tbuckley/cabot-search huggingface dataset:
Smoking adversely affects treatment response, outcome and relapse in tuberculosis
Authors: Chi C. Leung, Wing W. Yew, Chi K. Chan, Kwok C. Chang, Wing S. Law, Shuk N. Lee, Lai B. Tai, Eric C.C. Leung, Ronald K.F. Au, Shan S. Huang, Cheuk M. Tam
Journal: European Respiratory Journal (2014)

The impact of smoking on tuberculosis outcome was evaluated in a territory-wide treatment programme. 16,345 consecutive patients undergoing chemotherapy for active tuberculosis in government chest clinics in Hong Kong from 2001 to 2003 were followed up prospectively for 2 years for treatment outcome and subsequently tracked through the territory-wide tuberculosis notification registry for relapse until the end of 2012. Smoking was associated with more extensive lung disease, lung cavitation and positive sputum smear and culture at the baseline. In both current smokers and ex-smokers, sputum smears and cultures were significantly more likely to remain positive after 2 months of treatment. Both categories of smokers were significantly less likely to achieve cure or treatment completion within 2 years. Overall, 16.7% of unsuccessful treatment outcomes were attributable to smoking, with the key contributor being default in current smokers and death in ex-smokers. Among successful treatment completers, there was a clear gradient (hazard ratios of 1.00, 1.33 and 1.63) of relapse risk from never-smokers to ex-smokers and current smokers, with an overall population attributable risk of 19.4% (current smokers: 12.2%; ex-smokers: 7.2%). Smoking adversely affects baseline disease severity, bacteriological response, treatment outcome and relapse in tuberculosis. Smoking cessation likely reduces relapse and secondary transmission.
The origins, function, and regulation of T follicular helper cells
Authors: Cindy S. Ma, Elissa K. Deenick, Marcel Batten, Stuart G. Tangye
Journal: The Journal of Experimental Medicine (2012)

The generation of high-affinity antibodies (Abs) plays a critical role in the neutralization and clearance of pathogens and subsequent host survival after natural infection with a variety of microorganisms. Most currently available vaccines rely on the induction of long-lived protective humoral immune responses by memory B cells and plasma cells, underscoring the importance of Abs in host protection. Ab responses against most antigens (Ags) require interactions between B cells and CD4+ T helper cells, and it is now well recognized that T follicular helper cells (Tfh) specialize in providing cognate help to B cells and are fundamentally required for the generation of T cell–dependent B cell responses. Perturbations in the development and/or function of Tfh cells can manifest as immunopathologies, such as immunodeficiency, autoimmunity, and malignancy. Unraveling the cellular and molecular requirements underlying Tfh cell formation and maintenance will help to identify molecules that could be targeted for the treatment of immunological diseases that are characterized by insufficient or excessive Ab responses.
Rb induces a proliferative arrest and curtails Brn-2 expression in retinoblastoma cells.
Authors: David Cobrinik, Richard O Francis, David H Abramson, Thomas C Lee
Journal: Molecular Cancer (2006)

Retinoblastoma is caused by loss of the Rb protein in early retinal cells. Although numerous Rb functions have been identified, Rb effects that specifically relate to the suppression of retinoblastoma have not been defined. In this study, we examined the effects of restoring Rb to Y79 retinoblastoma cells, using novel retroviral and lentiviral vectors that co-express green fluorescent protein (GFP). The lentiviral vector permitted transduction with sufficient efficiency to perform biochemical analyses. Wild type Rb (RbWT) and to a lesser extent the low penetrance mutant Rb661W induced a G0/G1 arrest associated with induction of p27KIP1 and repression of cyclin E1 and cyclin E2. Microarray analyses revealed that in addition to down-regulating E2F-responsive genes, Rb repressed expression of Brn-2 (POU3F2), which is implicated as an important transcriptional regulator in retinal progenitor cells and other neuroendocrine cell types. The repression of Brn-2 was a specific Rb effect, as ectopic p27 induced a G0/G1 block, but enhanced, rather than repressed, Brn-2 expression. In addition to Rb effects that occur in many cell types, Rb regulates a gene that selectively governs the behavior of late retinal progenitors and related cells.
Home versus hospital treatment of acute cystic fibrosis pulmonary exacerbations - Is quality of life really better at home?
Authors: Iara Sequeiros, Nabil Jarad
Journal: European Respiratory Journal (2013)

Background: Home intravenous (IV) antibiotic treatment of cystic fibrosis (CF) acute pulmonary exacerbations (PExs) has become a widespread occurrence, preferred by most patients over hospital treatment. Better quality of life (QoL) has been quoted as one of the main reasons why patients favour home treatment over hospital care.  Patients & Methods: This was a prospective study, which analyzed 181 PExs needing treatment with IV antibiotics in 58 adult CF patients (32 male). FEV1, FVC and QoL scores using Quittner’s CF Questionnaire-Revised (CFQ-R) were recorded at the start (day 1) and end (day 14) of treatment. PExs were classified according to the site where the majority of treatment (>80%) had been delivered (at home or in hospital).  Results: Baseline day 1 FEV1 and FVC values were similar in the 2 groups, but after 14 days of IV treatment significantly greater improvement was observed in the hospital treatment group. Baseline total QoL scores were higher in the home treatment group (mean QoL (SEM) 711.8 (20.5) in the home group and 595.4 (35.8) in the hospital group, P=0.003). However, after 14 days of treatment, changes in the total QoL scores were higher in the hospital group (mean QoL (SEM) 49.8 (17.5) in the home group and 140.9 (16.8) in the hospital group, P=0.001). Consequently, on day 14 values of QoL were similar in the 2 groups (mean QoL (SEM) 742.4 (21.5) in the home group and 747.1 (33.4) in the hospital group).  Conclusions: QoL demonstrated a significantly greater improvement in the hospital group. On day 14 QoL for the hospital group was similar to that of the home group despite possible disadvantages imposed by the confinement in hospital.
DIRECT DEMONSTRATION OF THETA-POSITIVE ANTIGEN-BINDING CELLS, WITH ANTIGEN-INDUCED MOVEMENT OF THYMUS-DEPENDENT CELL RECEPTORS
Authors: Robert F. Ashman, Martin C. Raff
Journal: The Journal of Experimental Medicine (1973)

Anti-thetaAKR antibody conjugated to fluorescein has been used in direct immunofluorescence tests to identify spleen theta(+) (T) sheep erythrocyte rosette-forming cells in AKR mice. Specificity studies involving A and cogenic A/thetaAKR mice clearly demonstrated that the cell surface fluorescence and cytotoxicity produced by the antiserum is directed solely toward the thetaAKR alloantigen. Approximately (3/8) of rosette-forming and non-rosette-forming spleen cells were found to be theta(+). The tendency for T cells to bind less antigen and the tendency for antigen-binding T cells to bear less theta than other spleen T cells, first suggested by other studies involving rosette-elimination by anti-thetaC3H plus complement, were confirmed by direct immunofluorescence. All AKR rosettes are specifically inhibitable by anti-immunoglobulin, including T rosettes. Antigen-induced redistribution of T cell receptors, analogous to that previously described for B cell receptors (16), occurs as readily in theta(+)RFC as in theta(-) RFC, without altering the symmetrical ring distribution of thetaAKR antigen.
Targeting Asymptomatic Malaria Infections: Active Surveillance in Control and Elimination
Authors: Hugh J. W. Sturrock, Michelle S. Hsiang, Justin M. Cohen, David L. Smith, Bryan Greenhouse, Teun Bousema, Roly D. Gosling
Journal: PLoS Medicine (2013)

Hugh Sturrock and colleagues discuss the role of active case detection in low malaria transmission settings. They argue that the evidence for its effectiveness is sparse and that targeted mass drug administration should be evaluated as an alternative or addition to active case detection. Please see later in the article for the Editors' Summary
Alternative Methods of Titrating Continuous Positive Airway Pressure
Authors: Juan F. Masa, Antonio Jiménez, Joaquín Durán, Francisco Capote, Carmen Monasterio, Mercedes Mayos, Joaquín Terán, Lourdes Hernández, Ferrán Barbé, Andrés Maimó, Manuela Rubio, José M. Montserrat
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Standard practice for continuous positive airway pressure (CPAP) treatment in sleep apnea and hypopnea syndrome (SAHS) requires pressure titration during attended laboratory polysomnography. However, polysomnographic titration is expensive and time-consuming. The aim of this study was to ascertain, in a large sample of CPAP-naive patients, whether CPAP titration performed by an unattended domiciliary autoadjusted CPAP device or with a predicted formula was as effective as CPAP titration performed by full polysomnography. The main outcomes were the apnea-hypopnea index and the subjective daytime sleepiness. We included 360 patients with SAHS requiring CPAP treatment. Patients were randomly allocated into three groups: standard, autoadjusted, and predicted formula titration with domiciliary adjustment. The follow-up period was 12 weeks. With CPAP treatment, the improvement in subjective sleepiness and apnea-hypopnea index was very similar in the three groups. There were no differences in the objective compliance of CPAP treatment and in the dropout rate of the three groups at the end of the follow-up. Autoadjusted titration at home and predicted formula titration with domiciliary adjustment can replace standard titration. These procedures could lead to considerable savings in cost and to significant reductions in the waiting list.
Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors
Authors: Ketu Mishra-Gorur, Ahmet Okay Çağlayan, Ashleigh E. Schaffer, Chiswili Chabu, Octavian Henegariu, Fernando Vonhoff, Gözde Tuğce Akgümüş, Sayoko Nishimura, Wenqi Han, Shu Tu, Burçin Baran, Hakan Gümüş, Cengiz Dilber, Maha S. Zaki, Heba A.A. Hossni, Jean-Baptiste Rivière, Hülya Kayserili, Emily G. Spencer, Rasim Ö. Rosti, Jana Schroth, Hüseyin Per, Caner Çağlar, Çağri Çağlar, Duygu Dölen, Jacob F. Baranoski, Sefer Kumandaş, Frank J. Minja, E. Zeynep Erson-Omay, Shrikant M. Mane, Richard P. Lifton, Tian Xu, Haig Keshishian, William B. Dobyns, Neil C. Chi, Nenad Šestan, Angeliki Louvi, Kaya Bilgüvar, Katsuhito Yasuno, Joseph G. Gleeson, Murat Günel
Journal: Neuron (2014)
Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn's disease
Authors: R. Ciccocioppo, M. E. Bernardo, A. Sgarella, R. Maccario, M. A. Avanzini, C. Ubezio, A. Minelli, C. Alvisi, A. Vanoli, F. Calliada, P. Dionigi, C. Perotti, F. Locatelli, G. R. Corazza
Journal: Gut (2011)

<h3>Objective</h3> External fistulas represent a disabling manifestation of Crohn9s disease with a difficult curability and a high relapse rate despite a large therapeutic armamentarium. Stem cell therapy is a novel and promising approach for treatment of chronic inflammatory conditions. We therefore investigated the feasibility, safety and efficacy of serial intrafistular injections of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in the treatment of fistulising Crohn9s disease. <h3>Patients and methods</h3> We enrolled 12 consecutive outpatients (eight males, median age 32 years) refractory to or unsuitable for current available therapies. MSCs were isolated from bone marrow and expanded ex vivo to be used for both therapeutic and experimental purposes. Ten patients (two refused) received intrafistular MSC injections (median 4) scheduled every 4 weeks, and were monitored by surgical, MRI and endoscopic evaluation for 12 months afterwards. The feasibility of obtaining at least 50×10<sup>6</sup> MSCs from each patient, the appearance of adverse events, and the efficacy in terms of fistula healing and reduction of both Crohn9s disease and perianal disease activity indexes were evaluated. In addition, the percentage of both mucosal and circulating regulatory T cells expressing FoxP3, and the ability of MSCs to influence mucosal T cell apoptosis were investigated. <h3>Results</h3> MSC expansion was successful in all cases; sustained complete closure (seven cases) or incomplete closure (three cases) of fistula tracks with a parallel reduction of Crohn9s disease and perianal disease activity indexes (p&lt;0.01 for both), and rectal mucosal healing were induced by treatment without any adverse effects. The percentage of mucosal and circulating regulatory T cells significantly increased during the treatment and remained stable until the end of follow up (p&lt;0.0001 and p&lt;0.01, respectively). Furthermore, MSCs have been proven to affect mucosal T cell apoptotic rate. <h3>Conclusions</h3> Locally injected MSCs represent a feasible, safe and beneficial therapy in refractory fistulising Crohn9s disease.
Silencing of Thrombospondin-1 Is Critical for Myc-Induced Metastatic Phenotypes in Medulloblastoma
Authors: Limei Zhou, Daniel Picard, Young-Shin Ra, Meihua Li, Paul A. Northcott, Yaqi Hu, Duncan Stearns, Cynthia Hawkins, Michael D. Taylor, James Rutka, Sandy D. Der, Annie Huang
Journal: Cancer Research (2010)

Abstract Mechanisms by which c-Myc (Myc) amplification confers aggressive medulloblastoma phenotypes are poorly defined. Here, we show using orthotopic models that high Myc expression promotes cell migration/invasion and induces metastatic tumors, which recapitulate aggressive histologic features of Myc-amplified primary human medulloblastoma. Using ChIP-chip analysis, we identified cell migration and adhesion genes, including Tsp-1/THBS1, ING4, PVRL3, and PPAP2B, as Myc-bound loci in medulloblastoma cells. Expression of Tsp-1 was most consistently and robustly diminished in medulloblastoma cell lines and primary human tumors with high Myc expression (n = 101, P = 0.032). Strikingly, stable Tsp-1 expression significantly attenuated in vitro transformation and invasive/migratory properties of high Myc-expressing medulloblastoma cells without altering cell proliferation, whereas RNA interference–mediated Myc knockdown was consistently accompanied by increased Tsp-1 levels and reduced cell migration and invasion in medulloblastoma cells. Chromatin immunoprecipitation (ChIP) assays revealed colocalization of Myc and obligate partner Max and correlated diminished RNA polymerase II occupancy (∼3-fold decrease, P &amp;lt; 0.01) with increased Myc binding at a core Tsp-1 promoter. Reporter gene and/or gel shift assays confirmed direct repression of Tsp-1 transcription by Myc and also identified JPO2, a Myc interactor associated with metastatic medulloblastoma, as a cofactor in Myc-mediated Tsp-1 repression. These findings indicate the Myc-regulatory network targets Tsp-1 via multiple mechanisms in medulloblastoma transformation, and highlight a novel critical role for Tsp-1 in Myc-mediated aggressive medulloblastoma phenotypes. Cancer Res; 70(20); 8199–210. ©2010 AACR.
Quinidine Interactions With Human Atrial Potassium Channels
Authors: Neviana I. Nenov, William J. Crumb, John D. Pigott, Lynn H. Harrison, Craig W. Clarkson
Journal: Circulation Research (1998)

Abstract —Clinical studies have suggested that quinidine is less effective when used for the treatment of atrial arrhythmias in pediatric patients compared with its clinical effectiveness in the adult patient population. Age-related changes in the cardiac actions of quinidine on action potential duration and interaction with potassium channels in several mammalian species also have been reported. We investigated the effects of postnatal development on quinidine’s interaction with major repolarizing currents ( I to , I Kur , I ns , and I K1 ) in human atrial myocytes, using the whole-cell configuration of the voltage-clamp technique. Our results indicate that there are age-related changes in both the IC 50 for quinidine blockade of I to , as well as the mechanism of quinidine unblocking. In contrast, quinidine was found to inhibit both adult and pediatric I K1 and I Kur in an age-independent manner, whereas the nonselective cation current ( I ns ), which contributes to the sustained outward current ( I sus ), was insensitive to quinidine. The results from this study help to clarify the electrophysiological mechanism by which quinidine elicits its antiarrhythmic effect in the pediatric and adult human population.
Apatinib for Chemotherapy-Refractory Advanced Metastatic Gastric Cancer: Results From a Randomized, Placebo-Controlled, Parallel-Arm, Phase II Trial
Authors: Jin Li, Shukui Qin, Jianming Xu, Weijian Guo, Jianping Xiong, Yuxian Bai, Guoping Sun, Yan Yang, Liwei Wang, Nong Xu, Ying Cheng, Zhehai Wang, Leizhen Zheng, Min Tao, Xiaodong Zhu, Dongmei Ji, Xin Liu, Hao Yu
Journal: Journal of Clinical Oncology (2013)

Patients with metastatic gastric cancer (mGC) who do not respond to or who experience progression with second-line chemotherapy have no treatment options that clearly confer a survival benefit. This trial investigated the safety and efficacy of apatinib, an inhibitor of vascular endothelial growth factor receptor, as a treatment option for heavily pretreated patients with mGC.Patients who experienced treatment failure with at least two chemotherapeutic regimens were randomly assigned to receive placebo (group A), apatinib 850 mg once daily (group B), or apatinib 425 mg twice daily (group C).We enrolled 144 patients onto this study. In groups A, B, and C, the median overall survival (OS) times were 2.50 months (95% CI, 1.87 to 3.70 months), 4.83 months (95% CI, 4.03 to 5.97 months), and 4.27 months (95% CI, 3.83 to 4.77 months), respectively, and the median progression-free survival (PFS) times were 1.40 months (95% CI, 1.20 to 1.83 months), 3.67 months (95% CI, 2.17 to 6.80 months), and 3.20 months (95% CI, 2.37 to 4.53 months), respectively. There were statistically significant differences between the apatinib and placebo groups for both PFS (P < .001) and OS (P < .001 and P = .0017). Nine patients had a partial response (three patients in group B and six patients in group C). Toxicities were tolerable or could be clinically managed. The most common grade 3 to 4 adverse events were hand-foot syndrome and hypertension. Hematologic toxicities were moderate, and grade 3 to 4 hematologic toxicities were rare.Apatinib showed improved PFS and OS in heavily pretreated patients with mGC who had experienced treatment failure with two or more chemotherapy regimens.
Detection of adenovirus E1A DNA in pulmonary fibrosis using nested polymerase chain reaction
Authors: K Kuwano, Y Nomoto, R Kunitake, N Hagimoto, T Matsuba, Y Nakanishi, N Hara
Journal: European Respiratory Journal (1997)

The history of patients with idiopathic pulmonary fibrosis (IPF) shows that the disease may be preceded by a viral-like illness. Although viruses have not been demonstrated, it is possible that viruses were not detected in culture because they do not replicate during latency. We investigated the presence of adenovirus in IPF and interstitial pneumonia associated with collagen vascular disease (CVD-IP), using the nested polymerase chain reaction (PCR) and in situ hybridization (ISH) for the E1A region of the adenovirus genome. Studies were performed on lung tissues obtained by transbronchial lung biopsy from 19 patients with IPF, 10 patients with CVD-IP and, for comparison, from 20 patients with sarcoidosis. The E1A DNA was present in 3 out of 19 (16%) cases of IPF, in 5 of 10 (50%) cases of CVD-IP, and in 2 of 20 (10%) cases of sarcoidosis. The incidence of E1A DNA in CVD-IP was significantly higher than that in sarcoidosis (p<0.05). In patients with IPF and CVD-IP, E1A DNA was more prevalent in patients treated with corticosteroids (6 out of 9 cases; 67%) than in those without it (2 out of 20 cases; 10%) (p<0.01). ISH studies showed that 1 out of 8 cases of IPF and CVD-IP, in which E1A DNA was detected by PCR, was positive for E1A DNA. We conclude that adenovirus E1A is unlikely to be aetiologically involved in the pathogenesis of idiopathic pulmonary fibrosis or interstitial pneumonia associated with collagen vascular disease. However, a latent adenovirus infection may be reactivated or may newly infect the host following corticosteroid administration.
Correlation between acute reductions in myocardial blood flow and function in conscious dogs.
Authors: S F Vatner
Journal: Circulation Research (1980)

Decreases in regional endocardial function (ultrasonic dimension technique) and blood flow (radioactive microsphere technique) were correlated in 14 conscious dogs with acute graded levels of coronary stenosis. Coronary stenosis affected overall ventricular function only slightly, but induced gradual reductions in regional blood flow (BF) and segment length (SL) shortening in the ischemic zone. The relationship was best fit by an exponential function relating % change in SL to % change in BF; i.e., SL(% delta) = -161.6 e -0.047BF(% delta) (r = 0.92). In 14 segments, where no change in function was observed, blood flow fell by 6 +/- 1%. However, 10--20% reductions of blood flow impaired function significantly. Severe reduction of blood flow was required to reduce function completely. In 12 segments exhibiting paradoxical motion, blood flow fell by 95 +/- 2%, a value greater (P &lt; 0.01) than in four akinetic segments, i.e., those with no shortening or lengthening (-82 +/- 4%). These data, which show on one hand that only 10-20% reductions in blood flow impair function significantly and that, on the other hand, severe reductions in blood flow are required to abolish active shortening completely, indicate sensitive coupling between blood flow and function in the conscious dog with acute myocardial ischemia.
Survival Benefit With Proapoptotic Molecular and Pathologic Responses From Dual Targeting of Mammalian Target of Rapamycin and Epidermal Growth Factor Receptor in a Preclinical Model of Pancreatic Neuroendocrine Carcinogenesis
Authors: Christopher W. Chiu, Hiroaki Nozawa, Douglas Hanahan
Journal: Journal of Clinical Oncology (2010)

Pancreatic neuroendocrine tumors (PNETs), although rare, often metastasize, such that surgery, the only potentially curative therapy, is not possible. There is no effective systemic therapy for patients with advanced PNETs. Therefore, new strategies are needed. Toward that end, we investigated the potential benefit of dual therapeutic targeting of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) kinases, using a preclinical mouse model of PNET.Rapamycin and erlotinib, inhibitors of mTOR and EGFR, respectively, were used to treat RIP-Tag2 transgenic mice bearing advanced multifocal PNET. Tumor growth and survival were monitored, and tumors were surveyed for potential biomarkers of response to the therapeutics.Rapamycin monotherapy was notably efficacious, prolonging survival concomitant with tumor stasis (stable disease). However, the tumors developed resistance, as evidenced by eventual relapse to progressive tumor growth. Erlotinib monotherapy slowed tumor growth and elicited a marginal survival benefit. In combination, there was an unprecedented survival benefit in the face of this aggressive multifocal cancer and, in contrast to either monotherapy, the development of adaptive resistance was not apparent. Additionally, the antiapoptotic protein survivin was implicated as a biomarker of sensitivity and beneficial responses to the dual targeted therapy.Preclinical trials in a mouse model of endogenous PNET suggest that combined targeting of the mTOR and EGFR signaling pathways could have potential clinical benefit in treating PNET. These results have encouraged development of an ongoing phase II clinical trial aimed to evaluate the efficacy of this treatment regimen in human neuroendocrine tumors.