tbuckley/cabot-search huggingface dataset:
Model-Based Prediction of Phase III Overall Survival in Colorectal Cancer on the Basis of Phase II Tumor Dynamics
Authors: Laurent Claret, Pascal Girard, Paulo M. Hoff, Eric Van Cutsem, Klaas P. Zuideveld, Karin Jorga, Jan Fagerberg, René Bruno
Journal: Journal of Clinical Oncology (2009)

We developed a drug-disease simulation model to predict antitumor response and overall survival in phase III studies from longitudinal tumor size data in phase II trials.We developed a longitudinal exposure-response tumor-growth inhibition (TGI) model of drug effect (and resistance) using phase II data of capecitabine (n = 34) and historical phase III data of fluorouracil (FU; n = 252) in colorectal cancer (CRC); and we developed a parametric survival model that related change in tumor size and patient characteristics to survival time using historical phase III data (n = 245). The models were validated in simulation of antitumor response and survival in an independent phase III study (n = 1,000 replicates) of capecitabine versus FU in CRC.The TGI model provided a good fit of longitudinal tumor size data. A lognormal distribution best described the survival time, and baseline tumor size and change in tumor size from baseline at week 7 were predictors (P < .00001). Predicted change of tumor size and survival time distributions in the phase III study for both capecitabine and FU were consistent with observed values, for example, 431 days (90% prediction interval, 362 to 514 days) versus 401 days observed for survival in the capecitabine arm. A modest survival improvement of 39 days (90% prediction interval, -21 to 110 days) versus 35 days observed was predicted for capecitabine.The modeling framework successfully predicted survival in a phase III trial on the basis of capecitabine phase II data in CRC. It is a useful tool to support end-of-phase II decisions and design of phase III studies.
Sex Difference in Risk of Torsade de Pointes With <i>d,l-</i> Sotalol
Authors: Michael H. Lehmann, Sterling Hardy, Donald Archibald, Barry Quart, Daniel J. MacNeil
Journal: Circulation (1996)

The present study was undertaken to test the hypothesis that women are more prone than men to develop torsade de pointes (TdP) in a defined cohort of patients exposed to the QT-prolonging antiarrhythmic drug d,l-sotalol.In a database derived from 22 clinical trials involving 3135 adult patients who received oral d,l-sotalol (median follow-up, 164 days), TdP developed in 44 (1.9%) of 2336 men and in 33 (4.1%) of 799 women (P < .001). Logistic regression analysis identified female sex (P < .0001), presenting arrhythmia of sustained ventricular tachycardia or fibrillation (P < .0001), history of congestive heart failure (P < .001), and d,l-sotalol dose > 320 mg/d (P < .001) as factors most predictive of TdP; in addition to these, a serum creatinine > 1.4 mg/dL in women and > 1.6 mg/dL in men was weakly predictive (P < .05). After adjustment for these risk factors, women had threefold greater odds of developing TdP than men. The sex difference in TdP risk was age independent and could not be explained by differential dose-related bradycardic responses in women versus men.Women are at increased risk of developing TdP during-administration of d,l-sotalol. This finding needs to be taken into account, together with other TdP risk factors, when patients are treated with this antiarrhythmic agent. Given the consistency between the present and other recent observations, greater caution in women regarding use of QT-prolonging drugs, in general, is advisable.
Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity
Authors: Mireia Guerau-de-Arellano, Marianne Martinic, Christophe Benoist, Diane Mathis
Journal: The Journal of Experimental Medicine (2009)

There has long been conceptual and experimental support for, but also challenges to, the notion that the initial period of the immune system's development is particularly important for the establishment of tolerance to self. The display of self-antigens by thymic epithelial cells is key to inducing tolerance in the T lymphocyte compartment, a process enhanced by the Aire transcription factor. Using a doxycycline-regulated transgene to target Aire expression to the thymic epithelium, complementing the Aire knockout in a temporally controlled manner, we find that Aire is essential in the perinatal period to prevent the multiorgan autoimmunity that is typical of Aire deficiency. Surprisingly, Aire could be shut down soon thereafter and remain off for long periods, with few deleterious consequences. The lymphopenic state present in neonates was a factor in this dichotomy because inducing lymphopenia during Aire turnoff in adults recreated the disease, which, conversely, could be ameliorated by supplementing neonates with adult lymphocytes. In short, Aire expression during the perinatal period is both necessary and sufficient to induce long-lasting tolerance and avoid autoimmunity. Aire-controlled mechanisms of central tolerance are largely dispensable in the adult, as a previously tolerized T cell pool can buffer newly generated autoreactive T cells that might emerge.
Is centrilobular emphysema the link to the Dutch hypothesis
Authors: Andrea Ballarin, Erica Bazzan, Rafael Hernandez-Zenteno, Graziella Turato, Simonetta Baraldo, Elisabetta Balestro, Dora Zanovello, Marina Saetta, Manuel Cosio
Journal: European Respiratory Journal (2011)

Asthma and COPD are chronic obstructive diseases with a certain degree of physiologic and pathologic similarities and the Dutch Hypothesis proposes that these diseases could be phenotypes of the same process. This hypothesis has never been universally accepted due to the evident differences between the two diseases. However COPD has two distinct pathological phenotypes, Panlobular Emphysema (PLE) where airflow obstruction is secondary to loss of elasticity and Centrilobular Emphysema (CLE) where airflow obstruction is secondary to bronchiolar remodeling with increased muscle and smaller diameter. We hypothesize that CLE could have features of Asthma different from PLE, especially as far as mast cells (MC) inflammation and their relation to airway reactivity. Therefore, we quantified tryptase stained MC in all layers (submucosa, smooth muscle and adventitia) of small airways in 27 lungs with CLE, 24 with PLE, 8 smokers without emphysema (SNE) and 8 non smokers (NS). MC in smooth muscle of small airways were significantly higher in CLE (206±41 cells/mm 2 ) than in PLE (104±21 cells/mm 2 ; p=0.01), SNE (107±54 cells/mm 2 ; p=0.05) and NS (105±27 cells/mm 2 ; p=0.05). Moreover, the degree of MC infiltration in the smooth muscle was related with the degree of hyperresponsiveness, as it has been shown in Asthma (PC20 2 , PC20 3-8mg/ml: 89±69 cells/mm 2  and PC20>8mg/ml: 107±21 cells/mm 2 ; p=0.02 for all). In conclusion, MC infiltration of the muscle layer and its relation to airway reactivity, an important mechanism in the pathogenesis of Asthma, is a prominent feature of COPD patients with CLE, but not with PLE. These findings suggest that CLE could be the COPD link to the Dutch Hypothesis.
Serum Anti-p53 Antibodies and Prognosis of Patients With Small-Cell Lung Cancer
Authors: M. R. Rosenfeld, L. Schramm, J. B. Posner, J. Dalmau, N. Malats, M. Tora, F. X. Real, F. Graus, N. Vinolas, F. Cardenal, R. Rosell
Journal: JNCI Journal of the National Cancer Institute (1997)

Some patients with cancer develop antibodies against the p53 tumor suppressor protein. The presence of these antibodies in serum has been associated with the expression of mutant p53 by the tumor and in some studies with a poorer survival.The goals of this study were to determine the prevalence of anti-p53 antibodies in the serum of patients with newly diagnosed small-cell lung cancer (SCLC) and to assess the clinical relevance of the presence of these antibodies in the serum, particularly their relationship with tumor response to treatment and with patient survival.In this prospective study, serum was obtained from 170 patients at the time of diagnosis of SCLC who were to subsequently receive platinum- or doxorubicin-based chemotherapy at any one of four hospitals in Barcelona, Spain, from October 1991 through June 1994. Normal human sera from blood bank donors (n = 50) served as controls. The presence of anti-p53 antibodies was determined by western blot analysis with the use of purified recombinant p53 protein. As of January 1996, 96.5% of the patients had been treated and observed in the study, for a median follow-up time of 33.5 months. Survival was estimated by the Kaplan-Meier method. Cox proportional hazards regression and unconditional logistic regression analyses were conducted. All P values resulted from two-sided tests.Anti-p53 antibodies were detected in the serum of 27 (16%) of the 170 patients studied. None of 50 serum samples from normal individuals contained anti-p53 antibodies. Analysis of pretreatment clinical characteristics demonstrated that a weight loss of less than 5% (P = .025), a serum lactic acid dehydrogenase (LDH) level of less than 450 U/L (P = .002), and limited stage disease (i.e., tumor confined to one hemithorax, with local and regional lymph node positivity for tumor cells and/or ipsilateral pleural effusion allowed) (P < .001) were associated with a statistically significant complete response to therapy. The presence of serum anti-p53 antibodies was not associated with clinical characteristics, such as age (P = .622), functional status (P = 1.0), disease stage (P = .634), complete response to treatment (P = .572), and survival (P = .492) or with any laboratory parameters including known prognostic factors in SCLC, such as serum sodium or LDH concentration (P values of .731 and .246, respectively).The presence of anti-p53 antibodies in the serum of patients with newly diagnosed SCLC was not associated with any clinical characteristics or prognostic markers, suggesting that, in this context, the measurement of anti-p53 antibodies is not a useful prognostic marker.
Home use of closed-loop insulin delivery for overnight glucose control in adults with type 1 diabetes: a 4-week, multicentre, randomised crossover study
Authors: Hood Thabit, Alexandra Lubina-Solomon, Marietta Stadler, Lalantha Leelarathna, Emma Walkinshaw, Andrew Pernet, Janet M Allen, Ahmed Iqbal, Pratik Choudhary, Kavita Kumareswaran, Marianna Nodale, Chloe Nisbet, Malgorzata E Wilinska, Katharine D Barnard, David B Dunger, Simon R Heller, Stephanie A Amiel, Mark L Evans, Roman Hovorka
Journal: The Lancet Diabetes & Endocrinology (2014)

Background Closed-loop insulin delivery is a promising option to improve glycaemic control and reduce the risk of hypoglycaemia.We aimed to assess whether overnight home use of automated closed-loop insulin delivery would improve glucose control. MethodsWe did this open-label, multicentre, randomised controlled, crossover study between Dec 1, 2012, and Dec 23, 2014, recruiting patients from three centres in the UK.Patients aged 18 years or older with type 1 diabetes were randomly assigned to receive 4 weeks of overnight closed-loop insulin delivery (using a model-predictive control algorithm to direct insulin delivery), then 4 weeks of insulin pump therapy (in which participants used real-time display of continuous glucose monitoring independent of their pumps as control), or vice versa.Allocation to initial treatment group was by computer-generated permuted block randomisation.Each treatment period was separated by a 3-4 week washout period.The primary outcome was time spent in the target glucose range of 3•9-8•0 mmol/L between 0000 h and 0700 h.Analyses were by intention to treat.This trial is registered with ClinicalTrials.gov,number NCT01440140. FindingsWe randomly assigned 25 participants to initial treatment in either the closed-loop group or the control group, patients were later crossed over into the other group; one patient from the closed-loop group withdrew consent after randomisation, and data for 24 patients were analysed.Closed loop was used over a median of 8•3 h (IQR 6•0-9•6) on 555 (86%) of 644 nights.The proportion of time when overnight glucose was in target range was signifi cantly higher during the closed-loop period compared to during the control period (mean diff erence between groups 13•5%, 95% CI 7•3-19•7; p=0•0002).We noted no severe hypoglycaemic episodes during the control period compared with two episodes during the closed-loop period; these episodes were not related to closed-loop algorithm instructions.Interpretation Unsupervised overnight closed-loop insulin delivery at home is feasible and could improve glucose control in adults with type 1 diabetes.
Tumor cell invasion of collagen matrices requires coordinate lipid agonist-induced G-protein and membrane-type matrix metalloproteinase-1-dependent signaling
Authors: Kevin E Fisher, Andreia Pop, Wonshill Koh, Nicholas J Anthis, W Brian Saunders, George E Davis
Journal: Molecular Cancer (2006)

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are bioactive lipid signaling molecules implicated in tumor dissemination. Membrane-type matrix metalloproteinase 1 (MT1-MMP) is a membrane-tethered collagenase thought to be involved in tumor invasion via extracellular matrix degradation. In this study, we investigated the molecular requirements for LPA- and S1P-regulated tumor cell migration in two dimensions (2D) and invasion of three-dimensional (3D) collagen matrices and, in particular, evaluated the role of MT1-MMP in this process.LPA stimulated while S1P inhibited migration of most tumor lines in Boyden chamber assays. Conversely, HT1080 fibrosarcoma cells migrated in response to both lipids. HT1080 cells also markedly invaded 3D collagen matrices (approximatly 700 microm over 48 hours) in response to either lipid. siRNA targeting of LPA1 and Rac1, or S1P1, Rac1, and Cdc42 specifically inhibited LPA- or S1P-induced HT1080 invasion, respectively. Analysis of LPA-induced HT1080 motility on 2D substrates vs. 3D matrices revealed that synthetic MMP inhibitors markedly reduced the distance (approximately 125 microm vs. approximately 45 microm) and velocity of invasion (approximately 0.09 microm/min vs. approximately 0.03 microm/min) only when cells navigated 3D matrices signifying a role for MMPs exclusively in invasion. Additionally, tissue inhibitors of metalloproteinases (TIMPs)-2, -3, and -4, but not TIMP-1, blocked lipid agonist-induced invasion indicating a role for membrane-type (MT)-MMPs. Furthermore, MT1-MMP expression in several tumor lines directly correlated with LPA-induced invasion. HEK293s, which neither express MT1-MMP nor invade in the presence of LPA, were transfected with MT1-MMP cDNA, and subsequently invaded in response to LPA. When HT1080 cells were seeded on top of or within collagen matrices, siRNA targeting of MT1-MMP, but not other MMPs, inhibited lipid agonist-induced invasion establishing a requisite role for MT1-MMP in this process.LPA is a fundamental regulator of MT1-MMP-dependent tumor cell invasion of 3D collagen matrices. In contrast, S1P appears to act as an inhibitory stimulus in most cases, while stimulating only select tumor lines. MT1-MMP is required only when tumor cells navigate 3D barriers and not when cells migrate on 2D substrata. We demonstrate that tumor cells require coordinate regulation of LPA/S1P receptors and Rho GTPases to migrate, and additionally, require MT1-MMP in order to invade collagen matrices during neoplastic progression.
The Carcinogenicity of Small Amounts of N-Hydroxy-2-acetylaminofluorene and Its Cupric Chelate in the Rat
Authors: James A. Miller, Makoto Enomoto, Elizabeth C. Miller
Journal: Cancer Research (1962)

Summary  The carcinogenic metabolite of 2-acetylaminofluorene (AAF),  N -hydroxy-2-acetylaminofluorene ( N -hydroxy-AAF), was active at relatively low doses in the induction of mammary carcinomas and subcutaneous sarcomas in the rat. The intraperitoneal injection of 4.2 mg. of  N -hydroxy-AAF into weanling rats caused mammary carcinomas to develop in ten of seventeen rats by 22 weeks. AAF at higher doses was shown previously to be considerably less active than equimolar doses of  N -hydroxy-AAF in the induction of mammary carcinomas under similar conditions. Young male rats which received a single subcutaneous injection of 3.2 mg. of  N -hydroxy-AAF developed no tumors at the injection site by 6 months. However, the same amount of  N -hydroxy-AAF, injected subcutaneously in the form of the poorly soluble cupric chelate, caused a high incidence of sarcomas within 5 months. Repeated subcutaneous injections of AAF, cupric oxide, and cupric acetate induced no tumors by 8 months, even though the total amounts of these compounds which were injected were 6 times the molar level of the single injection of the cupric chelate of  N -hydroxy-AAF. Analyses of the subcutaneous injection sites demonstrated that over 60 per cent of the cupric chelate of  N -hydroxy-AAF was retained at the site for 2 weeks, whereas none of the injected  N -hydroxy-AAF was detectable in the subcutaneous tissue 1 day later. These data constitute additional evidence that  N -hydroxy-AAF is a proximal carcinogenic metabolite of AAF in the rat.
Effect of naloxone on circadian rhythms in lung function.
Authors: S Al-Damluji, P J Thompson, K M Citron, M Turner-Warwick
Journal: Thorax (1983)

To determine whether the endogenous opioid peptides play a part in the pathogenesis of asthmatic morning dipping, six patients with chronic asthma with a reproducible peak flow pattern of morning dipping were investigated in a double blind, randomised, crossover study of naloxone versus placebo. Naloxone was given as a loading dose of 8 mg followed by a continuous infusion of 5.6 mg/h from midnight until 10 am on two consecutive nights. Naloxone had no significant effect on PEFR, FEV1, or FVC at 6 am. There was, however, an improvement over placebo values in all these indices between the hours of 8 am and 8 pm on the day after the first naloxone infusion in all six patients. This effect was not observed after the second naloxone infusion.
Relationship of Cytokine and Regulatory Gene Expression to the Outcomes of Milk and Egg Allergy in an Atopic Cohort (COFAR2)
Authors: S.H. Sicherer, D. Stablein, R.A. Wood, A.W. Burks, A.H. Liu, S.M. Jones, D.M. Fleischer, L. Mayer, R. Lindblad, A. Grishin, H.A. Sampson
Journal: Journal of Allergy and Clinical Immunology (2012)
Loss of Human Epidermal Growth Factor Receptor 2 (HER2) Expression in Metastatic Sites of HER2-Overexpressing Primary Breast Tumors
Authors: Naoki Niikura, Jun Liu, Naoki Hayashi, Elizabeth A. Mittendorf, Yun Gong, Shana L. Palla, Yutaka Tokuda, Ana M. Gonzalez-Angulo, Gabriel N. Hortobagyi, Naoto T. Ueno
Journal: Journal of Clinical Oncology (2011)

Purpose We evaluated whether patients with human epidermal growth factor receptor 2 (HER2) –positive primary breast tumors had metastatic tumors that were HER2 positive (concordant) or HER2 negative (discordant). We then evaluated whether treatment with trastuzumab or chemotherapy before biopsy of the metastasis had any effect on the rate of HER2 discordance. We also compared the overall survival durations of patients with HER2-concordant and -discordant tumors. Patients and Methods We retrospectively identified all patients who initially had been diagnosed with HER2-positive (immunohistochemistry 3+ and/or fluorescent in situ hybridization positive) primary breast cancer between 1997 and 2008 at MD Anderson Cancer Center who also had metastatic tumor biopsy results available for review. Results We included 182 patients who met our criteria. Forty-three (24%) of the 182 patients with HER2-positive primary tumors had HER2-negative metastatic tumors. The HER2 discordance rates differed significantly on the basis of whether patients received chemotherapy (P = .022) but not on the basis of whether patients received trastuzumab (P = .296). Patients with discordant HER2 status had shorter overall survival than did patients with concordant HER2 status (hazard ratio [HR], 0.43; P = .003). A survival difference remained among the 67 patients who received trastuzumab (HR, 0.56; P = .083) and 101 patients who did not (HR, 0.53; P = .033) before their metastasis biopsies. Conclusion We confirmed that loss of HER2-positive status in metastatic tumors can occur in patients with primary HER2-positive breast cancer. Our data strongly support the need for biopsies of metastatic lesions to accurately determine patient prognosis and appropriate use of targeted therapy.
Inhibition of Histone Deacetylation Potentiates the Evolution of Acquired Temozolomide Resistance Linked to MGMT Upregulation in Glioblastoma Xenografts
Authors: Gaspar J. Kitange, Ann C. Mladek, Brett L. Carlson, Mark A. Schroeder, Jenny L. Pokorny, Ling Cen, Paul A. Decker, Wenting Wu, Gwen A. Lomberk, Shiv K. Gupta, Raul A. Urrutia, Jann N. Sarkaria
Journal: Clinical Cancer Research (2012)

Abstract Purpose: The therapeutic benefit of temozolomide in glioblastoma multiforme (GBM) is limited by resistance. The goal of this study was to elucidate mechanisms of temozolomide resistance in GBM. Experimental Design: We developed an in vivo GBM model of temozolomide resistance and used paired parental and temozolomide-resistant tumors to define the mechanisms underlying the development of resistance and the influence of histone deacetylation (HDAC) inhibition. Results: Analysis of paired parental and resistant lines showed upregulation of O6-methylguanine-DNA methyltransferase (MGMT) expression in 3 of the 5 resistant xenografts. While no significant change was detected in MGMT promoter methylation between parental and derivative-resistant samples, chromatin immunoprecipitation showed an association between MGMT upregulation and elevated acetylation of lysine 9 of histone H3 (H3K9-ac) and decreased dimethylation (H3K9-me2) in GBM12 and GBM14. In contrast, temozolomide resistance development in GBM22 was not linked to MGMT expression, and both parental and resistant lines had low H3K9-ac and high H3K9-me2 within the MGMT promoter. In the GBM12TMZ-resistant line, MGMT reexpression was accompanied by increased recruitment of SP1, C-JUN, NF-κB, and p300 within the MGMT promoter. Interestingly, combined treatment of GBM12 flank xenografts with temozolomide and the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) favored the evolution of temozolomide resistance by MGMT overexpression as compared with treatment with temozolomide alone. Conclusion: This study shows, for the first time, a unique mechanism of temozolomide resistance development driven by chromatin-mediated MGMT upregulation and highlights the potential for epigenetically directed therapies to influence the mechanisms of resistance development in GBM. Clin Cancer Res; 18(15); 4070–9. ©2012 AACR.