tbuckley/cabot-search huggingface dataset:
Stimulation of histamine release from human basophils by human platelet factor 4.
Authors: L L Brindley, J M Sweet, E J Goetzl
Journal: Journal of Clinical Investigation (1983)

Human basophils were stimulated to release histamine noncytotoxically by purified human platelet factor 4 (PF4) and the synthetic substituent peptide PF4(59-70). Histamine release was augmented significantly by 10(-7) M PF4 and 10(-5) M PF4(59-70), increased in a concentration-dependent manner, and attained a maximum at 3 X 10(-5) M PF4 and 3 X 10(-4) M PF4(59-70) similar to that achieved by goat anti-human myeloma IgE. PF4 (1-60) failed to initiate the release of histamine, which confirmed that the critical determinant of activity is in the carboxy-terminal sequence. Histamine release from basophils by optimally effective concentrations of PF4 and PF4(59-70) reached a plateau by 1-3 min, as contrasted with 10 min or longer for anti-IgE. The elimination of calcium and magnesium from the buffer suppressed the release of histamine by anti-IgE by 79-83%, but had no effect on that elicited by PF4(59-70). The rate of uptake of [125I]PF4 by purified basophils was similar on a molar basis to the rate of release of histamine by the same concentrations of PF4. The noncytotoxic release of histamine from human basophils by PF4 thus is temporally and biochemically distinct from that mediated by IgE and may be similar to that evoked by other polycationic stimuli.
Glutamine Repeats and Neurodegeneration
Authors: Huda Y. Zoghbi, Harry T. Orr
Journal: Annual Review of Neuroscience (2000)

A growing number of neurodegenerative diseases have been found to result from the expansion of an unstable trinucleotide repeat. Over the past 6 years, researchers have focused on identifying the mechanism by which the expanded polyglutamine tract renders a protein toxic to a subset of vulnerable neurons. In this review, we summarize the clinicopathologic features of these disorders (spinobulbar muscular atrophy, Huntington disease, and the spinocerebellar ataxias, including dentatorubropallidoluysian atrophy), describe the genes involved and what is known about their products, and discuss the model systems that have lent insight into pathogenesis. The review concludes with a model for pathogenesis that illuminates the unifying features of these polyglutamine disorders. This model may prove relevant to other neurodegenerative disorders as well.
Decline in Physical Fitness From Childhood to Adulthood Associated With Increased Obesity and Insulin Resistance in Adults
Authors: Terence Dwyer, Costan G. Magnussen, Michael D. Schmidt, Obioha C. Ukoumunne, Anne-Louise Ponsonby, Olli T. Raitakari, Paul Z. Zimmet, Steven N. Blair, Russell Thomson, Verity J. Cleland, Alison Venn
Journal: Diabetes Care (2008)

OBJECTIVE To examine how fitness in both childhood and adulthood is associated with adult obesity and insulin resistance. RESEARCH DESIGN AND METHODS A prospective cohort study set in Australia in 2004–2006 followed up a cohort of 647 adults who had participated in the Australian Schools Health and Fitness Survey in 1985 and who had undergone anthropometry and cardiorespiratory fitness assessment during the survey. Outcome measures were insulin resistance and obesity, defined as a homeostasis model assessment index above the 75th sex-specific percentile and BMI ≥30 kg/m2, respectively. RESULTS Lower levels of child cardiorespiratory fitness were associated with increased odds of adult obesity (adjusted odds ratio [OR] per unit decrease 3.0 [95% CI 1.6–5.6]) and insulin resistance (1.7 [1.1–2.6]). A decline in fitness level between childhood and adulthood was associated with increased obesity (4.5 [2.6–7.7]) and insulin resistance (2.1 [1.5–2.9]) per unit decline. CONCLUSIONS A decline in fitness from childhood to adulthood, and by inference a decline in physical activity, is associated with obesity and insulin resistance in adulthood. Programs aimed at maintaining high childhood physical activity levels into adulthood may have potential for reducing the burden of obesity and type 2 diabetes in adults.
Phase I/II trial of lenalidomide and high-dose melphalan with autologous stem cell transplantation for relapsed myeloma
Authors: N Shah, P F Thall, P S Fox, Q Bashir, J J Shah, S Parmar, P Lin, P Kebriaei, Y Nieto, U R Popat, C M Hosing, A Cornelison, E J Shpall, R Z Orlowski, R E Champlin, M H Qazilbash
Journal: Leukemia (2015)
Mediastinal Emphysema Produced by Air Turbine Dental Drills
Authors: Robert B. Hunt
Journal: JAMA (1968)

Two cases of mediastinal emphysema occurred after the use of high-speed air turbine dental drills. In each case, the initial diagnosis was incorrectly attributed to an anaphylactoid reaction caused by the drug which was used for local anesthesia. Each patient made an uneventful recovery. When summoned to see a dental patient, the physician should keep in mind the fact that the high-speed air turbine dental drill may be responsible for both mediastinal emphysema and air embolism.
Rhinovirus Viremia in Children with Respiratory Infections
Authors: Maria Xatzipsalti, Serena Kyrana, Mariza Tsolia, Stelios Psarras, Apostolos Bossios, Vasile Laza-Stanca, Sebastian L. Johnston, Nikolaos G. Papadopoulos
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Viremia has been implicated in many viral infections; however, viremia due to rhinovirus (RV; rhinoviremia) has been considered not to occur in normal individuals.To evaluate whether RV enters the bloodstream and identify the possible risk factors.Nasopharyngeal washes (NPWs) of 221 children with respiratory infections were examined for the presence of RV by reverse transcription-polymerase chain reaction. Blood from 88 children, whose NPW was RV-positive, and 31 of RV-negative control subjects was subsequently examined for the presence of RV in the blood by semi-nested reverse transcription-polymerase chain reaction. Rhinoviremia was then correlated with clinical characteristics of the disease.RV was detected in the blood of 10 out of 88 NPW RV-positive cases (11.4%): 7 of 28 children with asthma exacerbations (25.0%), 2 of 26 with common cold (7.7%), 1 of 25 with bronchiolitis (4.0%), and 0 of 9 with pneumonia (0%). All NPW RV-negative cases were negative in the blood. The proportion of rhinoviremia in children with asthma exacerbation was significantly higher compared with children suffering from the other diseases (25 vs. 5%, p = 0.01). Significant risk factors were: sampling <or= 24 hours from symptom initiation, personal history of asthma, and male sex. Age, fever, family, and personal history of atopy did not affect the presence of RV in the blood.Viremia may occur during RV respiratory infections in normal children and is rather common in the early course of acute asthma exacerbations, suggesting that rhinoviremia may be involved in asthma exacerbation pathogenesis.
Gallstones and Risk of Gallbladder Cancer&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: A B Lowenfels, C G Lindström, M J Conway, P R Hastings
Journal: JNCI Journal of the National Cancer Institute (1985)

The relationship between gallstones and gallbladder cancer was investigated in a case-control study in 131 subjects with gallbladder cancer and 2,399 subjects without gallbladder cancer. Included in the study were male and female subjects from 3 racial groups: white, black, and Southwestern American Indian. For the non-Indian group there was a significant relationship between gallstones and gallbladder cancer, with an overall estimated relative risk (RR) of 4.4 (95% confidence interval, 2.6-7.3). For the Indian population the overall estimated RR was much higher: RR = 20.9; 95% confidence interval = 8.1-54. By the combination of the RR, the prevalence of gallstones, and the overall incidence of gallbladder cancer, the risk of gallbladder cancer was calculated in each population for subjects with untreated gallstones. In older subjects with gallstones the estimated 20-year cumulative risk for gallbladder cancer ranged from 0.13% in black males to 1.5% in Indian females. It was concluded that the risk of gallbladder cancer in untreated subjects with gallstones is heterogeneous, depending on race and sex as well as the period of exposure to gallstones.
STRUCTURE-FUNCTION ASPECTS IN THE NITRIC OXIDE SYNTHASES
Authors: Dennis J. Stuehr
Journal: The Annual Review of Pharmacology and Toxicology (1997)

▪ Abstract Research on the biological roles of nitric oxide has revealed that it functions as an important signal and effector molecule in a variety of physiologic and pathologic settings. In animals, nitric oxide is synthesized enzymatically from l-arginine through the actions of the nitric oxide synthases (NOSs). The three known NOS isoforms are all dimeric, bi-domain enzymes that contain iron protoporphyrin IX, flavin adenine dinucleotide, flavin mononucleotide, and tetrahydrobiopterin as bound prosthetic groups. This chapter summarizes information regarding the structure-function aspects of the NOSs, which includes composition of the domains, the protein residues and regions involved in prosthetic group binding, catalytic properties of the domains, the relationship between dimeric structure and prosthetic group binding and function, and factors that control assembly of NOS in cells. A general model for NOS structure and assembly is presented.
Myocardial oxygenation at high workstates in hearts with left ventricular hypertrophy
Authors: R Bache
Journal: Cardiovascular Research (1999)

Background: High cardiac workloads produced by catecholamine infusion result in loss of myocardial phosphocreatine (PCr) and accumulation of inorganic phosphate (Pi) which are more prominent in hearts with left ventricular hypertrophy (LVH) than in normal hearts. Since ischemia can cause changes in phosphorylated compounds similar to those during catecholamine stimulation, this study tested the hypothesis that the exaggerated depletion of PCr and accumulation of Pi during high workloads in LVH is the result of impaired myocyte oxygenation. Methods and results:31P- and 1H-NMR spectroscopy were used to determine myocardial high energy phosphate levels and myoglobin desaturation, respectively, in eight normal dogs and nine dogs with LVH produced by ascending aortic banding. The mean LV weight/body weight ratio was approximately twice normal in the LVH group. Infusion of dobutamine (15 and 30 μg/kg/min), and dobutamine+dopamine (each 20 μg/kg/min) caused progressive similar increases in the heart rate×systolic LV pressure product to a maximum of 57.4±3.3·103 in normal and 63.9±2.7·103 in LVH animals, while myocardial oxygen consumption increased from 0.09±0.01 to 0.24±0.04 in normals and from 0.10±0.02 to 0.25±0.03 ml/min/g in LVH. PCr/ATP ratios during basal conditions were lower in LVH hearts (1.73±0.10, 1.61±0.09 and 1.51±0.09 in subepicardium, midwall and subendocardium, respectively) as compared with normals (2.24±0.09, 2.01±0.08 and 1.89±0.07; each p<0.01 normal vs. LVH). Catecholamine infusions caused dose-related decreases in PCr/ATP and appearance of Pi which was more marked in LVH than in normal hearts. 1H-NMR spectroscopy did not detect deoxymyoglobin in either normal or LVH hearts even during the highest workloads. In contrast, occlusion of the anterior descending coronary artery resulted in a large deoxymyoglobin signal. Conclusions: Increases of cardiac work produced by catecholamine stimulation resulted in greater decreases of PCr and greater increases of Pi in hypertrophied than in normal hearts. These abnormalities were not the result of inadequate intracellular oxygen availability and consequently cannot be ascribed to demand ischemia.
Genetic Signatures of HPV-related and Unrelated Oropharyngeal Carcinoma and Their Prognostic Implications
Authors: Jens P. Klussmann, Jeroen J. Mooren, Martin Lehnen, Sandra M.H. Claessen, Markus Stenner, Christian U. Huebbers, Soenke J. Weissenborn, Inga Wedemeyer, Simon F. Preuss, Jos M.J.A.A. Straetmans, Johannes J. Manni, Anton H.N. Hopman, Ernst-Jan M. Speel
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Patients with human papillomavirus (HPV)-containing oropharyngeal squamous cell carcinomas (OSCC) have a better prognosis than patients with HPV-negative OSCC. This may be attributed to different genetic pathways promoting cancer. Experimental Design: We used comparative genomic hybridization to identify critical genetic changes in 60 selected OSCC, 28 of which were associated with HPV-16 as determined by HPV-specific PCR and fluorescence in situ hybridization analysis and positive p16INK4A immunostaining. The results were correlated with HPV status and clinical data from patients. Results: Two thirds of OSCC harbored gain at 3q26.3-qter irrespective of HPV status. In HPV-negative tumors this alteration was associated with advanced tumor stage (P = 0.013). In comparison with HPV-related OSCC, the HPV-negative tumors harbored: (a) a higher number of chromosomal alterations and amplifications (P = 0.03 and 0.039, respectively); (b) significantly more losses at 3p, 5q, 9p, 15q, and 18q, and gains/amplifications at 11q13 (P = 0.002, 0.03; &amp;lt;0.001, 0.02, 0.004, and 0.001, respectively); and (c) less often 16q losses and Xp gains (P = 0.02 and 0.03). Survival analysis revealed a significantly better disease-free survival for HPV-related OSCC (P = 0.02), whereas chromosome amplification was an unfavorable prognostic indicator for disease-free and overall survival (P = 0.01 and 0.05, respectively). Interestingly, 16q loss, predominantly identified in HPV-related OSCC, was a strong indicator of favorable outcome (overall survival, P = 0.008; disease-free survival, P = 0.01) and none of these patients had a tumor recurrence. Conclusions: Genetic signatures of HPV-related and HPV-unrelated OSCC are different and most likely underlie differences in tumor development and progression. In addition, distinct chromosomal alterations have prognostic significance.
Measured alveolar volume is a marker for mortality risk after acquiring bronchiolitis obliterans following stem-cell transplantation
Authors: Patrick Jak, Herman Groepenhoff
Journal: European Respiratory Journal (2014)

Intro: 5% of stem cell transplantations (SCT) are complicated by bronchiolitis obliterans (BO), possibly leading to severe, irreversible airway obstruction. Identifying risk factors for adverse outcome after acquiring BO enhances efficiency of patient monitoring. Measured alveolar volume (VA) in single breath measurement of carbon-monoxide transfer factor (TLCO) is affected by lung volume and obstruction. An early, strong decline in VA after SCT might be a risk factor for mortality in BO.  Aim: To assess measured VA as risk factor for mortality in BO.  Method: Pulmonary function (PFT) data of 37 patients with extensive pulmonary chronic graft vs. host disease after SCT was used. PFT-data consisted of spirometry, TLCO measurements performed according to ATS/ERS-criteria (Vmax-Spectra PFT-equipment by Carefusion).  Association between measured VA one year (359 d; SD 44) after SCT and mortality (on day 1600) was evaluated by constructing an ROC-curve. A VA-cutoff value of 70.5%-predicted was used to split the group in high- and low-VA subgroups. Kaplan-Meier survival analysis was done on resulting data. (Statistical analyses: SPSS 20.0.)  Result: Survival between groups was significantly different (p=0.016). High-VA group had a median survival of 3095 (SE 908) days and low-VA group of 1346 (SE 444).  Conclusion: Lower measured VA one year after SCT is associated with higher mortality in BO.
Thymidylate synthase inhibition: A structure-based rationale for drug design
Authors: M. Paola Costi
Journal: Medicinal Research Reviews (1998)

Thymidylate synthase (TS) is a very interesting target in antiproliferative diseases. Its inhibition causes thimineless death of the cells and compounds inhibiting TS are widely used in anticancer therapy. The classical antifolate TS inhibitors are structural analogs of the folate cofactor; they often share the same metabolic pathways and this causes the development of resistance inside the cells. A detailed analysis of the available x-ray crystal structures of the complexes of the enzyme with different substrates and inhibitors support the finding of a structural basis of their biological activity. TS inhibitors nonstructural analog of folate, non-analog antifolate inhibitors (NAAI), are welcome as a new interesting research topic. Among the most recent and interesting ones, compounds from Agouron related to the indole structure, are independent on the folate metabolism, highly active and specific for human TS. Other compounds, phthalein derivatives, can inhibit TS enzymes from various sources and show an interesting biological activity profile: they inhibit better bacterial and fungal TS than human TS. The x-ray crystal structures of some of these inhibitors with TS show that they bind in a different binding site from that of the classical folate TS inhibitors. This indicates a potential allosteric binding site useful for future drug discovery studies. © 1998 John Wiley & Sons, Inc. Med Res Rev, 18, No. 1, 21-42, 1998.
Prognostic Significance of Interleukin-6 Single Nucleotide Polymorphism Genotypes in Neuroblastoma:<i>rs1800795</i>(Promoter) and<i>rs8192284</i>(Receptor)
Authors: Joanne P. Lagmay, Wendy B. London, Thomas G. Gross, Amanda Termuhlen, Nicholas Sullivan, Amy Axel, Bethany Mundy, Mark Ranalli, Jason Canner, Patrick McGrady, Brett Hall
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Neuroblastoma is a childhood cancer of the sympathetic nervous system and many patients present with high-risk disease. Risk stratification, based on pathology and tumor-derived biomarkers, has improved prediction of clinical outcomes, but overall survival (OS) rates remain unfavorable and new therapeutic targets are needed. Some studies suggest a link between interleukin (IL)-6 and more aggressive behavior in neuroblastoma tumor cells. Therefore, we examined the impact of two IL-6 single nucleotide polymorphisms (SNP) on neuroblastoma disease progression. Experimental Design: DNA samples from 96 high-risk neuroblastoma patients were screened for two SNP that are known to regulate the serum levels of IL-6 and the soluble IL-6 receptor, rs1800795 and rs8192284, respectively. The genotype for each SNP was determined in a blinded fashion and independent statistical analysis was done to determine SNP-related event-free survival (EFS) and OS rates. Results: The rs1800795 IL-6 promoter SNP is an independent prognostic factor for EFS and OS in high-risk neuroblastoma patients. In contrast, the rs8192284 IL-6 receptor SNP revealed no prognostic value. Conclusions: The rs1800795 SNP [−174 IL-6 (G &amp;gt; C)] represents a novel and independent prognostic marker for both EFS and OS in high-risk neuroblastoma. Because the rs1800795 SNP [−174 IL-6 (G &amp;gt; C)] has been shown to correlate with production of IL-6, this cytokine may represent a target for development of new therapies in neuroblastoma. (Clin Cancer Res 2009;15(16):5234–9)
Cooperative interaction of MUC1 with the HGF/c-Met pathway during hepatocarcinogenesis
Authors: Giray Bozkaya, Peyda Korhan, Murat Çokaklı, Esra Erdal, Özgül Sağol, Sedat Karademir, Christopher Korch, Neşe Atabey
Journal: Molecular Cancer (2012)

Abstract Background Hepatocyte growth factor (HGF) induced c-Met activation is known as the main stimulus for hepatocyte proliferation and is essential for liver development and regeneration. Activation of HGF/c-Met signaling has been correlated with aggressive phenotype and poor prognosis in hepatocellular carcinoma (HCC). MUC1 is a transmembrane mucin, whose over-expression is reported in most cancers. Many of the oncogenic effects of MUC1 are believed to occur through the interaction of MUC1 with signaling molecules. To clarify the role of MUC1 in HGF/c-Met signaling, we determined whether MUC1 and c-Met interact cooperatively and what their role(s) is in hepatocarcinogenesis. Results MUC1 and c-Met over-expression levels were determined in highly motile and invasive, mesenchymal-like HCC cell lines, and in serial sections of cirrhotic and HCC tissues, and these levels were compared to those in normal liver tissues. Co-expression of both c-Met and MUC1 was found to be associated with the differentiation status of HCC. We further demonstrated an interaction between c-Met and MUC1 in HCC cells. HGF-induced c-Met phosphorylation decreased this interaction, and down-regulated MUC1 expression. Inhibition of c-Met activation restored HGF-mediated MUC1 down-regulation, and decreased the migratory and invasive abilities of HCC cells via inhibition of β-catenin activation and c-Myc expression. In contrast, siRNA silencing of MUC1 increased HGF-induced c-Met activation and HGF-induced cell motility and invasion. Conclusions These findings indicate that the crosstalk between MUC1 and c-Met in HCC could provide an advantage for invasion to HCC cells through the β-catenin/c-Myc pathway. Thus, MUC1 and c-Met could serve as potential therapeutic targets in HCC.
Emerging role of Garcinol, the antioxidant chalcone from Garcinia indica Choisy and its synthetic analogs
Authors: Subhash Padhye, Aamir Ahmad, Nikhil Oswal, Fazlul H Sarkar
Journal: Journal of Hematology & Oncology (2009)

Abstract Garcinol, harvested from Garcinia indica , has traditionally been used in tropical regions and appreciated for centuries; however its biological properties are only beginning to be elucidated. There is ample data to suggest potent antioxidant properties of this compound which have been used to explain most of its observed biological activities. However, emerging evidence suggests that garcinol could be useful as an anti-cancer agent, and it is increasingly being realized that garcinol is a pleiotropic agent capable of modulating key regulatory cell signaling pathways. Here we have summarized the progress of our current research knowledge on garcinol and its observed biological activities. We have also provided an explanation of observed properties based on its chemical structure and provided an insight into the structure and properties of chalcones, the precursors of garcinol. The available data is promising but more detailed investigations into the various properties of this compound, particularly its anti-cancer activity are urgently needed, and it is our hope that this review will stimulate further research for elucidating and appreciating the value of this nature's wonder agent.