tbuckley/cabot-search huggingface dataset:
Re: The ras Oncogene-Mediated Sensitization of Human Cells to Topoisomerase II Inhibitor-Induced Apoptosis
Authors: H.-M. Koo, G. F. Vande Woude
Journal: JNCI Journal of the National Cancer Institute (1999)

Among the inhibitors of the enzyme topoisomerase II (an important target for chemotherapeutic drugs) tested in the National Cancer Institute's In Vitro Antineoplastic Drug Screen, NSC 284682 (3'-hydroxydaunorubicin) and NSC 659687 [9-hydroxy-5,6-dimethyl-1-(N-[2(dimethylamino)ethyl]carbamoyl)-6H-pyrido -(4,3-b)carbazole] were the only compounds that were more cytotoxic to tumor cells harboring an activated ras oncogene than to tumor cells bearing wild-type ras alleles. Expression of the multidrug resistance proteins P-glycoprotein and MRP (multidrug resistance-associated protein) facilitates tumor cell resistance to topoisomerase II inhibitors. We investigated whether tumor cells with activated ras oncogenes showed enhanced sensitivity to other topoisomerase II inhibitors in the absence of the multidrug-resistant phenotype.We studied 20 topoisomerase II inhibitors and individual cell lines with or without activated ras oncogenes and with varying degrees of multidrug resistance.In the absence of multidrug resistance, human tumor cell lines with activated ras oncogenes were uniformly more sensitive to most topoisomerase II inhibitors than were cell lines containing wild-type ras alleles. The compounds NSC 284682 and NSC 659687 were especially effective irrespective of the multidrug resistant phenotype. The ras oncogene-mediated sensitization to topoisomerase II inhibitors was far more prominent with the non-DNA-intercalating epipodophyllotoxins than with the DNA-intercalating inhibitors. This difference in sensitization appears to be related to a difference in apoptotic sensitivity, since the level of DNA damage generated by etoposide (an epipodophyllotoxin derivative) in immortalized human kidney epithelial cells expressing an activated ras oncogene was similar to that in the parental cells, but apoptosis was enhanced only in the former cells.Activated ras oncogenes appear to enhance the sensitivity of human tumor cells to topoisomerase II inhibitors by potentiating an apoptotic response. Epipodophyllotoxin-derived topoisomerase II inhibitors should be more effective than the DNA-intercalating inhibitors against tumor cells with activated ras oncogenes.
The Burlington Randomized Trial of the Nurse Practitioner: Health Outcomes of Patients
Authors: DAVID L. SACKETT
Journal: Annals of Internal Medicine (1974)

In a randomized trial of nurse practitioners as providers of primary clinical services, attention was devoted to the "outcomes" of clinical effectiveness and safety. These outcomes—expressed in physical, emotional, and social function—were assessed with newly developed methods that could be applied easily and objectively by nonclinicians to the two groups of patients under study: patients receiving conventional care and patients receiving care from nurse practitioners. Besides showing the comparability of these groups at the start of this study, these measurements showed similar levels of physical, emotional, and social function in the two groups after 1 year of receiving either nurse-practitioner or conventional care. Since the numbers of patients were large enough for a statistical detection of even small differences, the results indicate that the nurse practitioners were effective and safe. This study provides a base from which to explore the "process" of delivering primary clinical services by nurse practitioners.
Synthetic Generation of Influenza Vaccine Viruses for Rapid Response to Pandemics
Authors: Philip R. Dormitzer, Pirada Suphaphiphat, Daniel G. Gibson, David E. Wentworth, Timothy B. Stockwell, Mikkel A. Algire, Nina Alperovich, Mario Barro, David M. Brown, Stewart Craig, Brian M. Dattilo, Evgeniya A. Denisova, Ivna De Souza, Markus Eickmann, Vivien G. Dugan, Annette Ferrari, Raul C. Gomila, Liqun Han, Casey Judge, Sarthak Mane, Mikhail Matrosovich, Chuck Merryman, Giuseppe Palladino, Gene A. Palmer, Terika Spencer, Thomas Strecker, Heidi Trusheim, Jennifer Uhlendorff, Yingxia Wen, Anthony C. Yee, Jayshree Zaveri, Bin Zhou, Stephan Becker, Armen Donabedian, Peter W. Mason, John I. Glass, Rino Rappuoli, J. Craig Venter
Journal: Science Translational Medicine (2013)

Synthesis of viral genes from sequence information allows rapid generation of influenza vaccine viruses, facilitating rapid responses to influenza pandemics.
Characterisation of guinea pig precision-cut lung slices: comparison with human tissues
Authors: A. R. Ressmeyer, A. K. Larsson, E. Vollmer, S. E. Dahlèn, S. Uhlig, C. Martin
Journal: European Respiratory Journal (2006)

Precision-cut lung slices (PCLS) allow comparison of the airway responses of different species under identical experimental conditions. The aim of this study was to establish and characterise PCLS from guinea pigs (GPs) and to compare them with human PCLS. GP PCLS were prepared according to previously published procedures with the exception that the agarose solution and the initial incubation medium contained isoproterenol to avoid post mortem airway contraction. The median effective concentrations (EC50, expressed as nM) for agonist-induced bronchoconstriction in GP and human PCLS, respectively, were: leukotriene D4 (1.8, 5.0); thromboxane (16, 1.3); serotonin (69, unresponsive); histamine (217, 2,170); and methacholine (231, 234). Allergen-induced bronchoconstriction of passively sensitised PCLS was attenuated by histamine or thromboxane-prostanoid receptor antagonists and was almost completely prevented by their combination with leukotriene receptor antagonists. Airways pre-contracted with methacholine were relaxed by the beta-agonist salbutamol or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Simultaneous studies of airways and vessels are possible with, for example, EC50 values for endothelin-1 of 37 nM (pulmonary arteries), 10 nM (pulmonary veins) and 9.6 nM (airway). When compared with previous findings in rat and mouse, these data show that guinea pig lungs are a more appropriate model for human airway pharmacology than lungs from rats or mice.
Fatty Acid Synthase: A Metabolic Enzyme and Candidate Oncogene in Prostate Cancer
Authors: Toshiro Migita, Stacey Ruiz, Alessandro Fornari, Michelangelo Fiorentino, Carmen Priolo, Giorgia Zadra, Fumika Inazuka, Chiara Grisanzio, Emanuele Palescandolo, Eyoung Shin, Christopher Fiore, Wanling Xie, Andrew L. Kung, Phillip G. Febbo, Aravind Subramanian, Lorelei Mucci, Jing Ma, Sabina Signoretti, Meir Stampfer, William C. Hahn, Stephen Finn, Massimo Loda
Journal: JNCI Journal of the National Cancer Institute (2009)

Overexpression of the fatty acid synthase (FASN) gene has been implicated in prostate carcinogenesis. We sought to directly assess the oncogenic potential of FASN. We used immortalized human prostate epithelial cells (iPrECs), androgen receptor–overexpressing iPrECs (AR-iPrEC), and human prostate adenocarcinoma LNCaP cells that stably overexpressed FASN for cell proliferation assays, soft agar assays, and tests of tumor formation in immunodeficient mice. Transgenic mice expressing FASN in the prostate were generated to assess the effects of FASN on prostate histology. Apoptosis was evaluated by Hoechst 33342 staining and by fluorescence-activated cell sorting in iPrEC-FASN cells treated with stimulators of the intrinsic and extrinsic pathways of apoptosis (ie, camptothecin and anti-Fas antibody, respectively) or with a small interfering RNA (siRNA) targeting FASN. FASN expression was compared with the apoptotic index assessed by the terminal deoxynucleotidyltransferase-mediated UTP end-labeling method in 745 human prostate cancer samples by using the least squares means procedure. All statistical tests were two-sided. Forced expression of FASN in iPrECs, AR-iPrECs, and LNCaP cells increased cell proliferation and soft agar growth. iPrECs that expressed both FASN and androgen receptor (AR) formed invasive adenocarcinomas in immunodeficient mice (12 of 14 mice injected formed tumors vs 0 of 14 mice injected with AR-iPrEC expressing empty vector (P < .001, Fisher exact test); however, iPrECs that expressed only FASN did not. Transgenic expression of FASN in mice resulted in prostate intraepithelial neoplasia, the incidence of which increased from 10% in 8- to 16-week-old mice to 44% in mice aged 7 months or more (P = .0028, Fisher exact test), but not in invasive tumors. In LNCaP cells, siRNA-mediated silencing of FASN resulted in apoptosis. FASN overexpression protected iPrECs from apoptosis induced by camptothecin but did not protect iPrECs from Fas receptor–induced apoptosis. In human prostate cancer specimens, FASN expression was inversely associated with the apoptotic rate (mean percentage of apoptotic cells, lowest vs highest quartile of FASN expression: 2.76 vs 1.34, difference = 1.41, 95% confidence interval = 0.45 to 2.39, Ptrend = .0046). These observations suggest that FASN can act as a prostate cancer oncogene in the presence of AR and that FASN exerts its oncogenic effect by inhibiting the intrinsic pathway of apoptosis.
Lysosomal cysteine proteases in the lung: role in protein processing and immunoregulation
Authors: F. Bühling, N. Waldburg, A. Reisenauer, A. Heimburg, H. Golpon, T. Welte
Journal: European Respiratory Journal (2004)

Lysosomal cysteine proteases are a family comprising &gt;10 enzymes. For many years it was believed that these enzymes catalyse protein breakdown unselectively, are highly redundant in their substrate specificity and are also expressed ubiquitously. This view has changed dramatically since a number of new lysosomal cysteine proteases with restricted expression and outstanding enzymatic activity have been described. In addition, knockout mice and selective protease inhibitors have been used to characterise specific functions of single proteases. In this review, some of these functions are discussed in relation to the lungs, especially the role of lysosomal cysteine proteases in matrix remodelling, immunoregulation and surfactant protein processing.
Improving Quality of Care for Serious Illness
Authors: James A. Tulsky
Journal: JAMA Internal Medicine (2015)

Background In 1997, in response to growing public awareness and a landmark study,1 the IOM issueda report entitledApproachingDeath: Improving Care at the End of Life.2 This document, aswell as a subsequent report dedicated to children,3 focused attention on the excessive andunnecessarysufferingexperiencedbydyingpatientsandhelped tocatalyzeamovement for change.4 Impressively,manyof thegoals articulated in that report have been achieved, including the creationofpalliativemedicine specialty status, increasedaccess toopioids for patients with pain, and the widespread adoption of hospital palliative care teams. And yet, both research and the everyday experienceofpatients, familymembers, andclinicians suggest that huge gaps remain in the quality of care for themost vulnerable patients. This poor care continues against a backdrop of rising health care costs and a sense that the patients who account for the greatestpercentageof thisexpendituredonotbenefit from,andmayeven be harmed by, its excess. Furthermore, policy reform efforts have beenstymiedbyaccusationsof “deathpanels”andhijackedbyatoxic health care political debate. In response, the IOM decided to assemble a diverse expert panel, review the progress since the prior report, and restartmomentumtoward improving care.OnSeptember 17, 2014, this IOM committee issued Dying in America: ImprovingQualityandHonoring IndividualPreferencesNear theEndofLife.5
A case of small cell lung cancer treated with chemoradiotherapy followed by photodynamic therapy
Authors: J E Lee, H S Park, S S Jung, S Y Kim, J O Kim
Journal: Thorax (2009)

Here, we present the case of a 51-year-old man with limited-stage small cell lung cancer (LS-SCLC) who received concurrent chemoradiotherapy and photodynamic therapy (PDT). The patient was diagnosed as having LS-SCLC with an endobronchial mass in the left main bronchus. Following concurrent chemoradiotherapy, a mass remaining in the left lingular division was treated with PDT. Clinical and histological data indicate that the patient has remained in complete response for 2 years without further treatment. This patient represents a rare case of complete response in LS-SCLC treated with PDT.
Complement and immunoglobulins stimulate superoxide production by human leukocytes independently of phagocytosis.
Authors: I M Goldstein, D Roos, H B Kaplan, G Weissmann
Journal: Journal of Clinical Investigation (1975)

Human peripheral blood polymorphonuclear leukocytes, when exposed to appropriate stimuli, generate significant amounts of superoxide anion (O-.2), a highly reactive molecule which is possibly involved in bacterial killing. Since the subcellular localization and mechanism of activation of O-.2 generating systems are unknown, we have investigated superoxide dismutase-inhibitable cytochrome c reduction (attributable to O-.2) by, and lysosomal enzyme release from, normal polymorphonuclear leukocytes and cells rendered incapable of ingesting particles by treatment with cytochalasin B. Neither phagocytosis nor lysosomal degranulation were prerequisites for enhanced O-.2 generation. Cytochalasin B-treated cells exposed to (a) serum-treated zymosan, a C3b receptor stimulus; (b) heat aggregated human IgG, an Fc receptor stimulus; and (c) the complement component, C5a, generated enhanced amounts of O-.2 in a time and concentration-dependent fashion. These cells also responded by releasing lysosomal enzymes, but there was no correlation between the ability of any immune reactant to provoke enzyme release and its ability to stimulate O-.2 generation. The three stimuli also enhanced O-.2 generation by normal (untreated) polymorphonuclear leukocytes, but only serum-treated zymosan and aggregated IgG were capable of provoking lysosomal enzyme release from normal cells. Untreated zymosan and native IgG neither stimulated O-.2 production nor provoked lysomal enzyme release. Since enhanced O-.2 production was stimulated by immune reactants in the absence of phagocytosis, the O-.2 generating system is very likely associated with the external plasma membrane of the polymorphonuclear leukocyte. Leukocyte membrane receptors for complement and immunoglobulins may therefore not only serve in particle recognition but also may initiate biochemical events which accompany phagocytosis and killing.
FDA Approval: Belinostat for the Treatment of Patients with Relapsed or Refractory Peripheral T-cell Lymphoma
Authors: Hyon-Zu Lee, Virginia E. Kwitkowski, Pedro L. Del Valle, M. Stacey Ricci, Haleh Saber, Bahru A. Habtemariam, Julie Bullock, Erik Bloomquist, Yuan Li Shen, Xiao-Hong Chen, Janice Brown, Nitin Mehrotra, Sarah Dorff, Rosane Charlab, Robert C. Kane, Edvardas Kaminskas, Robert Justice, Ann T. Farrell, Richard Pazdur
Journal: Clinical Cancer Research (2015)

On July 3, 2014, the FDA granted accelerated approval for belinostat (Beleodaq; Spectrum Pharmaceuticals, Inc.), a histone deacetylase inhibitor, for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). A single-arm, open-label, multicenter, international trial in the indicated patient population was submitted in support of the application. Belinostat was administered intravenously at a dose of 1000 mg/m(2) over 30 minutes once daily on days 1 to 5 of a 21-day cycle. The primary efficacy endpoint was overall response rate (ORR) based on central radiology readings by an independent review committee. The ORR was 25.8% [95% confidence interval (CI), 18.3-34.6] in 120 patients that had confirmed diagnoses of PTCL by the Central Pathology Review Group. The complete and partial response rates were 10.8% (95% CI, 5.9-17.8) and 15.0% (95% CI, 9.1-22.7), respectively. The median duration of response, the key secondary efficacy endpoint, was 8.4 months (95% CI, 4.5-29.4). The most common adverse reactions (>25%) were nausea, fatigue, pyrexia, anemia, and vomiting. Grade 3/4 toxicities (≥5.0%) included anemia, thrombocytopenia, dyspnea, neutropenia, fatigue, and pneumonia. Belinostat is the third drug to receive accelerated approval for the treatment of relapsed or refractory PTCL.
Parp1 facilitates alternative NHEJ, whereas Parp2 suppresses IgH/c-myc translocations during immunoglobulin class switch recombination
Authors: Isabelle Robert, Françoise Dantzer, Bernardo Reina-San-Martin
Journal: The Journal of Experimental Medicine (2009)

Immunoglobulin class switch recombination (CSR) is initiated by DNA breaks triggered by activation-induced cytidine deaminase (AID). These breaks activate DNA damage response proteins to promote appropriate repair and long-range recombination. Aberrant processing of these breaks, however, results in decreased CSR and/or increased frequency of illegitimate recombination between the immunoglobulin heavy chain locus and oncogenes like c-myc. Here, we have examined the contribution of the DNA damage sensors Parp1 and Parp2 in the resolution of AID-induced DNA breaks during CSR. We find that although Parp enzymatic activity is induced in an AID-dependent manner during CSR, neither Parp1 nor Parp2 are required for CSR. We find however, that Parp1 favors repair of switch regions through a microhomology-mediated pathway and that Parp2 actively suppresses IgH/c-myc translocations. Thus, we define Parp1 as facilitating alternative end-joining and Parp2 as a novel translocation suppressor during CSR.
Long-Term Outcome of Allogeneic Hematopoietic Cell Transplantation for Patients With Mycosis Fungoides and Sézary Syndrome: A European Society for Blood and Marrow Transplantation Lymphoma Working Party Extended Analysis
Authors: Rafael F. Duarte, Ariane Boumendil, Francesco Onida, Ian Gabriel, Reyes Arranz, William Arcese, Xavier Poiré, Guido Kobbe, Franco Narni, Agostino Cortelezzi, Eduardo Olavarría, Norbert Schmitz, Anna Sureda, Peter Dreger
Journal: Journal of Clinical Oncology (2014)

In 2010, the European Society for Blood and Marrow Transplantation (EBMT) reported an overall survival (OS) of 66% at 1 year and 54% at 3 years after allogeneic hematopoietic cell transplantation (HCT) in patients with advanced-stage mycosis fungoides and Se ´zary syndrome (MF/SS). 1 The main shortcoming of this initial report was a limited follow-up of only 36 months; in particular, for a series in which 73% of the cases received reduced-intensity conditioning before HCT.Here, we present an extended analysis of this experience, with a median follow-up in survivors of 7 years (longest follow-up: 12 years; interquartile range: 6 to 9 years).The analysis focuses on nonrelapse mortality (NRM), cumulative incidence of relapse/progression, progression-free survival (PFS), OS, and the impact of disease and transplant factors on long-term patient outcome.All 60 patients with European Organisation for Research and Treatment of Cancer/International Society for Cutaneous Lymphomas advanced-stage (TNM stages IIB and higher) 2 MF (n ϭ 36) and SS (n ϭ 24) reported to the EBMT for a first allogeneic HCT between 1997 and 2007 and who were included in our original series were reanalyzed.The sample included 37 men and 23 women; median age at transplant was 46.5 years (range, 22 to 66 years).There were 45 matched related and 15 matched unrelated donors; 44 (73%) had TNM stage IV disease, 2 and 40 (67%) were at advanced disease phase at transplantation, defined as either those on third or later complete response, partial response or relapse/progression, or those primary refractory to systemic therapy.Only 16 patients (27%) received myeloablative conditioning regimens.Extended follow-up data were collected from the EBMT database as of April 30th, 2014.Our data show that patients with advanced-stage MF/SS continue to benefit from allogeneic HCT over time, with an OS of 46% at 5 years and 44% at 7 years (95% CI, 35% to 61% and 33% to 59%, respectively), and a PFS of 32% at 5 years and 30% at 7 years (95% CI, 22% to 47% and 20% to 45%, respectively; Fig 1A).Disease relapse/ progression is the main cause of postransplant failure, with a total of 27 patients (45%) experiencing relapse/progression at a median of 3.8 months after HCT (range, 1 to 59; only two occurring beyond 2 years, at 3 and 5 years).Of note, eight of these 27 patients remain alive at a median of 8 years after HCT (range, 1 year and 7 months to 10 years), suggesting that some patients can be successfully rescued with donor lymphocyte infusions and/or other salvage therapies.Indeed, 27 patients were alive, and 26 of them were in CR at last follow-up.Seven-
Patterns of care and outcome for patients with glioblastoma diagnosed during 2008-2010 in Spain
Authors: F. Graus, J. Bruna, J. Pardo, D. Escudero, D. Vilas, I. Barcelo, M. Brell, C. Pascual, J. A. Crespo, E. Erro, J. C. Garcia-Romero, J. Estela, J. Martino, A. Garcia-Castano, E. Mata, M. Lema, M. Gelabert, R. Fuentes, P. Perez, A. Manzano, J. Aguas, A. Belenguer, A. Simon, I. Henriquez, M. Murcia, R. Vivanco, I. Rojas-Marcos, D. Munoz-Carmona, I. Navas, P. de Andres, G. Mas, M. Gil, E. Verger
Journal: Neuro-Oncology (2013)

To assess management patterns and outcome in patients with glioblastoma multiforme (GBM) treated during 2008–2010 in Spain. Retrospective analysis of clinical, therapeutic, and survival data collected through filled questionnaires from patients with histologically confirmed GBM diagnosed in 19 Spanish hospitals. We identified 834 patients (23% aged >70 years). Surgical resection was achieved in 66% of patients, although the extent of surgery was confirmed by postoperative MRI in only 41%. There were major postoperative complications in 14% of patients, and age was the only independent predictor (Odds ratio [OR], 1.03; 95% confidence interval [CI],1.01–1.05; P = .006). After surgery, 57% received radiotherapy (RT) with concomitant and adjuvant temozolomide, 21% received other regimens, and 22% were not further treated. In patients treated with surgical resection, RT, and chemotherapy (n = 396), initiation of RT ≤42 days was associated with longer progression-free survival (hazard ratio [HR], 0.8; 95% CI, 0.64–0.99; P = .042) but not with overall survival (HR, 0.79; 95% CI, 0.62–1.00; P = .055). Only 32% of patients older than 70 years received RT with concomitant and adjuvant temozolomide. The median survival in this group was 10.8 months (95% CI, 6.8–14.9 months), compared with 17.0 months (95% CI, 15.5–18.4 months; P = .034) among younger patients with GBM treated with the same regimen. In a community setting, 57% of all patients with GBM and only 32% of older patients received RT with concomitant and adjuvant temozolomide. In patients with surgical resection who were eligible for chemoradiation, initiation of RT ≤42 days was associated with better progression-free survival.
Threat, safeness, and schizophrenia: Hidden issues in an evolutionary story
Authors: Paul Gilbert
Journal: Behavioral and Brain Sciences (2004)

There is evidence that people with schizophrenia have difficulties in some (recently evolved) competencies for processing social information. However, a case can be made that vulnerabilities can also lie in (previously evolved) threat and safeness processing systems. Evolutionary models may need to consider interactions between genetic sensitivities, early experiences of threat/safeness, and later cognitive vulnerabilities. Psychological treatments must address issues of experienced threat and safeness before working on more cognitive competencies.