tbuckley/cabot-search huggingface dataset:
Biologic Effects of Prolonged Melphalan Treatment of Murine Long-Term Bone Marrow Cultures and Interleukin 3-Dependent Hematopoietic Progenitor Cell Lines<xref ref-type="fn" rid="FN2">2</xref><xref ref-type="fn" rid="FN3">3</xref>
Authors: J S Greenberger, E W Palaszynski, J H Pierce, M A Sakakeeny, S K Ruscetti, J N Ihle, C Daugherty
Journal: JNCI Journal of the National Cancer Institute (1985)

The mechanism of alkylating agent-induced leukemia is unknown. For the determination of whether chronic alkylating agent treatment of hematopoietic stem cells in vitro was detectably leukemogenic, murine long-term bone marrow cultures (LTBMC) and clonal interleukin 3 (IL-3)-dependent multipotential hematopoietic progenitor cell lines [B6SUtA clone (cl) 27 and Ro cl 3-1] derived from LTBMC were chronically pulse treated in vitro with the alkylating agent melphalan [L-phenylalanine mustard (L-PAM)]. Weekly treatment of C3H/HeJ or CD-1 Swiss mouse LTBMC with 3 X 10(-6)M L-PAM significantly decreased cumulative production of nonadherent granulocytes and granulocyte-macrophage progenitor cells responsive to L-cell or WEH1-3 cell colony-stimulating factor compared to the production seen in untreated control cultures; it also significantly reduced the hematopoietic longevity (13 wk compared to greater than 20 wk for untreated control cultures). Weekly, twice weekly, or daily (3 X 10(-6)M) L-PAM treatment of IL-3-dependent cell lines induced gradual L-PAM adaptation in the absence of a detectable change in the maximum binding capacity of 125I-labeled IL-3. No leukemogenic variants of line B6SUtA cl 27 were detectably induced. However, 3 stably expressed marker chromosomes were induced after 12 months of L-PAM treatment of line B6SUtA cl 27. Thus IL-3-dependent hematopoietic progenitor cells slowly adapt to L-PAM when in suspension culture in vitro. Physiologic expression of drug toxicity in LTBMC may prevent this hematopoietic cell gradual adaptation.
Organization and Neuraminidase Susceptibility of Sialic Acid Residues in Human Melanoma Cell Lines With Different Heterotransplantabilities in Nude Mice&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: O Berthier-Vergnes, J Portoukalian, J F Doré
Journal: JNCI Journal of the National Cancer Institute (1985)

Quantitative analyses of sialic acid residues expressed at the surface of human melanoma cells have been performed on 6 cell lines differing in their ability to grow subcutaneously in nude mice. Whereas 3 of these cell lines showed low heterotransplantability (LT), 3 other cell lines showed high heterotransplantability (HT). It was found by several methodologic approaches that the 6 human melanoma cell lines varied significantly in their amount of sialic acid susceptible to Vibrio cholerae neuraminidase, but had similar amounts of total sialic acid residues. Cells in the LT group exhibited twice as much cell surface sialic acid residue susceptible to this enzyme as cells in the HT group. Specific fluorescent labeling of external cell surface sialic acid residues showed that the LT cells present a patch-like distribution of the label, whereas the HT cells are characterized by a more homogeneous distribution of the label. Thus the human melanoma cell lines could be distinguished not only by their heterotransplantability in nude mice but also by membrane properties, such as the topographic organization of their cell surface sialic acid residues.
Single nucleotide polymorphisms and clinical outcome in biliary tract carcinoma treated with epirubicin, cisplatin and capecitabine
Authors: P. Pacetti, E. Giovannetti, A. Mambrini, R. Tartarini, M. Del Tacca, R. Danesi, S. Grisanti, S. Nannizzi, S. Ricciardi, M. Cantore
Journal: Journal of Clinical Oncology (2008)

14558 Background: Biliary tract carcinoma is an uncommon malignancy. The activity of systemic chemotherapy is very low and there is no current therapy considered a gold standard. The poor prognosis of cholangiocarcinoma is a result of its biological aggressiveness and therapy resistant nature. Individual variation in DNA repair conferred by single nucleotide polymorphisms (SNPs) affects the clinical response to therapy and overall survival in several neoplasms. In this investigational pharmacogenetic study we retrospectively evaluated the correlations between the following polymorphisms (XPD Asp312Asn and Lys751Gln, ERCC1 C118T, XRCC1 Arg399Gln, and ABCB1 C3435T) and: drug response, progression free and overall survival. Methods: Between June 2006 and August 2007 33 patients (pts) entered this study: seven pts received epirubicin and cisplatin intravenous and 26 pts received epirubicin and cisplatin intra-arterially; all pts received orally capecitabine. Genomic DNA was extracted from blood samples (5 ml) before drug administration. The ERCC1 C118T, XPD Asp312Asn, XPD Lys751Gln, XRCC1 Arg399Gln, and ABCB1 C3435T polymorphisms were studied with Taqman® probes-based assays. Results: PR was observed in 6 out of the 33 evaluable pts (18.2%). SD was observed in 17 pts (51.5%) and PD occurred in 10 pts. (30.3%). After a median follow-up of 7.1 months (range 1–44.7), the median PFS was 4.8 months (range 0.7–21.7) and the median OS was 18.9 months. No significant correlations were observed between response, PFS and OS in patients grouped according to all the studied polymorphisms. However, the Log-rank test suggested an association of the XRCC1Arg/Arg variant with reduced OS which did not reach statistical significance. Furthermore, the analysis of survival starting from the date of diagnosis resulted in a significant association of the homozygous variant XRCC1 Arg/Arg with a shorter survival (11.0 vs 45.6 months, p=0.01). Conclusions: To our knowledge this study is the first pharmacogenetic one in patients affected by biliary tract carcinomas. The results observed in this homogeneous population suggested that the XRCC1 genotype would be useful as prognostic marker in these pts. No significant financial relationships to disclose.
Microspectrophotometric Studies of Deoxyribonucleic Acid Content of Murine Lymphoma Cells (Strain P388 D<sub>1</sub>) Infected With Polyoma Virus
Authors: Giancarlo Rabotti, Alan S. Rabson, Richard A. Malmgren
Journal: JNCI Journal of the National Cancer Institute (1963)

Microspectrophotometric studies of deoxyribonucleic acid (DNA) in Feulgen preparations of P388 D1 cells infected with polyoma virus were carried out during progression of viral growth and cytopathic effects. Twenty-four hours after infection, when there was no evidence of viral growth or cytopathic effects, no increase in nuclear DNA-Feulgen complex was found. Significant increases in nuclear volunie and nuclear DNA-Feulgen complex were observed, however, 48 and 72 hours after infection, when cytopathic effects were evident and viral growth had taken place.
Abstract 18921: Utility of a TTC Score to facilitate differentiation of Tako-Tsubo Cardiomyopathy from Ischemic ACS
Authors: Christopher J Neil, Thanh H Nguyen, Jeanette Stansborough, Cher-Rin Rong, Kuljit Singh, Angela Kucia, John D Horowitz
Journal: Circulation (2012)

Introduction: The diagnosis of tako-tsubo cardiomyopathy (TTC) is often made by default after emergent cardiac catheterization and potentially the inappropriate administration of thrombolytics or catecholamines. In view of the distinct pathogenesis of TTC, it is important that TTC be distinguished from ischemic ACS, clinically, if possible. We now report the utility of an arbitrarily derived “TTC score” based on clinical features of TTC versus ACS. Methods: Consecutive TTC (n=99) and female ACS (N=56) patients of similar ages were compared. The TTC score allocated 1 point for troponin T elevation, 1 or 2 points for NT-proBNP to ≥3000 or ≥6000pg/ml respectively, and 1 or 2 points for regional and multiregional ECG changes respectively, with analyses based on data at 24 hours post presentation. Additional analyses were performed to evaluate the potential additional impact of histories of antecedent severe stress, and that of the presence/absence of hemodynamic compromise (Killip Class ≥2). Results: Scores were substantially different (see Figure; TTC group median 4, vs. 2 in the ACS group; p&lt;0.0001). Receiver operator curve analysis demonstrated an area under the curve (AUC) of 0.74 (P&lt;0.0001), with 62% sensitivity and 75% specificity for a score ≥4. This differentiation was based primarily on NT-proBNP levels (median 5990 vs 1600 pg/ml). The rate of antecedent stressor exposure for TTC patients was 82%: modeling of imputed stressor exposure rates of 25 and 50% for ACS patients improved specificity to 79 and 75% respectively. The TTC score separated diagnostic groups in Killip 1 (AUC 0.80, P&lt;0.0001), but not in Killip ≥2 (AUC 0.66, P=NS). Conclusion: This TTC score facilitates differentiation of TTC from ischemic ACS, in the absence of pulmonary congestion/shock. Early diagnosis of TTC is an essential precursor to the development of disease-specific therapeutic regimens.
Phase I Dose-Escalation Study of Linsitinib (OSI-906) and Erlotinib in Patients with Advanced Solid Tumors
Authors: Valentine M. Macaulay, Mark R. Middleton, S. Gail Eckhardt, Charles M. Rudin, Rosalyn A. Juergens, Richard Gedrich, Sven Gogov, Sean McCarthy, Srinivasu Poondru, Andrew W. Stephens, Shirish M. Gadgeel
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Cross-talk between type I IGF receptor (IGF1R), insulin receptor (INSR), and epidermal growth factor receptor (EGFR) mediates resistance to individual receptor blockade. This study aimed to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of linsitinib, a potent oral IGF1R/INSR inhibitor, with EGFR inhibitor erlotinib. Experimental Design: This open-label, dose-escalation study investigated linsitinib schedules S1: once daily intermittent (days 1–3 weekly); S2, once daily continuous; S3, twice-daily continuous; each with erlotinib 100–150 mg once daily; and a non–small cell lung cancer (NSCLC) expansion cohort. Results: Ninety-five patients were enrolled (S1, 44; S2, 24; S3, 12; expansion cohort, 15) and 91 treated. Seven experienced dose-limiting toxicities: QTc prolongation (3), abnormal liver function (2), hyperglycemia (1), and anorexia (1). Common adverse events included drug eruption (84%), diarrhea (73%), fatigue (68%), nausea (58%), vomiting (40%). MTDs for linsitinib/erlotinib were 450/150 mg (S1), 400/100 mg (S2). On the basis of prior monotherapy data, S3 dosing at 150 mg twice daily/150 mg once daily was the recommended phase II dose for the expansion cohort. There was no evidence of drug–drug interaction. Pharmacodynamic data showed IGF-1 elevation and reduced IGF1R/INSR phosphorylation, suggesting pathway inhibition. Across schedules, 5/75 (7%) evaluable patients experienced partial responses: spinal chordoma (268+ weeks), rectal cancer (36 weeks), three NSCLCs including 2 adenocarcinomas (16, 72 weeks), 1 squamous wild-type EGFR NSCLC (36 weeks). Disease control (CR+PR+SD) occurred in 38 of 75 (51%), and 28 of 91 (31%) patients were on study &amp;gt;12 weeks. Conclusions: The linsitinib/erlotinib combination was tolerable with preliminary evidence of activity, including durable responses in cases unlikely to respond to erlotinib monotherapy. Clin Cancer Res; 22(12); 2897–907. ©2016 AACR.
A patient-initiated DMARD self-monitoring service for people with rheumatoid or psoriatic arthritis on methotrexate: a randomised controlled trial
Authors: Hayley McBain, Michael Shipley, Abigail Olaleye, Samantha Moore, Stanton Newman
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objective</h3> To determine the effectiveness of a patient-initiated disease-modifying antirheumatic drugs (DMARD) self-monitoring service for people with rheumatoid (RA) or psoriatic arthritis (PsA) on methotrexate. <h3>Methods</h3> A two-arm, single-centre, randomised controlled trial assessing superiority in relation to healthcare use, clinical and psychosocial outcomes. Participants were 100 adults with either RA or PsA on a stable dose of methotrexate, randomly assigned to usual care or the patient-initiated service. Intervention participants were trained how to understand and interpret their blood tests and use this information to initiate care from their clinical nurse specialist (CNS). The primary outcome was the number of outpatient visits to the CNS during the trial period. Differences between groups were analysed using Poisson regression models. Secondary outcomes were collected at baseline and after the third and sixth blood tests. Disease activity was measured using either the Disease Activity Score in 28 joints or Psoriatic Arthritis Response Criteria (PsARC), pain and fatigue using a visual numeric scale and the Health Assessment Question-II, Hospital Anxiety and Depression Scale and SF12 were completed to assess disability, mood and quality of life, respectively. Differences between groups over time on secondary outcomes were analysed using multilevel models. <h3>Results</h3> The patient-initiated DMARD self-monitoring service was associated with 54.55% fewer visits to the CNS (p&lt;0.0001), 6.80% fewer visits to the rheumatologist (p=0.23) and 38.80% fewer visits to the general practitioner (p=0.07), compared with control participants. There was no association between trial arm and any of the clinical or psychosocial outcomes. <h3>Conclusions</h3> The results suggest that a patient-initiated service that incorporates patients' self-monitoring DMARD therapy can lead to significant reductions in healthcare use, while maintaining clinical and psychosocial well-being. <h3>Trial registration number</h3> ISRCTN21613721.
Post discharge mortality in North Indian patients with exacerbation of COPD
Authors: Hilal Dar, Umar Khan, Parvaiz Koul
Journal: European Respiratory Journal (2011)

Background: Mortality rates at 2 years following discharge among patients with exacerbation of COPD have ranged from 22% to 49%. No mortality data is available for such patients from India, especially Kashmir, where COPD is common.

Objective: To determine the post discharge mortality rate and its determinants among patients with COPD hospitalized for acute exacerbation, in a 650-bedded tertiary care facility in Srinagar, Kashmir (India).

Methods: One hundred and fifty-one patients admitted with a diagnosis of acute exacerbation of COPD from October 2008 to October 2010 & discharged after treatment were followed prospectively for a period of 2 years for any deaths and recurrences of exacerbations. The relationship of mortality with potential patient factors was analysed statistically by employing multiple logistic regression analysis, Kaplan- Meier survival analysis and Cox regression.

Results: During a followup of two years following discharge, 39.7% patients died with the majority (34.4%) of deaths occurring during the first year. Risk factors associated with increased mortality included lower health status at discharge (SGRQ score > 60, p value < 0.001), GOLD stage 4 (p < 0.001), BMI < 18 kgs/m2 (p value < 0.001), SaO2 ≤ 90% at discharge (p < 0.001) and 6MWT distance of < 150 metres (p < 0.001). Frequency of exacerbations increased with increasing GOLD stage (p < 0.001).

Conclusion: Mortality after discharge is high among north Indian patients admitted with acute exacerbation. Poor functional status at discharge and advanced lung disease are predictive of excessive mortality. Advanced stage of lung disease is associated with frequent exacerbations.
Comparative characteristics of regulatory T cells populations between patients with bronchial asthma (BA) and COPD
Authors: Elena Kremer, Natalya Kirillova, Tatyana Perevozchikova, Elena Fajt, Ivan Deev, Ludmila Ogorodova
Journal: European Respiratory Journal (2011)

Background: T-regulatory cells (T-reg) are critical for controlling the degree of immune response to various types of antigens. Possibly due to late or insufficient activation of individual subpopulations of T-reg accumulation of activated immunocompetent cells and intensity of inflammation in COPD and BA is excessive.

Aim and objectives: To investigate differences in subpopulations of T-reg in COPD compared to that in BA and healthy donors (HD).

Methods: The circulating percentage of CD4+CD25high and CD4+FoxP3+ T-reg in peripheral blood was estimated by the flow cytometry analysis. We included 60 patients with COPD (57,8±1,09 years old), 20 patients with BA (54,1±2,2 years old) and 17 HD (54,1±2,2 years old).

Results: It was shown that COPD is associated with the increasing of percentage number of CD4+CD25high T-reg (2,82±0,24%) in the peripheral blood in comparison to BA (1,87±0,47%, p = 0,004) and HD (1,56±0,24%, p = 0,005). The patients with BA had the decreasing CD4+FoxP3+ T-reg (2,57±0,60, p<0,001) compared to COPD (8,37±0,38, p < 0,001) and HD (8,10±0,48, p < 0,001).

Conclusions: We consider that the observed increase of circulating in peripheral blood CD4+CD25high T-reg in COPD patients might be markers of disease severity. Our study suggests an association between differences in subpopulations of T-reg in patients with BA and COPD with varying degrees of inflammation.
Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis
Authors: Jaclyn Andricovich, Yan Kai, Weiqun Peng, Adlen Foudi, Alexandros Tzatsos
Journal: Journal of Clinical Investigation (2016)

The development of the hematopoietic system is a dynamic process that is controlled by the interplay between transcriptional and epigenetic networks to determine cellular identity. These networks are critical for lineage specification and are frequently dysregulated in leukemias. Here, we identified histone demethylase KDM2B as a critical regulator of definitive hematopoiesis and lineage commitment of murine hematopoietic stem and progenitor cells (HSPCs). RNA sequencing of Kdm2b-null HSPCs and genome-wide ChIP studies in human leukemias revealed that KDM2B cooperates with polycomb and trithorax complexes to regulate differentiation, lineage choice, cytokine signaling, and cell cycle. Furthermore, we demonstrated that KDM2B exhibits a dichotomous role in hematopoietic malignancies. Specifically, we determined that KDM2B maintains lymphoid leukemias, but restrains RAS-driven myeloid transformation. Our study reveals that KDM2B is an important mediator of hematopoietic cell development and has opposing roles in tumor progression that are dependent on cellular context.
Second-line chemotherapy (CT) with or without bevacizumab (BV) in metastatic colorectal cancer (mCRC) patients (pts) who progressed to a first-line treatment containing BV: Updated results of the phase III “BEBYP” trial by the Gruppo Oncologico Nord Ovest (GONO).
Authors: Gianluca Masi, Fotios Loupakis, Lisa Salvatore, Chiara Cremolini, Lorenzo Fornaro, Marta Schirripa, Cristina Granetto, Emanuela Miraglio, Francesco Di Costanzo, Lorenzo Antonuzzo, Lorenzo Marcucci, Cecilia Barbara, Corrado Boni, Maria Banzi, Silvana Chiara, Daniela Garbarino, Chiara Valsuani, Andrea Bonetti, Luca Boni, Alfredo Falcone
Journal: Journal of Clinical Oncology (2013)

3615 Background: Retrospective data suggested that the continuation of BV with second-line CT beyond progression (PD) in pts who received BV in first-line can improve the outcome. Recently, results of the AIO/AMG ML18147 study demonstrated an improved overall survival (OS) by continuing BV beyond PD. Methods: This phase III study randomized pts with measurable mCRC treated in first-line with BV plus fluoropyrimidine, FOLFIRI, FOLFOX or FOLFOXIRI, to receive in second-line mFOLFOX6 or FOLFIRI (depending on first-line CT) with or without BV. The primary end-point was progression free survival (PFS).To detect a HR for PFS of 0.70 with an α and β error of 0.05 and 0.20 respectively, the study required 249 events. Assuming an accrual time of 24 months (mos) and a follow up of 12 mos we planned to randomize 262 pts. Results: Considering the results of the AIO/AMG ML18147 trial, the study accrual was stopped prematurely. A total of 185 pts were randomized and 184 pts were included in the ITT analysis (1 pt randomized in error). Pts characteristics were (arm A/arm B): number 92/92, gender M75%-F25%/M57%-F43%, median age 66 (38-75)/62 (38-75) years, PS=0 82%/82%, multiple site of disease 76%/77%. At a median follow up of 18 mos the study met its primary endpoint by improving PFS in the BV arm. We updated results and at a median follow up of 22 mos the improvement in PFS for the experimental arm was confirmed with a median PFS of 5.2 mos for arm A and 6.7 mos for arm B (HR=0.66; 95% CI 0.49–0.90; unstratified p=0.0072). Subgroup analyses showed a consistent benefit in all subgroups including gender (F: HR=0.63; M: HR=0.72) and first-line PFS (≤10 mos: HR=0.57; &gt;10 mos: HR=0.71). Response rates (RECIST) were 18% and 21% (p=0.71). Toxicity profile was consistent with previously reported data. The OS data are still immature, with 56 events in arm A and 54 in arm B and the median OS is 16.0 mos and 16.5 mos respectively (HR=0.83; 95% CI 0.57-1.22; unstratified p=0.34). Conclusions: This study demonstrates an improvement in PFS by continuing BV in second-line in pts who had received CT+BV in first-line. Clinical trial information: NCT00720512.
The American College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis
Authors: Dinesh Khanna, Veronica J. Berrocal, Edward H. Giannini, James R. Seibold, Peter A. Merkel, Maureen D. Mayes, Murray Baron, Philip J. Clements, Virginia Steen, Shervin Assassi, Elena Schiopu, Kristine Phillips, Robert W. Simms, Yannick Allanore, Christopher P. Denton, Oliver Distler, Sindhu R. Johnson, Marco Matucci‐Cerinic, Janet E. Pope, Susanna M. Proudman, Jeffrey Siegel, Weng Kee Wong, Athol U. Wells, Daniel E. Furst
Journal: Arthritis & Rheumatology (2016)

Objective Early diffuse cutaneous systemic sclerosis (dcSSc) is characterized by rapid changes in the skin and internal organs. The objective of this study was to develop a composite response index in dcSSc (CRISS) for use in randomized controlled trials (RCTs). Methods We developed 150 paper patient profiles with standardized clinical outcome elements (core set items) using patients with dcSSc. Forty scleroderma experts rated 20 patient profiles each and assessed whether each patient had improved or not improved over a period of 1 year. Using the profiles for which raters had reached a consensus on whether the patients were improved versus not improved (79% of the profiles examined), we fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to followup were entered as covariates. We tested the final index in a previously completed RCT. Results Sixteen of 31 core items were included in the patient profiles after a consensus meeting and review of test characteristics of patient‐level data. In the logistic regression model in which the included core set items were change over 1 year in the modified Rodnan skin thickness score, the forced vital capacity, the patient and physician global assessments, and the Health Assessment Questionnaire disability index, sensitivity was 0.982 (95% confidence interval 0.982–0.983) and specificity was 0.931 (95% confidence interval 0.930–0.932), and the model with these 5 items had the highest face validity. Subjects with a significant worsening of renal or cardiopulmonary involvement were classified as not improved, regardless of improvements in other core items. With use of the index, the effect of methotrexate could be differentiated from the effect of placebo in a 1‐year RCT ( P = 0.02). Conclusion We have developed a CRISS that is appropriate for use as an outcome assessment in RCTs of early dcSSc.