner, T. D. V. Lawrie
Journal: Thorax (1974)

<b>Slater, S. D., Sallam, I. A., Bain, W. H., Turner, M. A., and Lawrie, T. D. V. (1974).</b><i>Thorax</i>, <b>29</b>, 624-632. <b>Haemolysis with Björk-Shiley and Starr-Edwards prosthetic heart valves: a comparative study.</b> A comparison was made of the haemolytic complications in 85 patients with two different types of Starr-Edwards cloth-covered ball and cage prosthesis with those in 44 patients with the Björk-Shiley tilting disc valve. Intravascular haemolysis, as detected by the presence of haemosiderinuria, occurred significantly less often with the Björk-Shiley than with the Starr-Edwards valve, the overall incidence with aortic, mitral or multiple replacements being 31%, 15%, and 20% for Björk-Shiley and 94%, 92%, and 88% for Starr-Edwards valves respectively. There was no significant difference in the frequency of haemolysis between each of the two types of Starr-Edwards prosthesis studied at either the aortic (2300 versus 2310 model) or mitral (6300 versus 6310) site. Haemolytic anaemia developed in only one patient with a Björk-Shiley valve but was common though usually mild with Starr-Edwards prostheses, particularly aortic valve replacements with the 2300 model and in aortic plus mitral (± tricuspid) replacements. The greater severity of haemolysis produced by Starr-Edwards valves, again especially of the latter types, was further demonstrated by higher serum lactate dehydrogenase and 24-hour urinary iron levels. It is concluded that the Björk-Shiley tilting disc valve represents a significant advance in the amelioration of the haemolytic complications of prosthetic valves.
Human Papillomavirus–Associated Oropharyngeal Cancer: Defining Risk Groups and Clinical Trials
Authors: Aarti Bhatia, Barbara Burtness
Journal: Journal of Clinical Oncology (2015)

Human papillomavirus-associated oropharynx cancer (HPVA-OPC) is rapidly increasing in incidence and has unique epidemiologic, molecular, and biologic characteristics. Despite being recognized as having superior prognosis, current evidence does not support less intense therapy compared with HPV-negative OPC. Current combined modality therapies confer a significant risk of morbidity, and patients with HPVA-OPC have a younger median age. These patients, therefore, live longer with the adverse effects of treatment, and this spurs the development of treatment deintensification trials that attempt to decrease treatment-related morbidity without compromising efficacy. Many radiation and chemotherapy de-escalation trials are underway. Minimally invasive surgical techniques are also being evaluated. It is important to identify the ideal patient group for treatment deintensification and to define prognostic risk groups to avoid undertreating the poorer-risk subset in HPVA-OPC, and validated biomarkers are needed to identify patients with the best prognosis. Significant smoking exposure mitigates the favorable prognosis of HPVA-OPC. Currently, less intense treatment is an option only in the setting of clinical trials, and patients with HPVA-OPC should be offered clinical trial options whenever they are available. Finally, recognition of novel therapeutic targets and signaling pathways is critical to the development of new treatment strategies that are desperately needed for patients with poor risk and those with recurrent and metastatic disease.
Accuracy of the Neuropad Test for the Diagnosis of Distal Symmetric Polyneuropathy in Type 2 Diabetes
Authors: Nikolaos Papanas, Paschalis Paschos, Dimitrios Papazoglou, Konstantinos Papatheodorou, Konstantinos Paletas, Efstratios Maltezos, Apostolos Tsapas
Journal: Diabetes Care (2011)

OBJECTIVE To estimate the accuracy of Neuropad for the diagnosis and staging of distal symmetric polyneuropathy (DPN) across different stages of neuropathy, using multiple-level likelihood ratios (LRs) to interpret the time necessary to complete the color change of the test. RESEARCH DESIGN AND METHODS We conducted a cross-sectional, cohort-type diagnostic accuracy study in 251 consecutive adult type 2 diabetic patients with no peripheral arterial disease or other potential causes of neuropathy, who were recruited between January 2005 and December 2008 from the diabetes outpatient clinics in Alexandroupolis Hospital, Greece. Patients were tested for DPN by means of the neuropathy disability score (NDS) and Neuropad. Multiple-level LRs for time to complete color change were calculated across different stages of neuropathy. RESULTS The areas under the curve for the diagnosis of any (NDS of ≥3), at least moderate (NDS of ≥6), or severe (NDS of ≥9) DPN were 0.91, 0.96, and 0.97, respectively. The calculation of multiple-level LRs showed that time to complete color change &amp;lt;360 s suggested the absence of neuropathy. Values between 360 and 1,000 s were indicative of mild neuropathy. Finally, values between 1,000 and 1,200 or &amp;gt;1,200 s were strongly suggestive of moderate or severe DPN, respectively. CONCLUSIONS Neuropad could be used as a triage test for the diagnosis and staging of DPN in patients with type 2 diabetes, prompting referral to specialized care setting.
Prognostic Value of Coronary Computed Tomographic Angiography in Diabetic Patients Without Known Coronary Artery Disease
Authors: Martin Hadamitzky, Franziska Hein, Tanja Meyer, Bernhard Bischoff, Stefan Martinoff, Albert Schömig, Jörg Hausleiter
Journal: Diabetes Care (2010)

OBJECTIVE Diabetic patients have a high prevalence of coronary artery disease (CAD), but timely diagnosis of CAD remains challenging. We assessed the ability of coronary computed tomography angiography (CCTA) to detect CAD in diabetic patients and to predict subsequent cardiac events. RESEARCH DESIGN AND METHODS We analyzed 140 diabetic patients without known CAD undergoing CCTA; 1,782 patients without diabetes were used as a control group. Besides calcium scoring and the degree of the most severe stenosis, the atherosclerotic burden score counting the number of segments having either a nonstenotic plaque or a stenosis was recorded. The primary end point was a composite of hard cardiac events defined as all-cause death, nonfatal myocardial infarction, or unstable angina requiring hospitalization. RESULTS During a mean follow-up of 33 months, there were seven events in the diabetic group and 24 events in the control group. The best predictor in diabetic patients was the atherosclerotic burden score: the annual event rate ranged from 0.5% for patients with &amp;lt;5 lesions to 9.6% for patients with &amp;gt;9 lesions, resulting in a hazard ratio (HR) of 1.3 (95% CI 1.1–1.7) for each additional lesion (P = 0.005). For comparison, in nondiabetic patients the annual event rate ranged from 0.3 to 2.2%, respectively, resulting in an HR of 1.2 (95% CI 1.1–1.3, P &amp;lt; 0.001). The atherosclerotic burden score improved the prognostic value of conventional risk factors significantly (P &amp;lt; 0.001). CONCLUSIONS In diabetic patients without known CAD, CCTA can identify a patient group at particularly high risk for subsequent hard cardiac events.
Of mice and men – the future of cardiovascular research in the molecular era
Authors: W Schaper
Journal: Cardiovascular Research (1998)

The advent of the molecular age has changed experimental cardiovascular research and continues to make these changes deeper and more and more irreversible by the day. Gradually over the last 12 years dogs and cats, the classical experimental animals in cardiovascular sciences, became unfashionable for a variety of reasons, some of them nonscientific (i.e., new legislation, expense, also to avoid clashes with animal rights activists etc.). They were replaced by rabbits and rats (less expensive, but not necessarily better suited) and, more recently, by transgenic mice. This description of the changing preferences for experimental animals shows that not all of these changes have their roots in the new opportunities of molecular approaches. That was to be expected because not all cardiovascular problems can be reduced to exercises in gene expression. Acute effects and most pharmacological problems are not necessarily solved utilizing the gene approach, although screening for new pharmacological agents uses more and more genetically altered cells and animals.

Gene expression studies are most appropriate when studying chronic adaptation of tissues to a change in the environment of cells or organs, like pressure overload, or the growth of new blood vessels or the adaptation to chronic hypoxia, to name only a few.

Molecular biology assumes its prominent place today because it promises a paradigm shift in modern medicine, namely that chronic degenerative diseases are amenable to causal treatment and that structural changes can be elicited by substituting failing or weakly expressed genes or by substituting mutated genes with the correct copy. It can be envisaged that atherosclerosis and its organ manifestations will be avoided by gene therapy and that already existing or threatening arterial occlusions can be compensated for by the stimulation of angiogenesis and arteriogenesis. Since these new methods will in all likelihood be less expensive than surgery and …
Cyclin A2 Induces Cardiac Regeneration After Myocardial Infarction Through Cytokinesis of Adult Cardiomyocytes
Authors: Scott D. Shapiro, Amaresh K. Ranjan, Yoshiaki Kawase, Richard K. Cheng, Rina J. Kara, Romit Bhattacharya, Gabriela Guzman-Martinez, Javier Sanz, Mario J. Garcia, Hina W. Chaudhry
Journal: Science Translational Medicine (2014)

Cyclin A2 mediates cardiac regeneration of infarcted porcine hearts.
THE EFFECT OF PILOCARPINE ON THE NUMBER OF SMALL LYMPHOCYTES IN THE CIRCULATING BLOOD FOLLOWING LIGATION OF THE THORACIC DUCT
Authors: Ferdinand C. Lee
Journal: The Journal of Experimental Medicine (1924)

In a series of animals in which the thoracic duct had been tied it was found that the relative increase in the number of small lymphocytes in the circulating blood following the intraperitoneal administration of pilocarpine nitrate was the same as for the control animals. While support is brought for Harvey's view that pilocarpine causes a lymphocytosis through the contraction of plain muscle, on the other hand evidence is presented which indicates that the spleen is no more specialized in the production of small lymphocytes than any other portion of the lymphopoietic system.
An Optimized Clinical Regimen for the Oncolytic Virus PV701
Authors: Sébastien J. Hotte, Robert M. Lorence, Hal W. Hirte, Susan R. Polawski, Michael K. Bamat, James D. O'Neil, M. Scot Roberts, William S. Groene, Pierre P. Major
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Previous phase 1 trials of i.v.-administered PV701 have shown this virus to be well-tolerated with toxicity primarily associated with the first dose. Our hypothesis, based on preclinical evidence, was that patient tolerability could be improved by slowing the i.v. infusion rate, and that this approach would allow for the safe administration of higher doses. Additionally, this phase 1 trial was the first to measure PV701 clearance. Experimental Design: For the first dose, a 3-h infusion was used compared with the 10- and 30-min infusions administered in the two previous trials. Subsequent doses were infused over 1 h. Six doses were given per 3-week cycle. Escalation of the first dose was done separately from the escalation of doses 2 to 6. Viral clearance was determined using whole blood reverse transcription-PCR. Results: Eighteen patients with advanced chemorefractory cancer were enrolled. The first dose was safely escalated to 24 × 109 plaque-forming units/m2 and doses 2 to 6 were safely escalated to 120 × 109 plaque-forming units/m2. Tolerability was improved compared with the rapid bolus dosing used previously with the elimination of severe flu-like symptoms. Furthermore, infusion reactions were markedly decreased in this trial compared with previous PV701 trials. The presence of neutralizing antibodies did not significantly affect PV701 clearance. Four major and two minor tumor responses were observed. Conclusions: Using slow infusion, patient tolerability was improved, while the first dose was safely escalated relative to two previous PV701 trials. Based on improved tolerability and encouraging signs of activity, this slow infusion regimen was selected for further PV701 clinical development.
Monoclonal antibody to Theiler's murine encephalomyelitis virus defines a determinant on myelin and oligodendrocytes, and augments demyelination in experimental allergic encephalomyelitis.
Authors: M Yamada, A Zurbriggen, R S Fujinami
Journal: The Journal of Experimental Medicine (1990)

Theiler's murine encephalomyelitis virus (TMEV) causes a chronic demyelinating disease in mice. The mechanisms underlying the demyelination have not been fully elucidated. We have raised a mAb to TMEV (DA strain), H8, that reacts both with TMEV VP-1 and galactocerebroside (GC). In mouse brain cultures, cells positive for the mAb H8 epitope were double labeled with antibody to myelin basic protein, indicating that those cells were oligodendrocytes. Further, mAb H8 could immunostain myelin structures in frozen sections from mouse brains. When injected intravenously into mice with acute allergic encephalomyelitis, mAb H8 increased by 10-fold the size of demyelinated areas within the spinal cords. This is the first report demonstrating that an antibody to virus can enhance demyelination of a central nervous system disease. Ig fractions from the sera of mice with chronic TMEV infection had antibody(s) to GC, as well as to TMEV, as determined by ELISA. Furthermore, a competition ELISA for TMEV or GC antigen revealed that sera from these infected mice contained antibody(s) with the same specificity as mAb H8. Our results indicate that antibodies generated by immune response to TMEV can react with myelin and oligodendrocytes, and contribute to demyelination through an immune process.
A Critical Role of Natural Immunoglobulin M in Immediate Defense Against Systemic Bacterial Infection
Authors: Marianne Boes, Andrey P. Prodeus, Tara Schmidt, Michael C. Carroll, Jianzhu Chen
Journal: The Journal of Experimental Medicine (1998)

To evaluate the role of natural immunoglobulin (Ig)M in the immediate response against microbial infection, we tested mutant mice that are deficient in secreted (s)IgM in an acute peritonitis model induced by cecal ligation and puncture (CLP). 20% of wild-type mice died within 32 h of CLP, whereas 70% of sIgM-deficient mice died within the same time period. The increased susceptibility was associated with a reduced level of tumor necrosis factor (TNF)-alpha, a decreased neutrophil recruitment and an increased bacterial load in the peritoneum, and elevated levels of endotoxin and proinflammatory cytokines in the circulation. Resistance to CLP by sIgM-deficient mice was restored by reconstitution with polyclonal IgM from normal mouse serum. Reconstitution with a monoclonal IgM specific to phosphatidylcholine, a conserved cell membrane component, has a modest effect but a monoclonal IgM specific to phosphocholine is not protective. These findings demonstrate a critical role of natural IgM in the immediate defense against severe bacterial infection.
A Randomized Study of Alglucosidase Alfa in Late-Onset Pompe's Disease
Authors: Ans T. van der Ploeg, Paula R. Clemens, Deyanira Corzo, Diana M. Escolar, Julaine Florence, Geert Jan Groeneveld, Serge Herson, Priya S. Kishnani, Pascal Laforet, Stephen L. Lake, Dale J. Lange, Robert T. Leshner, Jill E. Mayhew, Claire Morgan, Kenkichi Nozaki, Dorothy J. Park, Alan Pestronk, Barry Rosenbloom, Alison Skrinar, Carine I. van Capelle, Nadine A. van der Beek, Melissa Wasserstein, Sasa A. Zivkovic
Journal: New England Journal of Medicine (2010)

Pompe's disease is a metabolic myopathy caused by a deficiency of acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompe's disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompe's disease.Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC).At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1+/-13.1 m on the 6-minute walk test and an absolute increase of 3.4+/-1.2 percentage points in FVC; P=0.03 and P=0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients).In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.)