tbuckley/cabot-search huggingface dataset:
Improved Tumor Control through Circadian Clock Induction by Seliciclib, a Cyclin-Dependent Kinase Inhibitor
Authors: Ida Iurisci, Elisabeth Filipski, Jens Reinhardt, Stéphane Bach, Athos Gianella-Borradori, Stefano Iacobelli, Laurent Meijer, Francis Lévi
Journal: Cancer Research (2006)

Abstract The circadian timing system and the cell division cycle are frequently deregulated in cancer. The therapeutic relevance of the reciprocal interactions between both biological rhythms was investigated using Seliciclib, a cyclin-dependent kinase (CDK) inhibitor (CDKI). Mice bearing Glasgow osteosarcoma received Seliciclib (300 mg/kg/d orally) or vehicle for 5 days at Zeitgeber time (ZT) 3, 11, or 19. On day 6, tumor mRNA 24-hour expression patterns were determined for clock genes (Per2, Rev-erbα, and Bmal1) and clock-controlled cell cycle genes (c-Myc, Wee1, cyclin B1, and CDK1) with quantitative reverse transcription-PCR. Affinity chromatography on immobilized Seliciclib identified CDK1/CDK2 and extracellular signal-regulated kinase (ERK) 1/ERK2, CDK7/CDK9, and casein kinase CK1ε as Seliciclib targets, which respectively regulate cell cycle, transcription, and circadian clock in Glasgow osteosarcoma. Seliciclib reduced tumor growth by 55% following dosing at ZT3 or ZT11 and by 35% at ZT19 compared with controls (P &amp;lt; 0.001). Tolerability was also best at ZT3. Mean transcriptional activity of Rev-erbα, Per2, and Bmal1 was arrhythmic in the tumors of untreated mice. Seliciclib induced rhythmic clock gene expression patterns with physiologic phase relations only after ZT3 dosing. c-Myc and Wee1 mRNAs displayed synchronous circadian rhythms in the tumors of control mice receiving vehicle only but not in those of mice given the drug. Seliciclib further enhanced Wee1 expression irrespective of dosing time, an effect that reinforced G2-M gating. Seliciclib also inhibited CK1ε, which determines circadian period length. The coordination of clock gene expression patterns in tumor cells was associated with best antitumor activity of Seliciclib. The circadian clock and its upstream regulators represent relevant targets for CDKIs. (Cancer Res 2006; 66(22): 10720-8)
Cancer Gene Therapy: Scientific Basis
Authors: Punit D. Wadhwa, Steven P. Zielske, Justin C. Roth, Christopher B. Ballas, Janice E. Bowman, Stanton L. Gerson
Journal: Annual Review of Medicine (2002)

▪ Abstract Gene therapy of cancer has been one of the most exciting and elusive areas of therapeutic research in the past decade. Critical developments have occurred in gene therapy targeting cancer cells, cancer vasculature, the immune system, and the bone marrow, itself often the target for severe toxicity from therapeutic agents. We review some recent developments in the field. In each instance, clear preclinical models validated the therapeutic approach and efforts have been made to evaluate the target impact in both preclinical and early clinical trials. Although no cures can consistently be expected from today's cancer gene therapy, the rapid progress may imply that such cures are a few short years away.
Multifactorial origin of high incidence of Serratia marcescens in a cardio-thoracic ICU: Analysis of risk factors and epidemiological characteristics
Authors: M.G.J. de Boer, A.H. Brunsveld-Reinders, E.M.A. Salomons, L. Dijkshoorn, A.T. Bernards, P.C.M. van den Berg, P.J. van den Broek
Journal: Journal of Infection (2008)
Body composition and exercise performance in patients with chronic obstructive pulmonary disease.
Authors: A M Schols, R Mostert, P B Soeters, E F Wouters
Journal: Thorax (1991)

To investigate whether a compromised nutritional state may limit exercise performance in patients with chronic obstructive pulmonary disease we studied 54 such patients (FEV1 less than 50% and arterial oxygen tension (PaO2) greater than 7.3 kPa) whose clinical condition was stable and who were admitted to a pulmonary rehabilitation centre. Fat free mass was assessed anthropometrically (from skinfold measurements at four sites) and by bioelectrical impedance; creatinine height index and arm muscle circumference were also assessed. The mean (SD) distance walked in 12 minutes was 845 (178) m. No association was established between the distance walked and spirometric measures. A good correlation was found between the distance walked and fat free mass in the whole group (r = 0.73 for impedance measurements and 0.65 for skinfold thickness) and in a subgroup of 23 lean patients (body weight less than 90% of ideal weight; r = 0.66 for impedance measurements and 0.46 for skinfold thickness). Body weight correlated with the distance walked only in the whole group (r = 0.61). On stepwise regression analysis fat free mass measured by bioelectrical impedance, maximal inspiratory mouth pressure, and PaO2 accounted for 60% of the variation in the distance walked in 12 minutes. We conclude that fat free mass, independently of airflow obstruction, is an important determinant of exercise performance in patients with severe chronic obstructive pulmonary disease.
Combined use of exhaled nitric oxide and airway hyperresponsiveness in characterizing asthma in a large population survey
Authors: A.H. Henriksen, T. Lingaas-Holmen, M. Sue-Chu, L. Bjermer
Journal: European Respiratory Journal (2000)

The aim of the present study was to see whether measurements of airway hyperresponsiveness (AHR) and nitric oxide (NO) in exhaled air (ENO) either separately or in combination, could differentiate between asthmatics and healthy control subjects in a population based survey. In central Norway 8,571 adolescents participated in a large-scale epidemiological survey (Young Helseundersokelsen i Nord-Trondelag (Health Survey in North-Trondelag; HUNT). Asthmatic symptoms when exposed to pollen, pets or house-dust were reported by 7.8% (suspected asthmatics), while 56% reported no asthmatic or allergic symptoms (control subjects). From these respective groups 151 and 213 adolescents were investigated with allergy screening, measurements of exhaled and nasal NO, and methacholine challenge test. AHR (provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second (PD20) &lt;2 mg) was confirmed in 75% of the suspected asthmatics versus 25% of the control subjects, whereas 52% versus 20% had elevated levels of ENO (&gt; or =8 parts per billion (ppb)). ENO and dose response ratio to methacholine (DRR) were positively correlated (r=0.41, p&lt;0.001). ENO was significantly elevated in atopic versus nonatopic suspected asthmatics (11.7 ppb and 5.6 ppb respectively, p&lt;0.001). Suspected asthmatics with both AHR and atopy had the highest levels of ENO (14.2 ppb). It is concluded that measurements of nitric oxide in exhaled air alone are not a useful tool in diagnosing asthma in population surveys, but that the combination of airway hyperresponsiveness and elevated nitric oxide in exhaled air is a very specific finding for allergic asthma. The use of dose response ratio to methacholine did not provide any additional information to the provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second in this study.
FORMATION OF SLOW-REACTING SUBSTANCE OF ANAPHYLAXIS IN HUMAN LUNG TISSUE AND CELLS BEFORE RELEASE
Authors: Robert A. Lewis, Stephen I. Wasserman, Edward J. Goetzl, K. Frank Austen
Journal: The Journal of Experimental Medicine (1974)

The capacity to extract slow-reacting substance of anaphylaxis (SRS-A) from human lung tissue or cells after immunologic activation, together with the measurement of SRS-A in both the extract and the surrounding fluid, permits study of total SRS-A generation. That the material extracted is SRS-A was established by both differential bioassay and purification. SRS-A accumulation was entirely intracellular after limited IgE-dependent direct or reversed anaphylactic activation. Intracellular accumulation also generally preceded release, with generation of SRS-A continuing well beyond a plateau in the cellular SRS-A level and the release of preformed mediators. The quantity of SRS-A generated after immunologic activation was modulated by the introduction of exogenous cyclic nucleotides, revealing a site of cyclic nucleotide action distinct from that on mediator release. The capacity to determine not only the release of preformed mediators but also the generation of a newly formed mediator, the sum of SRS-A in cells and supernate, adds an additional dimension to the analysis of the cellular events of immediate hypersensitivity.
MesoVATS: video-assisted thoracic surgery partial pleurectomy versus talc pleurodesis
Authors: M M Brown
Journal: Thorax (2015)

The role of surgery in malignant pleural mesothelioma remains a contentious issue. This randomised control trial compared two palliative interventions: cytoreductive surgery versus talc pleurodesis in patients with suspected or confirmed malignant mesothelioma and pleural effusion.1 The authors hoped to show an improvement in survival for video assisted thoracic partial pleurectomy (VAT-PP) and compare …
MSF-A Interacts with Hypoxia-Inducible Factor-1α and Augments Hypoxia-Inducible Factor Transcriptional Activation to Affect Tumorigenicity and Angiogenesis
Authors: Sharon Amir, Ruoxiang Wang, Haim Matzkin, Jonathan W. Simons, Nicola J. Mabjeesh
Journal: Cancer Research (2006)

Abstract Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor in the signaling pathway that controls the hypoxic responses of cancer cells. Activation of the HIF system has been observed in carcinogenesis and numerous cancers. We found an interaction between a member of the mammalian septin gene family (MSF-A) and the HIF system. MSF-A is a nuclear protein that interacts with HIF-1α protein to prevent its ubiquitination and degradation, thus activating the HIF transcriptome. Cells overexpressing MSF-A protein exhibit increased HIF transcriptional activity and higher proliferation rates in vitro and in vivo. Xenograft-derived human tumors from these cells were larger and more vascular. These findings link a function of a septin protein with angiogenesis through activation of the HIF pathway. (Cancer Res 2006; 66(2): 856-66)
Pouch permeability: breaching barriers to understanding pouchitis?
Authors: I Bjarnason, I Menzies, A Macpherson
Journal: Gut (1996)

Pouch permeability: breaching bafflers to understanding pouchitis?After restorative proctocolectomy with ileoanal pouch anastomosis, there are predictable morphological changes in the neorectum, which consist of shortening ofvilli, crypt hyperplasia, and chronic inflammatory cell infiltration.These adaptive changes are asymptomatic and parallel the increase in the anaerobic bacterial flora of the pouch, which occur as a consequence of faecal stasis. 1 2 A propor- tion of patients develop pouchitis which, by definition, is characterised by neutrophil infiltration of the pouch.The acute inflammation is recurrent and is associated with symptoms that may differ between patients.As pouchitis
In vivo gene transfer targeting in pancreatic adenocarcinoma with cell surface antigens
Authors: Marie Lafitte, Benoit Rousseau, Isabelle Moranvillier, Miguel Taillepierre, Evelyne Peuchant, Véronique Guyonnet-Dupérat, Aurélie Bedel, Pierre Dubus, Hubert de Verneuil, François Moreau-Gaudry, Sandrine Dabernat
Journal: Molecular Cancer (2012)

Abstract Background Pancreatic ductal adenocarcinoma is a deadly malignancy resistant to current therapies. It is critical to test new strategies, including tumor-targeted delivery of therapeutic agents. This study tested the possibility to target the transfer of a suicide gene in tumor cells using an oncotropic lentiviral vector. Results Three cell surface markers were evaluated to target the transduction of cells by lentiviruses pseudotyped with a modified glycoprotein from Sindbis virus. Only Mucin-4 and the Claudin-18 proteins were found efficient for targeted lentivirus transductions in vitro . In subcutaneous xenografts of human pancreatic cancer cells models, Claudin-18 failed to achieve efficient gene transfer but Mucin-4 was found very potent. Human pancreatic tumor cells were modified to express a fluorescent protein detectable in live animals by bioimaging, to perform a direct non invasive and costless follow up of the tumor growth. Targeted gene transfer of a bicistronic transgene bearing a luciferase gene and the herpes simplex virus thymidine kinase gene into orthotopic grafts was carried out with Mucin-4 oncotropic lentiviruses. By contrast to the broad tropism VSV-G carrying lentivirus, this oncotropic lentivirus was found to transduce specifically tumor cells, sparing normal pancreatic cells in vivo . Transduced cells disappeared after ganciclovir treatment while the orthotopic tumor growth was slowed down. Conclusion This work considered for the first time three aspect of pancreatic adenocarcinoma targeted therapy. First, lentiviral transduction of human pancreatic tumor cells was possible when cells were grafted orthotopically. Second, we used a system targeting the tumor cells with cell surface antigens and sparing the normal cells. Finally, the TK/GCV anticancer system showed promising results in vivo . Importantly, the approach presented here appeared to be a safer, much more specific and an as efficient way to perform gene delivery in pancreatic tumors, in comparison with a broad tropism lentivirus. This study will be useful in future designing of targeted therapies for pancreatic cancer.
Nonreceptor Tyrosine Kinase BMX Maintains Self-Renewal and Tumorigenic Potential of Glioblastoma Stem Cells by Activating STAT3
Authors: Olga A. Guryanova, Qiulian Wu, Lin Cheng, Justin D. Lathia, Zhi Huang, Jinbo Yang, Jennifer MacSwords, Christine E. Eyler, Roger E. McLendon, John M. Heddleston, Weinian Shou, Dolores Hambardzumyan, Jeongwu Lee, Anita B. Hjelmeland, Andrew E. Sloan, Markus Bredel, George R. Stark, Jeremy N. Rich, Shideng Bao
Journal: Cancer Cell (2011)
Molecular Basis for the Induction of an Angiogenesis Inhibitor, Thrombospondin-1, by 5-Fluorouracil
Authors: Hong-Ye Zhao, Akio Ooyama, Masatatsu Yamamoto, Ryuji Ikeda, Misako Haraguchi, Sho Tabata, Tatsuhiko Furukawa, Xiao-Fang Che, Shaoxuan Zhang, Toshinori Oka, Masakazu Fukushima, Masayuki Nakagawa, Mayumi Ono, Michihiko Kuwano, Shin-ichi Akiyama
Journal: Cancer Research (2008)

Abstract 5-Fluorouracil (5-FU) is one of the most commonly used anticancer drugs in chemotherapy against various solid tumors. 5-FU dose-dependently increased the expression levels of intrinsic antiangiogenic factor thrombospondin-1 (TSP-1) in human colon carcinoma KM12C cells and human breast cancer MCF7 cells. We investigated the molecular basis for the induction of TSP-1 by 5-FU in KM12C cells. Promoter assays showed that the region with the Egr-1 binding site is critical for the induction of TSP-1 promoter activity by 5-FU. The binding of Egr-1 to the TSP-1 promoter was increased in KM12C cells treated with 5-FU. Immunofluorescence staining revealed that 5-FU significantly increased the level of Egr-1 in the nuclei of KM12C cells. The suppression of Egr-1 expression by small interfering RNA decreased the expression level of TSP-1. Furthermore, 5-FU induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and heat shock protein 27 (HSP27). Blockade of the p38 MAPK pathway by SB203580 remarkably inhibited the phosphorylation of HSP27 induced by 5-FU and decreased the induction of Egr-1 and TSP-1 by 5-FU in KM12C cells. These findings suggest that the p38 MAPK pathway plays a crucial role in the induction of Egr-1 by 5-FU and that induced Egr-1 augments TSP-1 promoter activity, with the subsequent production of TSP-1 mRNA and protein. [Cancer Res 2008;68(17):7035–41]
Multinucleate cell angiohistiocytoma—a new entity
Authors: Neil P. Smith, E. Wilson Jones
Journal: British Journal of Dermatology (1985)

A series of five cases is reported of unusual papular skin lesions which had unique and previously undescribed histological appearances. Four of the five patients were female and their ages ranged from 47 to 66 years. The lesions developed slowly over many months, were multiple, reddish-purple in colour, and individual papules measured 2–10 mm. In four of the patients the lesions were situated on acral sites, usually unilateral, and all were asymptomatic. Clinical diagnoses had included lichen planus, Kaposi's sarcoma, histiocytoma and granuloma annulare. The striking histological features of these lesions included the presence of numerous small blood vessels in the mid-dermis associated with scattered inflammatory cells and larger bizarre histiocytoid cells. Many of these latter cells were multinucleate and had an irregular or angulated cell outline. The pattern of vascular proliferation was quite unlike that seen in venous stasis, Kaposi's sarcoma or histiocytoma, and we believe these lesions represent a previously unrecognized disorder. Full clinical and pathological details of these five cases will be summarized and the value of newer histochemical, immunological and monoclonal antibody labelling techniques in deter mining the histogenesis of such lesions will be emphasized.
Dopaminergic influences beyond extraversion
Authors: Douglas Derryberry, Marjorie A. Reed
Journal: Behavioral and Brain Sciences (1999)

Studies of human performance indicate that extraverts show enhanced motivation in relation to reward signals, but not in relation to safety signals under defensive conditions. When it occurs under defensive conditions, enhanced motivation may be related to neuroticism. While extraverts show some attentional skills consistent with frontal dopaminergic facilitation, other frontal capacities may be related to conscientiousness. These findings suggest that dopaminergic influences on response and attentional processes may contribute to additional personality dimensions such as neuroticism and conscientiousness.
Inflammatory/Antiinflammatory Properties of High-Density Lipoprotein Distinguish Patients From Control Subjects Better Than High-Density Lipoprotein Cholesterol Levels and Are Favorably Affected by Simvastatin Treatment
Authors: Benjamin J. Ansell, Mohamad Navab, Susan Hama, Naeimeh Kamranpour, Gregg Fonarow, Greg Hough, Shirin Rahmani, Rachel Mottahedeh, Ravi Dave, Srinivasa T. Reddy, Alan M. Fogelman
Journal: Circulation (2003)

Background— The inflammatory/antiinflammatory properties of HDL were compared with HDL cholesterol in 2 groups of patients and in age- and sex-matched control subjects. Methods and Results— Group 1 consisted of 26 patients not yet taking a statin who presented with coronary heart disease (CHD) or CHD equivalents by National Cholesterol Education Program Adult Treatment Panel III criteria studied before and 6 weeks after 40 mg/d of simvastatin. Group 2 consisted of 20 patients with documented CHD and HDL cholesterol ≥84 mg/dL. The inflammatory/antiinflammatory properties of HDL were determined by the ability of the subject’s HDL to alter LDL-induced monocyte chemotactic activity (MCA) in a human artery wall coculture. Induction of MCA by a control LDL was determined in the absence or presence of the subject’s HDL. Values in the absence of HDL were normalized to 1.0. Values &gt;1.0 after the addition of HDL indicated proinflammatory HDL; values &lt;1.0 indicated antiinflammatory HDL. Group 1 values before simvastatin were LDL cholesterol, 118±24 mg/dL; HDL cholesterol, 57±13 mg/dL; triglycerides, 125±64 mg/dL; and high-sensitivity C-reactive protein (hs-CRP), 1.7±1.9 mg/L; and MCA values were 1.38±0.91, compared with 0.38±0.14 for control subjects ( P =1.5×10 −5 ). After simvastatin, values were LDL cholesterol, 73±24 mg/dL; HDL cholesterol, 61±14 mg/dL; triglycerides, 99±52 mg/dL; and hs-CRP, 1.3±1.3 mg/L; and MCA values were 1.08±0.71. In group 2, values were LDL cholesterol, 108±34 mg/dL; HDL cholesterol, 95±14 mg/dL; triglycerides, 89±44 mg/dL; and hs-CRP, 0.8±0.7 mg/L; and MCA values were 1.28±0.29, compared with 0.35±0.11 for control subjects ( P =1.7×10 −14 ). Similar results were obtained with the cell-free assay. Conclusions— The inflammatory/antiinflammatory properties of HDL distinguished patients from control subjects better than HDL cholesterol and were improved with simvastatin.
Randomized phase II study of trabectedin in patients with liposarcoma and leiomyosarcoma (L-sarcomas) after failure of prior anthracylines (A) and ifosfamide (I)
Authors: J. A. Morgan, A. Le Cesne, S. Chawla, M. von Mehren, S. Schuetze, P. G. Casali, A. Nieto, Y. Elsayed, M. A. Izquierdo, G. D. Demetri
Journal: Journal of Clinical Oncology (2007)

10060 Background: Trabectedin, a marine-derived antineoplastic agent, binds to the minor groove of DNA and has previously shown activity in L-sarcomas in single-arm trials. This multicenter, randomized study aimed to characterize the anticancer efficacy with two dosing regimens of trabectedin in pts with treatment-refractory L-sarcomas. Methods: Eligible pts had measurable advanced L-sarcoma, progression despite at least prior A and I, PS 0–1 and adequate organ function. Pts were randomized to IV trabectedin, 1.5 mg/m 2 , 24h every 3 weeks (q3wk-24h) or 0.58 mg/m 2 , 3h weekly × 3 on a 28-day cycle (qwk-3h). Primary endpoint is time-to-progression (TTP) and secondary endpoints PFS, overall survival, response, and safety. With 217 events, study provided 90% power to detect a 37% risk reduction in TTP (2-sided 5% significance). Results: 270 pts were randomized as of 5/31/06. Baseline characteristics were comparable: median (range) 2 (1–7) metastatic sites and 2 (1–6) prior regimens; 62% had additional prior agents; 67% had bulky (≥5cm) disease. In the q3wk-24h vs qwk-3h arms median n. cycles were 5 (1–37) vs 2 (1–21); 38% vs 19% received ≥7 cycles. In protocol-specified primary analysis, median (95% CI) TTP was 3.7 (2.1–5.4) vs 2.3 (2.0–3.5) mo [HR: 0.734; p=0.0302] favoring the q3wk-24h arm. Median PFS was 3.3 (2.1–4.6) vs 2.3 (2.0–3.4) mo [HR: 0.755; p=0.0418] and median survival (n=175 events) was 13.8 (12.5–17.9) vs. 11.8 (9.9–13.9) mo [HR: 0.823; p=0.1984]. Benefit from the q3wk-24h arm was more pronounced in pts with central pathology confirmed diagnosis of L-sarcomas. More neutropenia, ↑AST/ALT, emesis and fatigue occurred in the q3wk 24-h. Febrile neutropenia was rare (0.8–1.6%). No cumulative toxicities were noted. Conclusions: Trabectedin can provide clinical benefit to pts with L-sarcoma following failure of all conventional treatment options. Significantly better TTP was noted with the q3wk-24h regimen, although this resulted in somewhat more neutropenia and transaminitis without clinical consequences. No cumulative toxicities were apparent in either arm. Although both dosing regimens are efficacious, there appears to superior disease control with the q3wk-24h arm in this population. [Table: see text]