tbuckley/cabot-search huggingface dataset:
Superior Long-Term Outcome With Idarubicin Compared With High-Dose Daunorubicin in Patients With Acute Myeloid Leukemia Age 50 Years and Older
Authors: Claude Gardin, Sylvie Chevret, Cécile Pautas, Pascal Turlure, Emmanuel Raffoux, Xavier Thomas, Bruno Quesnel, Thierry de Revel, Stéphane de Botton, Nathalie Gachard, Aline Renneville, Nicolas Boissel, Claude Preudhomme, Christine Terré, Pierre Fenaux, Dominique Bordessoule, Karine Celli-Lebras, Sylvie Castaigne, Hervé Dombret
Journal: Journal of Clinical Oncology (2012)

Although standard chemotherapy remains associated with a poor outcome in older patients with acute myeloid leukemia (AML), it is unclear which patients can survive long enough to be considered as cured. This study aimed to identify factors influencing the long-term outcome in these patients.The study included 727 older patients with AML (median age, 67 years) treated in two idarubicin (IDA) versus daunorubicin (DNR) Acute Leukemia French Association trials. Prognostic analysis was based on standard univariate and multivariate models and also included a cure fraction model to focus on long-term outcome.Age, WBC count, secondary AML, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and adverse-risk and favorable-risk AML subsets (European LeukemiaNet classification) all influenced complete remission (CR) rate and overall survival (OS). IDA random assignment was associated with higher CR rate, but not with longer OS (P = .13). The overall cure rate was 13.3%. Older age and ECOG-PS more than 1 negatively influenced cure rate, which was higher in patients with favorable-risk AML (39.1% v 8.0% in adverse-risk AML; P < .001) and those treated with IDA (16.6% v 9.8% with DNR; P = .018). The long-term impact of IDA was still observed in patients younger than age 65 years, although all of the younger patients in the DNR control arm received high DNR doses (cure rate, 27.4% for IDA v 15.9% for DNR; P = .049). In multivariate analysis, IDA random assignment remained associated with a higher cure rate (P = .04), together with younger age and favorable-risk AML, despite not influencing OS (P = .11).In older patients with AML, younger age, favorable-risk AML, and IDA treatment predict a better long-term outcome.
Cytokines and cytokine network in silicosis and coal workers' pneumoconiosis
Authors: D Vanhee, P Gosset, A Boitelle, B Wallaert, AB Tonnel
Journal: European Respiratory Journal (1995)

The alveolar macrophage (AM) is a critically important cell playing a prominent role in lung inflammation via the production of oxygen radicals, enzymes, arachidonic acid metabolites, and also a large panel of cytokines. Among interstitial lung disorders, silicosis and coal workers' pneumoconiosis (CWP) are the most widespread fibrotic lung diseases. Although their pathophysiology remains incompletely understood, several lines of evidence suggest the participation of cytokines produced by AMs at least in the initiation of the alveolitis. In vitro exposure of AMs (obtained from healthy subjects) to coal dust particles triggered a significant release of tumour necrosis factor (TNF) and interleukin-6, by comparison with titanium dioxide used as a biologically inert control dust. Moreover, it appeared that coal mine dust was more aggressive than similar concentrations of pure silica, suggesting that cytokine secretion induced by coal mine dust was not exclusively related to the presence of silica but resulted from a complex interaction between the different components. In silicosis and CWP, bronchoalveolar lavage showed a large influx of mononuclear phagocytes, with an increased spontaneous production of oxidants, fibronectin, neutrophil chemotactic factor, and also of interleukin-6 and TNF-alpha. This spontaneous cytokine release was associated with an increased cytokine messenger ribonucleic acid (mRNA) expression in the lungs of coal miners.(ABSTRACT TRUNCATED AT 250 WORDS)
Mitofusin 2-Containing Mitochondrial-Reticular Microdomains Direct Rapid Cardiomyocyte Bioenergetic Responses Via Interorganelle Ca <sup>2+</sup> Crosstalk
Authors: Yun Chen, György Csordás, Casey Jowdy, Timothy G. Schneider, Norbert Csordás, Wei Wang, Yingqiu Liu, Michael Kohlhaas, Maxie Meiser, Stefanie Bergem, Jeanne M. Nerbonne, Gerald W. Dorn, Christoph Maack
Journal: Circulation Research (2012)

Rationale: Mitochondrial Ca 2+ uptake is essential for the bioenergetic feedback response through stimulation of Krebs cycle dehydrogenases. Close association of mitochondria to the sarcoplasmic reticulum (SR) may explain efficient mitochondrial Ca 2+ uptake despite low Ca 2+ affinity of the mitochondrial Ca 2+ uniporter. However, the existence of such mitochondrial Ca 2+ microdomains and their functional role are presently unresolved. Mitofusin (Mfn) 1 and 2 mediate mitochondrial outer membrane fusion, whereas Mfn2 but not Mfn1 tethers endoplasmic reticulum to mitochondria in noncardiac cells. Objective: To elucidate roles for Mfn1 and 2 in SR-mitochondrial tethering, Ca 2+ signaling, and bioenergetic regulation in cardiac myocytes. Methods and Results: Fruit fly heart tubes deficient of the Drosophila Mfn ortholog MARF had increased contraction-associated and caffeine-sensitive Ca 2+ release, suggesting a role for Mfn in SR Ca 2+ handling. Whereas cardiac-specific Mfn1 ablation had no effects on murine heart function or Ca 2+ cycling, Mfn2 deficiency decreased cardiomyocyte SR-mitochondrial contact length by 30% and reduced the content of SR-associated proteins in mitochondria-associated membranes. This was associated with decreased mitochondrial Ca 2+ uptake (despite unchanged mitochondrial membrane potential) but increased steady-state and caffeine-induced SR Ca 2+ release. Accordingly, Ca 2+ -induced stimulation of Krebs cycle dehydrogenases during β-adrenergic stimulation was hampered in Mfn2-KO but not Mfn1-KO myocytes, evidenced by oxidation of the redox states of NAD(P)H/NAD(P) + and FADH 2 /FAD. Conclusions: Physical tethering of SR and mitochondria via Mfn2 is essential for normal interorganelle Ca 2+ signaling in the myocardium, consistent with a requirement for SR-mitochondrial Ca 2+ signaling through microdomains in the cardiomyocyte bioenergetic feedback response to physiological stress.
Heavy habitual marijuana smoking does not cause an accelerated decline in FEV1 with age.
Authors: D P Tashkin, M S Simmons, D L Sherrill, A H Coulson
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

To assess the possible role of daily smoking of marijuana in the development of chronic obstructive pulmonary disease (COPD), we evaluated the effect of habitual use of marijuana with or without tobacco on the age-related change in lung function (measured as FEV1) in comparison with the effect of nonsmoking and regular tobacco smoking. A convenience sample of 394 healthy young Caucasian adults (68% men; age: 33 +/- 6 yr; mean +/- SD) including, at study entry, 131 heavy, habitual smokers of marijuana alone, 112 smokers of marijuana plus tobacco, 65 regular smokers of tobacco alone, and 86 nonsmokers of either substance were recruited from the greater Los Angeles community. FEV1 was measured in all 394 participants at study entry and in 255 subjects (65 %) on up to six additional occasions at intervals of > or = 1 yr (1.7 +/- 1.1 yr) over a period of 8 yr. Random-effects models were used to estimate mean rates of decline in FEV1 and to compare these rates between smoking groups. Although men showed a significant effect of tobacco on FEV1 decline (p < 0.05), in neither men nor women was marijuana smoking associated with greater declines in FEV1 than was nonsmoking, nor was an additive effect of marijuana and tobacco noted, or a significant relationship found between the number of marijuana cigarettes smoked per day and the rate of decline in FEV1. We conclude that regular tobacco, but not marijuana, smoking is associated with greater annual rates of decline in lung function than is nonsmoking. These findings do not support an association between regular marijuana smoking and chronic COPD but do not exclude the possibility of other adverse respiratory effects.
Principles of Appropriate Antibiotic Use for Acute Pharyngitis in Adults: Background
Authors: Richelle J. Cooper, Jerome R. Hoffman, John G. Bartlett, Richard E. Besser, Ralph Gonzales, John M. Hickner, Merle A. Sande
Journal: Annals of Internal Medicine (2001)

The following principles of appropriate antibiotic use for adults with acute pharyngitis apply to immunocompetent adults without complicated comorbid conditions, such as chronic lung or heart disease, and history of rheumatic fever. They do not apply during known outbreaks of group A streptococcus. 1. Group A β-hemolytic streptococcus (GABHS) is the causal agent in approximately 10% of adult cases of pharyngitis. The large majority of adults with acute pharyngitis have a self-limited illness, for which supportive care only is needed. 2. Antibiotic treatment of adult pharyngitis benefits only those patients with GABHS infection. All patients with pharyngitis should be offered appropriate doses of analgesics and antipyretics, as well as other supportive care. 3. Limit antibiotic prescriptions to patients who are most likely to have GABHS infection. Clinically screen all adult patients with pharyngitis for the presence of the four Centor criteria: history of fever, tonsillar exudates, no cough, and tender anterior cervical lymphadenopathy [lymphadenitis]. Do not test or treat patients with none or only one of these criteria, since these patients are unlikely to have GABHS infection. For patients with two or more criteria the following strategies are appropriate: a) Test patients with two, three, or four criteria by using a rapid antigen test, and limit antibiotic therapy to patients with positive test results; b] test patients with two or three criteria by using a rapid antigen test, and limit antibiotic therapy to patients with positive test results or patients with four criteria; or c) do not use any diagnostic tests, and limit antibiotic therapy to patients with three or four criteria. 4. Throat cultures are not recommended for the routine primary evaluation of adults with pharyngitis or for confirmation of negative results on rapid antigen tests when the test sensitivity exceeds 80%. Throat cultures may be indicated as part of investigations of outbreaks of GABHS disease, for monitoring the development and spread of antibiotic resistance, or when such pathogens as gonococcus are being considered. 5. The preferred antibiotic for treatment of acute GABHS pharyngitis is penicillin, or erythromycin in a penicillin-allergic patient.
Tumor-Specific Low Molecular Weight Forms of Cyclin E Induce Genomic Instability and Resistance to p21, p27, and Antiestrogens in Breast Cancer
Authors: Said Akli, Ping-Ju Zheng, Asha S. Multani, Hannah F. Wingate, Sen Pathak, Ning Zhang, Susan L. Tucker, Sandy Chang, Khandan Keyomarsi
Journal: Cancer Research (2004)

Abstract The deregulated expression of cyclin E as measured by the overexpression of its low molecular weight (LMW) isoforms is a powerful predictor of poor outcome in patients with breast cancer. The mechanism by which these LMW forms give tumor cells a growth advantage is not known and is the subject of this article. In this article, we provide the pathobiological mechanisms of how these LMW forms are involved in disease progression. Specifically, we show that overexpression of the LMW forms of cyclin E but not the full-length form in MCF-7 results in (a) their hyperactivity because of increased affinity for cdk2 and resistance to inhibition by the cyclin-dependent kinase inhibitors p21 and p27, (b) resistance to the growth inhibiting effects of antiestrogens, and (c) chromosomal instability. Lastly, tumors from breast cancer patients overexpressing the LMW forms of cyclin E are polyploid in nature and are resistant to endocrine therapy. Collectively, the biochemical and functional differences between the full-length and the LMW isoforms of cyclin E provide a molecular mechanism for the poor clinical outcome observed in breast cancer patients harboring tumors expressing high levels of the LMW forms of cyclin E. These properties of the LMW forms cyclin E suggest that they are not just surrogate markers of poor outcome but bona fide mediators of aggressive disease and potential therapeutic targets for patients whose tumors overexpress these forms.
Primer on tumor immunology and cancer immunotherapy
Authors: Timothy J Harris, Charles G Drake
Journal: Journal for ImmunoTherapy of Cancer (2013)

Individualized cancer therapy is a central goal of cancer biologists. Immunotherapy is a rational means to this end—because the immune system can recognize a virtually limitless number of antigens secondary to the biology of genetic recombination in B and T lymphocytes. The immune system is exquisitely structured to distinguish self from non-self, as demonstrated by anti-microbial immune responses. Moreover the immune system has the potential to recognize self from "altered-self", which is the case for cancer. However, the immune system has mechanisms in place to inhibit self-reactive responses, many of which are usurped by evolving tumors. Understanding the interaction of cancer with the immune system provides insights into mechanisms that can be exploited to disinhibit anti-tumor immune responses. Here, we summarize the 2012 SITC Primer, reviewing past, present, and emerging immunotherapeutic approaches for the treatment of cancer—including targeting innate versus adaptive immune components; targeting and/or utilizing dendritic cells and T cells; the role of the tumor microenvironment; and immune checkpoint blockade.
A new tuberculosis vaccine
Authors: M. Wilczynska
Journal: Thorax (2011)

A new tuberculosis vaccineThe BCG vaccine, designed as a prophylactic vaccine for pre-infection administration, is currently the only tuberculosis vaccine approved for human use.In this study researchers developed a new multistage tuberculosis vaccine (H56) which can be used before and after exposure, and tested it in a mouse model.To construct the H56 vaccine, the authors purified the recombinant fusion protein (Ag85B-ESAT6-Rv2660c) from Escherichia coli.They hypothesised that it is possible to selectively target Mycobacterium tuberculosis (Mtb) in the persistent stage of infection by combining early protective antigens such as Ag85B and ESAT-6 (the H1 vaccine) with the latency protein Rv2660c which is involved in stress responses and characterises long-term Mtb adaptation in the immune host.The authors assessed the effectiveness of H56, H1 and BCG vaccines administrated in mice 6 weeks before Mtb exposure.They demonstrated a statistically significant reduction in bacterial load and induction of immune response with the H56 vaccination compared to the H1 and BCG vaccines starting from 12 weeks after the introduction of infection.The H56 vaccine also enhanced the immunological reaction when administrated to mice with earlier treated tuberculosis infection as well as improving response in previously BCG-vaccinated mice later exposed to Mtb.The new vaccine induces vaccine-specific polyfunctional CD4 + T cells providing efficient containment of early-and late-stage infection in addition to protection against disease reactivation.This emergence of a novel tuberculosis vaccine in mouse models is an important step forward to guide studies in humans.
Sequence and structure of Brassica rapa chromosome A3
Authors: Jeong-Hwan Mun, Soo-Jin Kwon, Young-Joo Seol, Jin A Kim, Mina Jin, Jung Sun Kim, Myung-Ho Lim, Soo-In Lee, Joon Ki Hong, Tae-Ho Park, Sang-Choon Lee, Beom-Jin Kim, Mi-Suk Seo, Seunghoon Baek, Min-Jee Lee, Ja Young Shin, Jang-Ho Hahn, Yoon-Jung Hwang, Ki-Byung Lim, Jee Young Park, Jonghoon Lee, Tae-Jin Yang, Hee-Ju Yu, Ik-Young Choi, Beom-Soon Choi, Su Ryun Choi, Nirala Ramchiary, Yong Pyo Lim, Fiona Fraser, Nizar Drou, Eleni Soumpourou, Martin Trick, Ian Bancroft, Andrew G Sharpe, Isobel AP Parkin, Jacqueline Batley, Dave Edwards, Beom-Seok Park
Journal: Genome biology (2010)

The species Brassica rapa includes important vegetable and oil crops. It also serves as an excellent model system to study polyploidy-related genome evolution because of its paleohexaploid ancestry and its close evolutionary relationships with Arabidopsis thaliana and other Brassica species with larger genomes. Therefore, its genome sequence will be used to accelerate both basic research on genome evolution and applied research across the cultivated Brassica species.We have determined and analyzed the sequence of B. rapa chromosome A3. We obtained 31.9 Mb of sequences, organized into nine contigs, which incorporated 348 overlapping BAC clones. Annotation revealed 7,058 protein-coding genes, with an average gene density of 4.6 kb per gene. Analysis of chromosome collinearity with the A. thaliana genome identified conserved synteny blocks encompassing the whole of the B. rapa chromosome A3 and sections of four A. thaliana chromosomes. The frequency of tandem duplication of genes differed between the conserved genome segments in B. rapa and A. thaliana, indicating differential rates of occurrence/retention of such duplicate copies of genes. Analysis of 'ancestral karyotype' genome building blocks enabled the development of a hypothetical model for the derivation of the B. rapa chromosome A3.We report the near-complete chromosome sequence from a dicotyledonous crop species. This provides an example of the complexity of genome evolution following polyploidy. The high degree of contiguity afforded by the clone-by-clone approach provides a benchmark for the performance of whole genome shotgun approaches presently being applied in B. rapa and other species with complex genomes.
NT-07 * PHASE 1-2 DOSE-ESCALATION STUDY OF VB-111, AN ANTI-ANGIOGENIC GENE THERAPY, AS MONOTHERAPY AND IN COMBINATION WITH BEVACIZUMAB, IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: A. Brenner, Y. Cohen, J. Vredenburgh, K. Peters, D. Blumenthal, F. Bokstein, E. Breitbart, L. Bangio, N. Sher, D. Harats, P. Wen
Journal: Neuro-Oncology (2014)

BACKGROUND: VB-111 is an anti-angiogenic agent consisting of a non-replicating adenovirus vector (Ad-5) with a modified murine pre-proendothelin promoter leading to apoptosis of tumor vasculature by expressing a fas-chimera transgene in angiogenic endothelial cells. Safety and efficacy of VB-111 alone and in combination with bevacizumab (BEV) were evaluated for patients with recurrent Glioblastoma (rGBM) in this phase 1-2 dose-escalation study. METHODS: VB-111 was administered as a single intravenous infusion at escalating doses from 1x1012 to 1x1013 viral particles (VPs), followed by repeat doses of 3x1012 or 1x1013 every 2 months. The protocol was amended to add-on BEV 10mg/Kg every 2 weeks upon further progression. Assessments included safety, pharmacokinetics, tumor response (RANO criteria) and overall survival (OS). RESULTS: Forty-six patients at 4 recruiting medical centers in the US and Israel received up to 13 repeat doses of VB-111. Of these 30 received the high dose (1x1013). There were 22 related adverse events, 19 CTCAE grade 1-2. The median OS was 360 [range: 70-574] and 266 days [range: 28-664] for patients receiving at least one high dose vs. subjects who received lower doses, respectively (p NS). Progression free survival was 63 vs. 55 days for patients who received high vs. lower doses, respectively (p = 0.01). Median follow-up was 232 days. Six patients had a partial response and/or prolonged disease stability (≥180 days). Tumor growth rates showed a statistically significant dose response. Eleven patients received combination therapy of VB-111 with BEV after progression on VB-111 alone. Median time to second progression was 93 days. VB-111 was safe and well tolerated both as monotherapy and combined therapy. CONCLUSIONS: VB-111 was safe and well tolerated as monotherapy and in combination with BEV in patients with recurrent glioblastoma. Encouraging tumor growth attenuation and responses were seen. Overall survival was about 3 months longer than historical rGBM data.
Vagal impairment of gastric secretion in diabetic autonomic neuropathy.
Authors: D J Hosking, F Moody, I M Stewart, M Atkinson
Journal: BMJ (1975)

Gastric acid output in response to insulin-induced hypoglycaemia and pentagastrin was measured in 18 diabetic patients with symptoms of autonomic neuropathy. Two patients had achlorhydria but the rest responded normally to pentagastrin. The acid output evoked by insulin-induced hypoglycaemia was low in 10 of the 16 patients who secreted acid in response to pentagastrin. These changes suggest that vagal impairment is common in diabetics with autonomic symptoms, which might explain the infrequency of duodenal ulcer in diabetics.
A Phase I study of AD5-GUCY2C-PADRE in stage I and II colon cancer patients
Authors: Adam Snook, Trevor Baybutt, Michael Mastrangelo, Nancy Lewis, Scott Goldstein, Walter Kraft, Yaa Oppong, Terry Hyslop, Ronald Myers, Vitali Alexeev, Laurence Eisenlohr, Takami Sato, Scott Waldman
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Ad5-GUCY2C-PADRE is a replication-deficient human type 5 recombinant adenovirus (Ad5) vaccine encoding guanylyl cyclase C (GUCY2C) fused to the PAn DR Epitope (PADRE). GUCY2C, a paracrine hormone receptor producing the second messenger cyclic GMP (cGMP), is selectively expressed
P115 Vitamin D binding protein in COPD exacerbations
Authors: M. Newnham, R. Carter, L. Sapey, R. A. Stockley, A. M. Wood
Journal: Thorax (2010)

<h3>Introduction</h3> Vitamin D binding protein (DBP) plays a role in macrophage activation and neutrophil chemotaxis, both functions being relevant to COPD and airway infection. We have shown previously that DBP is present in the COPD lung and relates directly to macrophage activation.1 Transcription of DBP is stimulated by inflammatory cytokines,2 which tend to be raised in exacerbations. DBP is also cleaved from its binding site on neutrophils by the action of neutrophil elastase.3 We reasoned that DBP would be elevated in the lung and systemic circulation during exacerbations of COPD compared to the stable state. <h3>Methods</h3> 20 patients with a known diagnosis of COPD were studied in the stable state and at the start of an exacerbation. Circulating CRP, elastase, AAT and DBP were measured at each time point, together with sol phase DBP, AAT and CRP, where sufficient sample was available (n=9). All clinical parameters were studied in the stable state only. Relationships between exacerbation and stable state were sought using pair-wise tests for each individual, whilst group relationships between DBP, CRP and elastase were sought using Spearman9s rank correlation. <h3>Results</h3> No significant differences between stable state and exacerbation were seen for circulating or sol phase DBP (both p&gt;0.4). Circulating CRP and AAT were significantly higher in exacerbation (mean difference 3.95, p&lt;0.0001 and 137.39, p=0.03 respectively), as were sol phase CRP and AAT (mean difference 18.29, p=0.003 and 0.60, p=0.009 respectively). DBP did not relate to elastase in either stable state (p=0.61) or exacerbation (p=0.17), nor to CRP (p=0.71 and 0.98, respectively). <h3>Conclusions</h3> The level of local and systemic inflammation, with consequent elastase release, during a COPD exacerbation is insufficient to alter DBP levels. As such it is unlikely that DBP-derived macrophage activation is important in their pathogenesis or resolution.