tbuckley/cabot-search huggingface dataset:
Increased frequencies of CD4+CD25high regulatory T cells in acute dengue infection
Authors: Kerstin Lühn, Cameron P. Simmons, Edward Moran, Nguyen Thi Phuong Dung, Tran Nguyen Bich Chau, Nguyen Than Ha Quyen, Le Thi Thu Thao, Tran Van Ngoc, Nguyen Minh Dung, Bridget Wills, Jeremy Farrar, Andrew J. McMichael, Tao Dong, Sarah Rowland-Jones
Journal: The Journal of Experimental Medicine (2007)

Dengue virus infection is an increasingly important tropical disease, causing 100 million cases each year. Symptoms range from mild febrile illness to severe hemorrhagic fever. The pathogenesis is incompletely understood, but immunopathology is thought to play a part, with antibody-dependent enhancement and massive immune activation of T cells and monocytes/macrophages leading to a disproportionate production of proinflammatory cytokines. We sought to investigate whether a defective population of regulatory T cells (T reg cells) could be contributing to immunopathology in severe dengue disease. CD4+CD25highFoxP3+ T reg cells of patients with acute dengue infection of different severities showed a conventional phenotype. Unexpectedly, their capacity to suppress T cell proliferation and to secrete interleukin-10 was not altered. Moreover, T reg cells suppressed the production of vasoactive cytokines after dengue-specific stimulation. Furthermore, T reg cell frequencies and also T reg cell/effector T cell ratios were increased in patients with acute infection. A strong indication that a relative rise of T reg cell/effector T cell ratios is beneficial for disease outcome comes from patients with mild disease in which this ratio is significantly increased (P &amp;lt; 0.0001) in contrast to severe cases (P = 0.2145). We conclude that although T reg cells expand and function normally in acute dengue infection, their relative frequencies are insufficient to control the immunopathology of severe disease.
Reengineering Inducible Cardiac-Specific Transgenesis With an Attenuated Myosin Heavy Chain Promoter
Authors: Atsushi Sanbe, James Gulick, Mark C. Hanks, Qiangrong Liang, Hanna Osinska, Jeffrey Robbins
Journal: Circulation Research (2003)

Despite the advantages of reversibly altering cardiac transgene expression, the number of successful studies with inducible cardiac-specific transgene expression remains limited. The utility of the current system is hampered by the large number of lines needed before a nonleaky inducible line is isolated and by the use of a heterologous virus-based minimal promoter in the responder line. We developed an efficient, experimentally flexible system that enables us to reversibly affect both abundant and nonabundant cardiomyocyte proteins. The use of bacterial-codon-based transactivators led to aberrant splicing, whereas other more efficient transactivators, by themselves, caused disease when expressed in the heart. The redesign of the system focused on developing stable transactivator-expressing lines in which expression was driven by the mouse alpha-myosin heavy chain promoter. A minimal responder locus was derived from the same promoter, in which the GATA sites and thyroid responsive elements responsible for robust cardiac specific expression were ablated, leading to an attenuated promoter that could be inducibly controlled. In all cases, whether activated or not, expression mimicked that of the parental promoter. By use of this system, an inducible expression of an abundant contractile protein, the atrial isoform of essential myosin light chain 1, and a powerful biological effector, glycogen synthase kinase-3beta (GSK-3beta), were obtained. Subsequently, we tested the hypothesis that GSK-3beta expression could reverse a preexisting hypertrophy. Inducible expression of GSK-3beta could both attenuate a hypertrophic response and partially reverse a pressure-overload-induced hypertrophy. The system appears to be robust and can be used to temporally control high levels of cardiac-specific transgene expression.
Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study
Authors: E Zeggini, K Panoutsopoulou, L Southam, N W Rayner, A G Day-Williams, M C Lopes, V Boraska, T Esko, E Evangelou, A Hoffman, J J Houwing-Duistermaat, T Ingvarsson, I Jonsdottir, H Jonnson, H J Kerkhof, M Kloppenburg, S D Bos, M Mangino, S Metrustry, P E Slagboom, G Thorleifsson, Raine Eva., M Ratnayake, M Ricketts, C Beazley, H Blackburn, S Bumpstead, K S Elliott, S E Hunt, S C Potter, Shin S-Y., V K Yadav, G Zhai, K Sherburn, K Dixon, E Arden, N Aslam, Battley P-K., I Carluke, S Doherty, A Gordon, J Joseph, R Keen, N C Koller, S Mitchell, F O'Neill, E Paling, M R Reed, F Rivadeneira, D Swift, K Walker, B Watkins, M Wheeler, F Birrell, Ioannidis Jpa., I Meulenbelt, A Metspalu, A Rai, D Salter, K Stefansson, U Stykarsdottir, A G Uitterlinden, van Meurs Jbj., K Chapman, P Deloukas, Ollier Wer., G A Wallis, N Arden, A Carr, M Doherty, A McCaskie, J M Willkinson, S H Ralston, A M Valdes, T D Spector, J Loughlin
Journal: The Lancet (2012)
Smad2 and Smad6 as predictors of overall survival in oral squamous cell carcinoma patients
Authors: Flavia RR Mangone, Fernando Walder, Simone Maistro, Fátima S Pasini, Carlos N Lehn, Marcos B Carvalho, M Mitzi Brentani, Igor Snitcovsky, Miriam HH Federico
Journal: Molecular Cancer (2010)

To test if the expression of Smad1-8 mRNAs were predictive of survival in patients with oral squamous cell carcinoma (SCC). We analyzed, prospectively, the expression of Smad1-8, by means of Ribonuclease Protection Assay in 48 primary, operable, oral SCC. In addition, 21 larynx, 10 oropharynx and 4 hypopharynx SCC and 65 matched adjacent mucosa, available for study, were also included. For survival analysis, patients were categorized as positive or negative for each Smad, according to median mRNA expression. We also performed real-time quantitative PCR (QRTPCR) to asses the pattern of TGFβ1, TGFβ2, TGFβ3 in oral SCC. Our results showed that Smad2 and Smad6 mRNA expression were both associated with survival in Oral SCC patients. Cox Multivariate analysis revealed that Smad6 positivity and Smad2 negativity were both predictive of good prognosis for oral SCC patients, independent of lymph nodal status (P = 0.003 and P = 0.029, respectively). In addition, simultaneously Smad2- and Smad6+ oral SCC group of patients did not reach median overall survival (mOS) whereas the mOS of Smad2+/Smad6- subgroup was 11.6 months (P = 0.004, univariate analysis). Regarding to TGFβ isoforms, we found that Smad2 mRNA and TGFβ1 mRNA were inversely correlated (p = 0.05, R = -0.33), and that seven of the eight TGFβ1+ patients were Smad2-. In larynx SCC, Smad7- patients did not reach mOS whereas mOS of Smad7+ patients were only 7.0 months (P = 0.04). No other correlations were found among Smad expression, clinico-pathological characteristics and survival in oral, larynx, hypopharynx, oropharynx or the entire head and neck SCC population. Smad6 together with Smad2 may be prognostic factors, independent of nodal status in oral SCC after curative resection. The underlying mechanism which involves aberrant TGFβ signaling should be better clarified in the future.
A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits
Authors: Yoon Shin Cho, Min Jin Go, Young Jin Kim, Jee Yeon Heo, Ji Hee Oh, Hyo-Jeong Ban, Dankyu Yoon, Mi Hee Lee, Dong-Joon Kim, Miey Park, Seung-Hun Cha, Jun-Woo Kim, Bok-Ghee Han, Haesook Min, Younjhin Ahn, Man Suk Park, Hye Ree Han, Hye-Yoon Jang, Eun Young Cho, Jong-Eun Lee, Nam H Cho, Chol Shin, Taesung Park, Ji Wan Park, Jong-Keuk Lee, Lon Cardon, Geraldine Clarke, Mark I McCarthy, Jong-Young Lee, Jong-Koo Lee, Bermseok Oh, Hyung-Lae Kim
Journal: Nature Genetics (2009)
Phase I Clinical and Pharmacokinetic Trial of Flavone Acetic Acid
Authors: A. K. Havlin, J. G. Kuhn, J. B. Craig, D. H. Boldt, G. R. Weiss, J. Koeller, G. Harman, R. Schwartz, G. N. Clark, D. D. Von Hoff
Journal: JNCI Journal of the National Cancer Institute (1991)

Flavone acetic acid is a synthetic benzopyrone derivative with an unknown mechanism of action. Thirty-eight patients (30 men and 8 women) were treated once a week for 4 weeks every 5 weeks with doses of flavone acetic acid ranging from 0.33 to 12.5 g/m 2 . At doses less than or equal to 3.9 g/m 2 , the drug was administered intravenously over 1 hour; at doses greater than or equal to 5.28 g/m 2 , the infusion period was lengthened to 6 hours. Treatment of all patients included hydration before and after treatment and alkalization to maintain urine pH at greater than or equal to 6.5. A dose-limiting toxic effect was hypotension at 10 g/m 2 . Pharmaco-kinetic studies revealed linear behavior in the eight patients studied, beginning at 3.9 g/m 2 . Peak plasma levels ranged from 125 to 630 μg/mL, with a mean terminal half-life of 22.4 hours. Immunologic monitoring was performed in three patients at 10 g/m 2 . A transient increase in CD16- and/or Leu-19-positive cells was noted in all three patients. In one patient, this increase correlated with a 10-fold increase in K562 cell killing. There were no objective tumor responses seen in this trial. The recommended phase II dose on this schedule is 8 g/m 2 . Further studies to elucidate the drug's mechanism of action and to define its immunologic properties are recommended. [J Natl Cancer Inst 83: 124–128, 1991]
Association of Low PaCO_2 with Central Sleep Apnea and Ventricular Arrhythmias in Ambulatory Patients with Stable Heart Failure
Authors: Shahrokh Javaheri
Journal: Annals of Internal Medicine (1998)

Background: Central sleep apnea frequently occurs in patients with heart failure. Because it is not practical to perform sleep studies on all patients, readily available laboratory tests that predict sleep apnea would be clinically useful. Arterial Pco 2 has a profound influence on breathing during sleep: When it decreases below a certain threshold, apnea occurs. Objective: To study the value of a low Paco 2 while patients are awake in predicting central sleep apnea in patients with stable, treated heart failure. Design: Prospective study. Setting: Referral sleep laboratory of a Department of Veterans Affairs Medical Center. Participants: 59 patients with left ventricular ejection fractions of 45% or less. Measurements: Arterial blood gases and hydrogen ion concentrations were measured, and cardiac radionuclide ventriculography, Holter monitoring, and polysomnography were done. Results: Patients were classified as eucapnic (Paco 2 > 35 and < 44 mm Hg [n = 41]) or hypocapnic (Paco 2 ≤ 35 mm Hg [n = 18]). The mean (±SD) hourly episodes of apnea or hypopnea (36 ± 25 and 20 ± 27; P = 0.015), the prevalence of central sleep apnea (78% and 39%; P = 0.01), and the mean hourly occurrences of ventricular tachycardia (2 ± 3 and 0.1 ± 0.1; P = 0.003) were significantly greater in hypocapnic patients than in eucapnic patients. Conclusion: Data on patients with heart failure in this study are consistent with the physiologic notion that a low Paco 2 results in ventilatory instability and central apnea during sleep. The positive predictive value of a low Paco 2 for central sleep apnea is 78%. The prevalence of ventricular tachycardia was 20 times greater in hypocapnic patients than in eucapnic patients.
Comparative Study of Fluoroscopy and Intracardiac Echocardiographic Guidance for the Creation of Linear Atrial Lesions
Authors: Laurence M. Epstein, Mark A. Mitchell, Timothy W. Smith, David E. Haines
Journal: Circulation (1998)

Background —Recently, attempts have been made to cure atrial fibrillation by creating multiple linear atrial lesions with radiofrequency energy. Intracardiac echocardiography (ICE) offers imaging of endocardial anatomy and the ablation electrode–tissue interface not available with standard fluoroscopy. This study sought to prospectively compare fluoroscopic with ICE guidance for the creation of linear atrial lesions in a canine model. Methods and Results —The creation of 3 linear atrial lesions was attempted in each of 10 dogs, half guided by fluoroscopy alone and half by ICE. Coil-tissue contact was prospectively graded. After ablation, animals were euthanized, and the location and continuity of lesions were evaluated. ICE guidance led to a higher percentage of successful applications ( P =0.02) and mean achieved temperature ( P =0.004). The contact scores of excellent, fair, and poor correlated well with successful energy delivery, mean temperature, and efficiency of heating ( P &lt;0.0001). In 25% of the blinded energy deliveries, the location, as determined by the ablation operator, differed from that of ICE. Pathological evaluation revealed improved lesion formation in the ICE-guided compared with the ICE-blinded group. Lesions were found outside the target areas in the ICE-blinded but not the ICE-guided group. Conclusions —Compared with fluoroscopy, ICE guidance improved targeting, energy delivery, and lesion formation in this canine model. This study suggests that ICE guidance improves lesion formation and prevents energy delivery to potentially dangerous sites.
Cisplatin-Based Chemotherapy and the Risk of Solid Tumors in Patients With Testicular Nonseminoma: Still a Matter of Debate
Authors: Giorgio Gandaglia, Pierre I. Karakiewicz, Quoc-Dien Trinh, Maxine Sun
Journal: Journal of Clinical Oncology (2014)

TO THE EDITOR: Fung et al compared the risks of secondary malignancies among patients treated with chemotherapy or surgery alone for testicular nonseminoma. Utilizing the population-based SEER cohort, Fung et al found that chemotherapy-treated men had a 40% increased risk of developing secondary malignancies after initial diagnosis. Although the study is without doubt an important assessment given the rising incidence of testicular cancer in the last decades, several limitations should be raised, which may weaken the clinical applicability of their findings in the contemporary era. First, since the study span covered diagnoses from 1980 to 2008, Fung et al could not account for the variable chemotherapy regimens that were introduced over time. Patients diagnosed and treated in more recent years with newer and less toxic chemotherapy regimens might be at considerably lower risk of secondary malignancies compared to historical chemotherapy regimens used 30 years ago. Second, the lack of consideration for disease stage in the calculation of standardized incidence ratios for secondary malignancies further augments the heterogeneity of the studied population. Of note, 34% of patients treated with chemotherapy harbored metastatic disease versus 1.7% in the surgery group. Given the prevalence of metastatic patients in the chemotherapy group, Fung et al are unable to rule out the confounding effect of biologic mechanisms. Specifically, inheritance of both rare genetic variants and polygenic trait predisposing to the development of advanced disease, may ultimately increase the risks of a new onset of secondary malignancies. Third, the number of cycles and dosage received is equally unknown. For example, metastatic patients are likely to be exposed to significantly higher cumulative doses of chemotherapeutic agents compared to individuals with stage I testicular nonseminoma. Thus, the current study is not able to provide insight into the dose-response relationship between chemotherapy and the subsequent risk of solid malignancies. In conclusion, the evaluation of the potential role of chemotherapy on the development of secondary malignancies relative to surgery in patients with testicular nonseminoma is highly relevant. However several other important aspects—improvements in chemotherapy regimens used in contemporary years, a better defined population according to disease stage, better knowledge of dosage and cycles used—need to be factored in the assessment of this association to avoid over-attributing the long-term adverse effects of chemotherapy.
What is a sports medicine specialist? A pilot study
Authors: B Thompson, O Mcnally, S O Neill, D Macauley
Journal: British Journal of Sports Medicine (2000)

Nicotinic acid is a lipid-lowering agent widely used to treat hypertriglyceridemia and to elevate low high density lipoprotein levels. However, the underlying mechanisms are poorly understood. In this study, G protein activation by nicotinic acid and derivatives was assessed as stimulation of guanosine 5′-(γ-[<sup>35</sup>S]-thio)triphosphate ([<sup>35</sup>S]GTPγS) binding, and [<sup>3</sup>H]nicotinic acid was used for specific labeling of binding sites. Nicotinic acid (EC<sub>50</sub> ∼1 μM) stimulated [<sup>35</sup>S]GTPγS binding in membranes from rat adipocytes and spleen, but not from other tissues. G protein activation in adipocyte membranes in the presence of maximally activating concentrations of the selective A<sub>1</sub>adenosine receptor agonist 2-chloro-<i>N</i><sup>6</sup>-cyclopentyladenosine and nicotinic acid was almost additive, indicating that G proteins of mostly distinct pools were activated by these agonists. G protein activation by nicotinic acid and related substances in spleen and adipocytes revealed identical pharmacological profiles. [<sup>3</sup>H]Nicotinic acid specifically detected guanine nucleotide-sensitive binding sites of identical pharmacology in adipocyte and spleen membranes. The site of action of nicotinic acid is distinct from other G protein-coupled receptors. These data indicate that nicotinic acid most probably acts on a specific G protein-coupled receptor.
Phosphorylation of Ezrin by Cyclin-Dependent Kinase 5 Induces the Release of Rho GDP Dissociation Inhibitor to Inhibit Rac1 Activity in Senescent Cells
Authors: Hi-Su Yang, Philip W. Hinds
Journal: Cancer Research (2006)

Abstract Normal somatic cells enter a state of irreversible proliferation arrest-designated cellular senescence, which is characterized by biochemical changes and a distinctive morphology. Cellular stresses, including oncogene activation, can lead to senescence. Consistent with an antioncogenic role in this process, the tumor suppressor pRb plays a critical role in senescence. Reexpression of pRb in human tumor cells results in senescence-like changes, including cell cycle exit and cell shape alteration. Here, we show that pRb-induced senescent SAOS-2 cells and senescent human diploid fibroblasts are accompanied by increased phosphorylation of ezrin at T235 by cyclin-dependent kinase 5 and consequent dissociation of Rho GDP dissociation inhibitor (Rho-GDI) from an ezrin/Rho-GDI complex. The release of Rho-GDI results in increased interaction with Rac1 GTPase and inhibition of Rac1 GTPase activity. In addition, reduction of Rho-GDI by small interfering RNA in pRb-transfected cells prevented senescence-associated flat cell formation, suggesting that Rho-GDI plays an important role in contributing to cellular morphology in the process of senescence. (Cancer Res 2006; 66(5): 2708-15)
Pulmonary Function in Pigeon Breeders' Disease
Authors: DONALD P. SCHLUETER
Journal: Annals of Internal Medicine (1969)

Pulmonary function studies were performed in 13 patients with clinical and immunologic evidence of pigeon breeders' disease. In the nine subjects with the acute form of the disease the most consistent abnormality demonstrated was an increased residual volume. Two subjects had changes in arterial PO2 and dead space to tidal volume (VD/VT) ratios with exercise compatible with disturbance in ventilation-perfusion relationships. One individual had a low diffusing capacity at rest but a normal value with exercise. Studies of respiratory mechanics showed an elevated maximum inspiratory transpulmonary pressure in two subjects as well as a low static and dynamic compliance. Delayed reversible reductions in vital capacity and flow rates as well as changes in respiratory mechanics after exposure to pigeons were demonstrated in two of these breeders. In the two subjects with the subacute form of the disease the response to acute pigeon exposure was less dramatic, but restrictive respiratory impairment was present during chronic exposure and resolved slowly but completely with avoidance of pigeons. However, a nonreversible increase in pulmonary elasticity was demonstrated in one of these individuals. Nonreversible restrictive and obstructive respiratory impairment as well as disturbances in carbon monoxide diffusing capacity were found in the two patients with the chronic form of the disease. The most significant findings in this group were changes in respiratory mechanics that are identical to those found in pulmonary emphysema. From these studies it is apparent that permanent lung damage can occur in pigeon breeders' disease, particularly in its chronic form.
Management of Clinical Stage I Testicular Cancer: How Should We Define Success?
Authors: Lance C. Pagliaro, Nizar M. Tannir, Shi-Ming Tu, Christopher J. Logothetis
Journal: Journal of Clinical Oncology (2015)

vivalwas99.7%.InthestudybyDaugaardetal, 2 of1,226patientswith CSI NSGCT managed with AS, the 15-year disease-specific survival was99.1%.BotharticlesreinforcethenotionthatASforCSItesticular cancer is safe and that it allows potentially toxic chemotherapy to be restricted to only the patients who actually need it. The editorial by de Wit 3 and the Oncology Grand Rounds discussions by Feldman 4 and Vaughn 5 were largely supportive of AS as the standard management for CSI testicular cancer, with the caveats that poorly compliant patients are not ideal candidates for this approach, and that primary retroperitoneal lymph node dissection
FOLFIRI with or without celecoxib in advanced colorectal cancer: a randomized phase II study of the Gruppo Oncologico dell'Italia Meridionale (GOIM)
Authors: E. Maiello, F. Giuliani, V. Gebbia, N. Di Renzo, G. Pezzella, S. Romito, R. Mallamaci, M. Lopez, G. Colucci
Journal: Annals of Oncology (2006)
Adverse Health Effects of Marijuana Use
Authors: Nora D. Volkow, Ruben D. Baler, Wilson M. Compton, Susan R.B. Weiss
Journal: New England Journal of Medicine (2014)

As marijuana use becomes legal in some states, the dominant public opinion is that marijuana is a harmless source of mood alteration. Although the harms associated with marijuana use have not been well studied, enough information is available to cause concern.
Expression of IL-1α, IL-6, TGF-β, FasL and ZNF265 During Sertoli Cell Infection by Ureaplasma Urealyticum
Authors: Rongping Li, Yebin Xi, Xiuzhi Liu, Guangjie Chen, Baoguo Wang, Lihua Jiang, Weiyi Li
Journal: Cellular and Molecular Immunology (2009)