tbuckley/cabot-search huggingface dataset:
Navitoclax (ABT-263) Accelerates Apoptosis during Drug-Induced Mitotic Arrest by Antagonizing Bcl-xL
Authors: Jue Shi, Yuan Zhou, Hsiao-Chun Huang, Timothy J. Mitchison
Journal: Cancer Research (2011)

Abstract Combining microtubule-targeting antimitotic drugs with targeted apoptosis potentiators is a promising new chemotherapeutic strategy to treat cancer. In this study, we investigate the cellular mechanism by which navitoclax (previously called ABT-263), a Bcl-2 family inhibitor, potentiates apoptosis triggered by paclitaxel and an inhibitor of kinesin-5 (K5I, also called a KSP inhibitor), across a panel of epithelial cancer lines. By using time-lapse microscopy, we showed that navitoclax has little effect on cell death during interphase, but strongly accelerates apoptosis during mitotic arrest, and greatly increases the fraction of apoptosis-resistant cells that die. By systematically knocking down individual Bcl-2 proteins, we determined that Mcl-1 and Bcl-xL are the primary negative regulators of apoptosis during prolonged mitotic arrest. Mcl-1 levels decrease during mitotic arrest because of an imbalance between synthesis and turnover, and turnover depends in part on the MULE/HUWE1 E3 ligase. The combination of Mcl-1 loss with inhibition of Bcl-xL by navitoclax causes rapid apoptosis in all lines tested. Variation in expression levels of Mcl-1 and Bcl-xL largely determines variation in response to antimitotics alone, and antimitotics combined with navitoclax, across our panel. We concluded that Bcl-xL is a critical target of Bcl-2 family inhibitors for enhancing the lethality of antimitotic drugs in epithelial cancers, and combination treatment with navitoclax and a spindle specific antimitotic, such as a K5I, might be more effective than paclitaxel alone. Cancer Res; 71(13); 4518–26. ©2011 AACR.
Acetyl glyceryl ether phosphorylcholine (AGEPC). A putative mediator of cardiac anaphylaxis in the guinea pig.
Authors: R Levi, J A Burke, Z G Guo, Y Hattori, C M Hoppens, L M McManus, D J Hanahan, R N Pinckard
Journal: Circulation Research (1984)

Platelet-activating factor is a novel phospholipid that has been implicated as an important mediator of acute allergic reactions. The intravenous administration of acetyl glyceryl ether phosphorylcholine, a pure, synthetic platelet-activating factor, causes electrocardiographic changes in the rabbit similar to those which are characteristic manifestations of systemic anaphylaxis. To determine whether platelet-activating factor contributes to anaphylactic cardiac dysfunction, we measured platelet-activating factor release from the sensitized guinea pig heart challenged in vitro with specific antigen and compared the resulting cardiac dysfunction with that induced by the injection of acetyl glyceryl ether phosphorylcholine into nonsensitized hearts. The results of these studies document that, during anaphylaxis in the isolated guinea pig heart, a platelet-activating factor is released into the coronary effluent that has physicochemical and functional properties similar to those of acetyl glyceryl ether phosphorylcholine. The intracardiac administration of acetyl glyceryl ether phosphorylcholine (10(-14) to 3 X 10(-9) mol) induced dose-related decreases in left ventricular contractile force (-5 to -85%) and coronary flow (-5 to -85%), as well as impaired atrioventricular conduction. The negative inotropic effect of acetyl glyceryl ether phosphorylcholine also was present in hearts perfused at constant flow. Although, in these hearts, acetyl glyceryl ether phosphorylcholine increased coronary resistance, which may have caused regional shunting and ischemia, it is unlikely that the negative inotropic effect of acetyl glyceryl ether phosphorylcholine was secondary to changes in coronary flow, since acetyl glyceryl ether phosphorylcholine also caused a dose-dependent negative inotropic effect in the electrically paced, noncoronary-perfused left atrium and right ventricular papillary muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
Impact of folate and homocysteine metabolism on human reproductive health
Authors: Thierry Forges, P. Monnier-Barbarino, J.M. Alberto, R.M. Guéant-Rodriguez, J.L. Daval, J.L. Guéant
Journal: Human Reproduction Update (2007)

Folates belong to the vitamin B group and are involved in a large number of biochemical processes, particularly in the metabolism of homocysteine. Dietary or genetically determined folate deficiency leads to mild hyperhomocysteinemia, which has been associated with various pathologies. Molecular mechanisms of homocysteine-induced cellular dysfunction include increased inflammatory cytokine expression, altered nitric oxide bioavailability, induction of oxidative stress, activation of apoptosis and defective methylation. Whereas the involvement of folate metabolism and homocysteine in ageing-related diseases, in several developmental abnormalities and in pregnancy complications has given rise to a large amount of scientific work, the role of these biochemical factors in the earlier stages of mammalian reproduction and the possible preventive effects of folate supplementation on fertility have, until recently, been much less investigated. In the present article, the possible roles of folates and homocysteine in male and female subfertility and related diseases are systematically reviewed, with regard to the epidemiological, pathological, pharmacological and experimental data of the literature from the last 25 years.
Development of irreversible airflow obstruction in a patient with eosinophilic bronchitis without asthma
Authors: CE Brightling, G Woltmann, AJ Wardlaw, ID Pavord
Journal: European Respiratory Journal (1999)

Eosinophilic bronchitis is a recently described condition presenting with chronic cough and sputum eosinophilia without the abnormalities of airway function seen in asthma. The patient, a 48-yr-old male who had never smoked, presented with an isolated chronic cough. He had normal spirometric values, peak flow variability and airway responsiveness, but an induced sputum eosinophil count of 33% (normal &lt;1%). Although his cough improved with inhaled corticosteroids the sputum eosinophilia persisted. Over 2 yrs he developed airflow obstruction, which did not improve following nebulized bronchodilators and a 2-week course of prednisolone 30 mg once daily sufficient to return the sputum eosinophilia to normal (0.5%). It is suggested that the progressive irreversible airflow obstruction was due to persistent structural change to the airway secondary to eosinophilic airway inflammation, and it is further speculated that eosinophilic bronchitis may be a prelude to chronic obstructive pulmonary disease in some patients.
Quality and quantity of T <sub>FH</sub> cells are critical for broad antibody development in SHIV <sub>AD8</sub> infection
Authors: Takuya Yamamoto, Rebecca M. Lynch, Rajeev Gautam, Rodrigo Matus-Nicodemos, Stephen D. Schmidt, Kristin L. Boswell, Sam Darko, Patrick Wong, Zizhang Sheng, Constantinos Petrovas, Adrian B. McDermott, Robert A. Seder, Brandon F. Keele, Lawrence Shapiro, Daniel C. Douek, Yoshiaki Nishimura, John R. Mascola, Malcolm A. Martin, Richard A. Koup
Journal: Science Translational Medicine (2015)

T follicular helper cells associate with development of highly mutated neutralizing antibodies against SHIV.
Hypoxia induces unique proliferative response in adventitial fibroblasts by activating PDGFβ receptor-JNK1 signalling
Authors: Evgeniy Panzhinskiy, W. Michael Zawada, Kurt R. Stenmark, Mita Das
Journal: Cardiovascular Research (2012)

AimsPulmonary hypertension (PH) is a devastating condition for which no disease-modifying therapies exist. PH is recognized as proliferative disease of the pulmonary artery (PA). In the experimental newborn calf model of hypoxia-induced PH, adventitial fibroblasts in the PA wall exhibit a heightened replication index. Because elevated platelet-derived growth factor β receptor (PDGFβ-R) signalling is associated with PH, we tested the hypothesis that the activation of PDGFβ-R contributes to fibroblast proliferation and adventitial remodelling in PH.
Abbreviated Course of Radiation Therapy in Older Patients With Glioblastoma Multiforme: A Prospective Randomized Clinical Trial
Authors: W. Roa, P.M.A. Brasher, G. Bauman, M. Anthes, E. Bruera, A. Chan, B. Fisher, D. Fulton, S. Gulavita, C. Hao, S. Husain, A. Murtha, K. Petruk, D. Stewart, P. Tai, R. Urtasun, J.G. Cairncross, P. Forsyth
Journal: Journal of Clinical Oncology (2004)

To prospectively compare standard radiation therapy (RT) with an abbreviated course of RT in older patients with glioblastoma multiforme (GBM).One hundred patients with GBM, age 60 years or older, were randomly assigned after surgery to receive either standard RT (60 Gy in 30 fractions over 6 weeks) or a shorter course of RT (40 Gy in 15 fractions over 3 weeks). The primary end point was overall survival. The secondary end points were proportionate survival at 6 months, health-related quality of life (HRQoL), and corticosteroid requirement. HRQoL was assessed using the Karnofsky performance status (KPS) and Functional Assessment of Cancer Therapy-Brain (FACT-Br).All patients had died at the time of analysis. Overall survival times measured from randomization were similar at 5.1 months for standard RT versus 5.6 months for the shorter course (log-rank test, P =.57). The survival probabilities at 6 months were also similar at 44.7% for standard RT versus 41.7% for the shorter course (lower-bound 95% CI, -13.7). KPS scores varied markedly but were not significantly different between the two groups (Wilcoxon test, P =.63). Low completion rates of the FACT-Br (45%) precluded meaningful comparisons between the two groups. Of patients completing RT as planned, 49% of patients (standard RT) versus 23% required an increase in posttreatment corticosteroid dosage (chi(2) test, P =.02).There is no difference in survival between patients receiving standard RT or short-course RT. In view of the similar KPS scores, decreased increment in corticosteroid requirement, and reduced treatment time, the abbreviated course of RT seems to be a reasonable treatment option for older patients with GBM.
Combined CMV prophylaxis reduces short term complications after lung transplantation
Authors: Elisabetta Balestro, Emanuela Rossi, Francesca Lunardi, Marco Damin, Nazarena Nannini, Monica Loy, Giuseppe Marulli, Federico Rea, Fiorella Calabrese
Journal: European Respiratory Journal (2012)

Among solid organ transplant recipients, lung transplant ones are at highest risk of cytomegalovirus (CMV) infection. The advent of CMV prophylaxis and changes in prophylactic protocols have contributed to a steady decline in CMV infection and mortality; however its potential impact on short-term outcome needs further investigation. The aim of the study is to evaluate the effect of combined CMV prophylaxis in reducing short term acute illness after transplant. A consecutive series of 52 CMV high-risk lung transplant recipients who had more than one year follow-up, were studied. The study group (n=26; age 44±2yrs) received ganciclovir or valganciclovir from postoperative day 15 and CMV-Immunoglobulins for six months, while the control group (n=26; 40±2yrs) was treated with pre-emptive therapy. Viral Infection Index (number of BAL with infection/total BAL number), acute rejection index (ARI, number of acute rejections/total transbronchial biopsies number), incidence of CMV pneumonia and early onset BOS were obtained. Viral Infection Index, infection index simply related to CMV as well as ARI were significantly reduced in the study group than in the control group (mean 33%Vs50% p=0.02; 14%Vs27% p=0.05 and 13%Vs26% p=0.04, respectively), while the incidence of CMV-pneumonia and BOS were similar in the two groups. A significant relationship between combined CMV prophylaxis and a reduced prevalence of acute rejection was observed by logistic regression analysis, even when considering grade A3 only (p=0.01). In conclusion our data underline the strong efficacy of combined CMV prophylaxis in reducing infections as well as acute rejections, particularly the most severe ones, in lung transplant recipients.
Dual Inactivation of Akt and ERK by TIC10 Signals Foxo3a Nuclear Translocation, TRAIL Gene Induction, and Potent Antitumor Effects
Authors: Joshua E. Allen, Gabriel Krigsfeld, Patrick A. Mayes, Luv Patel, David T. Dicker, Akshal S. Patel, Nathan G. Dolloff, Evangelos Messaris, Kimberly A. Scata, Wenge Wang, Jun-Ying Zhou, Gen Sheng Wu, Wafik S. El-Deiry
Journal: Science Translational Medicine (2013)

TIC10 is a small molecule that activates Foxo3a through dual inactivation of Akt and ERK, up-regulates the expression of the TRAIL gene, an endogenous tumor suppressor, and effectively improves the therapeutic properties and utility of TRAIL as an anticancer therapy.
Glomerular Lesions in the Acquired Immunodeficiency Syndrome
Authors: VICTORIANO PARDO
Journal: Annals of Internal Medicine (1984)

Between January 1982 and December 1983, 75 patients with the acquired immunodeficiency syndrome were identified in our hospitals: 35% used intravenous drugs, 50% had proteinuria in excess of 0. 5 g/dL, and 10% were nephrotic. Glomerular changes seen at autopsy in 36 patients included frequent mesangial lesions and deposits associated with mild asymptomatic proteinuria. Focal and segmental glomerular sclerosis was found in 5 patients and 4 of these had the nephrotic syndrome. Whereas reversible episodes of acute renal failure were not uncommon, terminal episodes of acute renal insufficiency occurred in 14 patients. The short survival of these patients may prevent the development of chronic renal failure.
Suppressive Effects of 24,25-Dihydroxycholecalciferol on Bone Resorption Induced by Acute Bilateral Nephrectomy in Rats
Authors: Jana Henriette Pavlovitch, Giulia Cournot-Witmer, Agnes Bourdeau, Sonia Balsan, Jan A. Fischer, Guy Heynen
Journal: Journal of Clinical Investigation (1981)

The possible suppressive effects of 24,25-dihydroxycholecalciferol on secondary hyperparathyroidism and increased bone resorption were investigated in adult rats raised on a diet normal in calcium, phosphorus, and vitamin D, and subjected to acute bilateral nephrectomy. The animals had received subcutaneous radiocalcium 4 wk before the experiment. 5 h after nephrectomy an increase in serum total calcium, 45Ca-specific activity, citrate, phosphorus, and magnesium concentrations were observed. Serum immunoreactive parathyroid hormone increased, while serum calcitonin decreased. The osteoclast count in the tibial metaphyses was augmented. The biochemical and histological changes observed were partly parathyroid hormone and calcitonin independent, as they also occurred in parathyroidectomized hypocalcemic rats. Pretreatment with 650 pmol of 24,25-dihydroxycholecalciferol 16 h before nephrectomy prevented bone calcium mobilization and diminished the rise in serum total calcium and citrate both in parathyroid-intact and in parathyroidectomized animals. In parathyroid-intact rats, serum immunoreactive parathyroid hormone and calcitonin remained normal in spite of the fall in serum-ionized calcium, and the number of osteoclasts did not increase. In parathyroidectomized rats, 24,25-dihydroxycholecalciferol did not prevent the postnephrectomy rise in the osteoclast count. This latter observation suggests that this metabolite exerts its effect on bone either by acting on cells other than osteoclasts, i.e., the osteocytes, or by inhibiting cell activity. At equimolar dosage 1,25-dihydroxycholecalciferol had a potent stimulatory effect on bone resorption. This effect of 1,25-dihydroxycholecalciferol was partly blocked by the simultaneous administration of 24,25-dihydroxycholecalciferol.
Global transcriptome analysis reveals circadian regulation of key pathways in plant growth and development
Authors: Michael F Covington, Julin N Maloof, Marty Straume, Steve A Kay, Stacey L Harmer
Journal: Genome biology (2008)

Abstract Background As nonmotile organisms, plants must rapidly adapt to ever-changing environmental conditions, including those caused by daily light/dark cycles. One important mechanism for anticipating and preparing for such predictable changes is the circadian clock. Nearly all organisms have circadian oscillators that, when they are in phase with the Earth's rotation, provide a competitive advantage. In order to understand how circadian clocks benefit plants, it is necessary to identify the pathways and processes that are clock controlled. Results We have integrated information from multiple circadian microarray experiments performed on Arabidopsis thaliana in order to better estimate the fraction of the plant transcriptome that is circadian regulated. Analyzing the promoters of clock-controlled genes, we identified circadian clock regulatory elements correlated with phase-specific transcript accumulation. We have also identified several physiological pathways enriched for clock-regulated changes in transcript abundance, suggesting they may be modulated by the circadian clock. Conclusion Our analysis suggests that transcript abundance of roughly one-third of expressed A. thaliana genes is circadian regulated. We found four promoter elements, enriched in the promoters of genes with four discrete phases, which may contribute to the time-of-day specific changes in the transcript abundance of these genes. Clock-regulated genes are over-represented among all of the classical plant hormone and multiple stress response pathways, suggesting that all of these pathways are influenced by the circadian clock. Further exploration of the links between the clock and these pathways will lead to a better understanding of how the circadian clock affects plant growth and leads to improved fitness.
Low Values of Allergen Specific IgE Antibodies are Clinically Useful and Give Predictive Information for Very Young Children
Authors: L. Soderstrom, M. Nordlund, C. Nilsson, G. Lilja
Journal: Journal of Allergy and Clinical Immunology (2007)

RATIONALE: Evaluate the diagnostic efficacy of low levels of IgE sensitisation to food and inhalant allergens among children below 5 years of age.METHODS: Two hundred and sixty-nine children, 136 boys and 133 girls, with double, maternal or no heredity of atopic disease were followed prospectively from birth to 5 years of age, for the presence of IgE sensitisation and the development of atopic manifestations. Allergen specific IgE antibody levels were measured at the age of 6, 12, 24 and 60 months to food and inhalant allergens (ImmunoCAP™, Phadia AB, Sweden), measuring range 0.1 _ 100 kU/L.RESULTS: At the age of 6 months 25% were sensitized to egg, 22% to milk, 1% to cat and no one to birch. At the age of 60 months 53% were sensitized to egg, 47% to milk, 16% to cat and 23% to birch. The low quantitative levels of specific IgE (0.1-0.35 kUA/L) were predictive for rhinitis at age 60 months of age using the birch specific IgE at age 24 months, OR = 7.3 at 0.2 kUA/L (p = 0.017) and predictive for eczema at 24 months using the milk specific IgE at 6 months of age, OR = 5.6 at 0.2 kUA/L (p = 0.007).CONCLUSION: Prospectively following levels of allergen specific IgE antibodies in children is a useful tool both as an aid in diagnosing IgE mediated allergy and for the prediction of later atopic manifestation. RATIONALE: Evaluate the diagnostic efficacy of low levels of IgE sensitisation to food and inhalant allergens among children below 5 years of age. METHODS: Two hundred and sixty-nine children, 136 boys and 133 girls, with double, maternal or no heredity of atopic disease were followed prospectively from birth to 5 years of age, for the presence of IgE sensitisation and the development of atopic manifestations. Allergen specific IgE antibody levels were measured at the age of 6, 12, 24 and 60 months to food and inhalant allergens (ImmunoCAP™, Phadia AB, Sweden), measuring range 0.1 _ 100 kU/L. RESULTS: At the age of 6 months 25% were sensitized to egg, 22% to milk, 1% to cat and no one to birch. At the age of 60 months 53% were sensitized to egg, 47% to milk, 16% to cat and 23% to birch. The low quantitative levels of specific IgE (0.1-0.35 kUA/L) were predictive for rhinitis at age 60 months of age using the birch specific IgE at age 24 months, OR = 7.3 at 0.2 kUA/L (p = 0.017) and predictive for eczema at 24 months using the milk specific IgE at 6 months of age, OR = 5.6 at 0.2 kUA/L (p = 0.007). CONCLUSION: Prospectively following levels of allergen specific IgE antibodies in children is a useful tool both as an aid in diagnosing IgE mediated allergy and for the prediction of later atopic manifestation.
Transport of invalids by air.
Authors: K. G. Bergin
Journal: BMJ (1967)

Sick persons, including those at both extremes of the age scale, tolerate modern flying conditions with very little, if any, discomfort. The number of invalids wishing to travel by air who have to be refused passage is steadily decreasing, and the great majority of cases benefit by the advantages air travel has to offer over surface travel, including speed, smoothness, and comfort. In many cases this form of transport is not merely desirable but actually life-saving.
Role of Endoplasmic Reticulum Stress in Metabolic Disease and Other Disorders
Authors: Lale Ozcan, Ira Tabas
Journal: Annual Review of Medicine (2011)

Perturbations in the normal functions of the endoplasmic reticulum (ER) trigger a signaling network that coordinates adaptive and apoptotic responses. There is accumulating evidence implicating prolonged ER stress in the development and progression of many diseases, including neurodegeneration, atherosclerosis, type 2 diabetes, liver disease, and cancer. With the improved understanding of the underlying molecular mechanisms, therapeutic interventions that target the ER stress response would be potential strategies to treat various diseases driven by prolonged ER stress.
Cells and mediators from pharyngeal secretions in infants with acute wheezing episodes
Authors: FP Counil, B Lebel, M Segondy, C Peterson, M Voisin, J Bousquet, B Arnoux
Journal: European Respiratory Journal (1997)

An acute wheezing episode is the most common feature of severe lower respiratory tract infection during infancy. Respiratory syncytial virus (RSV) is the major causative agent. In order to study inflammation during acute wheezing episodes in infants, we wanted to assess the feasibility and contribution of induction of pharyngeal secretions. We therefore compared inflammatory markers in the pharyngeal secretions of 27 infants suffering from acute wheezing episodes with an RSV infection (RSV+) and 18 infants suffering with acute wheezing episodes without RSV infection (RSV-). Pharyngeal secretions were recovered by physiotherapy using isotonic saline. The safety of the procedure was carefully checked. Pharyngeal secretions were homogenized with dithiothreitol. Total cells and eosinophils were counted and levels of eosinophil cationic protein (ECP) and histamine were measured. Induction of pharyngeal secretion was always well tolerated. Eosinophils were present in five RSV+ and seven RSV- patients. ECP levels were not significantly different between the groups. Histamine levels after protein adjustment were significantly increased in RSV+ patients (p<0.01) in comparison to RSV- patients. In this study, we have shown, that pharyngeal secretion can be safely recovered from infants suffering from acute wheezing episodes, and that it can be analysed for enumeration of inflammatory cells and measurement of inflammatory mediators.