tbuckley/cabot-search huggingface dataset:
Genomic Alterations in Tumor Stroma
Authors: Charis Eng, Gustavo Leone, Mohammed S. Orloff, Michael C. Ostrowski
Journal: Cancer Research (2009)

It was traditionally believed that the tumor was the seed that lay in the passive soil of the microenvironment, with the latter providing "permissive elements" for the tumor to grow and invade. Subsequently, it was recognized that both neoplasia and its microenvironment interacted as equal partners. Recent advances addressing genomic alterations in the tumor microenvironment, relevant to clinical outcome and treatment choices, are summarized. These include microenvironmental genomic alterations not only in different solid tumors, but also, rather surprisingly, in inflammatory bowel disease. These observations promise new biomarkers of prognosis and a new compartment to target therapy.
Memantine Treatment in Patients With Moderate to Severe Alzheimer Disease Already Receiving Donepezil
Authors: Pierre N. Tariot, Martin R. Farlow, George T. Grossberg, Stephen M. Graham, Scott McDonald, Ivan Gergel, None for the Memantine Study Group
Journal: JAMA (2004)

Memantine is a low- to moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist. Controlled trials have demonstrated the safety and efficacy of memantine monotherapy for patients with moderate to severe Alzheimer disease (AD) but no controlled trials of memantine in patients receiving a cholinesterase inhibitor have been performed.To compare the efficacy and safety of memantine vs placebo in patients with moderate to severe AD already receiving stable treatment with donepezil.A randomized, double-blind, placebo-controlled clinical trial of 404 patients with moderate to severe AD and Mini-Mental State Examination scores of 5 to 14, who received stable doses of donepezil, conducted at 37 US sites between June 11, 2001, and June 3, 2002. A total of 322 patients (80%) completed the trial.Participants were randomized to receive memantine (starting dose 5 mg/d, increased to 20 mg/d, n = 203) or placebo (n = 201) for 24 weeks.Change from baseline on the Severe Impairment Battery (SIB), a measure of cognition, and on a modified 19-item AD Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL19). Secondary outcomes included a Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), the Neuropsychiatric Inventory, and the Behavioral Rating Scale for Geriatric Patients (BGP Care Dependency Subscale).The change in total mean (SE) scores favored memantine vs placebo treatment for SIB (possible score range, 0-100), 0.9 (0.67) vs -2.5 (0.69), respectively (P<.001); ADCS-ADL19 (possible score range, 0-54), -2.0 (0.50) vs -3.4 (0.51), respectively (P =.03); and the CIBIC-Plus (possible score range, 1-7), 4.41 (0.074) vs 4.66 (0.075), respectively (P =.03). All other secondary measures showed significant benefits of memantine treatment. Treatment discontinuations because of adverse events for memantine vs placebo were 15 (7.4%) vs 25 (12.4%), respectively.In patients with moderate to severe AD receiving stable doses of donepezil, memantine resulted in significantly better outcomes than placebo on measures of cognition, activities of daily living, global outcome, and behavior and was well tolerated. These results, together with previous studies, suggest that memantine represents a new approach for the treatment of patients with moderate to severe AD.
Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity.
Authors: M Stumvoll, A Mitrakou, W Pimenta, T Jenssen, H Yki-Järvinen, T Van Haeften, W Renn, J Gerich
Journal: Diabetes Care (2000)

The oral glucose tolerance test (OGTT) has often been used to evaluate apparent insulin release and insulin resistance in various clinical settings. However, because insulin sensitivity and insulin release are interdependent, to what extent they can be predicted from an OGTT is unclear.We studied insulin sensitivity using the euglycemic-hyperinsulinemic clamp and insulin release using the hyperglycemic clamp in 104 nondiabetic volunteers who had also undergone an OGTT. Demographic parameters (BMI, waist-to-hip ratio, age) and plasma glucose and insulin values from the OGTT were subjected to multiple linear regression to predict the metabolic clearance rate (MCR) of glucose, the insulin sensitivity index (ISI), and first-phase (1st PH) and second-phase (2nd PH) insulin release as measured with the respective clamps.The equations predicting MCR and ISI contained BMI, insulin (120 min), and glucose (90 min) and were highly correlated with the measured MCR (r = 0.80, P < 0.00005) and ISI (r = 0.79, P < 0.00005). The equations predicting 1st PH and 2nd PH contained insulin (0 and 30 min) and glucose (30 min) and were also highly correlated with the measured 1st PH (r = 0.78, P < 0.00005) and 2nd PH (r = 0.79, P < 0.00005). The parameters predicted by our equations correlated better with the measured parameters than homeostasis model assessment for secretion and resistance, the delta30-min insulin/delta30-min glucose ratio for secretion and insulin (120 min) for insulin resistance taken from the OGTT.We thus conclude that predicting insulin sensitivity and insulin release with reasonable accuracy from simple demographic parameters and values obtained during an OGTT is possible. The derived equations should be used in various clinical settings in which the use of clamps or the minimal model would be impractical.
Development and Potential Clinical Uses of Human Prolactin Receptor Antagonists
Authors: Vincent Goffin, Sophie Bernichtein, Philippe Touraine, Paul A. Kelly
Journal: Endocrine Reviews (2005)

There is a large body of literature showing that prolactin (PRL) exerts growth-promoting activities in breast cancer, and possibly in prostate cancer and prostate hyperplasia. In addition, increasing evidence argues for the involvement of locally produced (autocrine) PRL, perhaps even more than pituitary-secreted (endocrine) PRL, in tumor growth. Because dopamine analogs are unable to inhibit PRL production in extrapituitary sites, alternative strategies need investigation. To that end, several PRL receptor antagonists have been developed by introducing various mutations into its natural ligands. For all but one of these analogs, the mechanism of action involves a competition with endogenous PRL for receptor binding. Such compounds are thus candidates to counteract the undesired actions of PRL, not only in tumors, but also in dopamine-resistant prolactinomas. In this review, we describe the different versions of antagonists that have been developed, with emphasis on the controversies regarding their characterization, and the limits for their potential development as a drug. The most recently developed antagonist, Δ1–9-G129R-hPRL, is the only one that is totally devoid of residual agonistic activity, meaning it acts as pure antagonist. We discuss to what extent this new molecule could be considered as a lead compound for inhibiting the actions of human PRL in the above-mentioned diseases. We also speculate on the multiple questions that could be addressed with respect to the therapeutic use of PRL receptor antagonists in patients.
Psychological changes and improvement in chronic airflow limitation after corticosteroid treatment.
Authors: D M Mitchell, P Gildeh, M Rehahn, A Dimond, J V Collins
Journal: Thorax (1984)

Corticosteroids may produce mood changes. This could account for improvement in patients with chronic airflow limitation following trials of oral corticosteroid treatment as mood elevation might improve performance in objective measurements. This proposition was tested in 21 patients with chronic airflow limitation, who underwent detailed psychological assessment during a randomised controlled double blind crossover trial of the effect of prednisolone 40 mg daily compared with that of a placebo. Self rating visual analogue scales for various qualities of mood were completed before the study and after each phase in addition to depression and psychological symptom questionnaires. After treatment with the placebo, patients showed increases in cheerfulness (p less than 0.01) and sociability (p less than 0.01) and a decrease in depression (p less than 0.01). After treatment with prednisolone there were increases in cheerfulness (p less than 0.01), optimism (p less than 0.01), activity (p less than 0.05), and sociability (p less than 0.02) and there was a decrease in depression (p less than 0.01). When placebo and prednisolone values were compared, however, there were no significant differences. Some patients showed improvements (greater than 20%) in peak expiratory flow, FEV1 or forced vital capacity (FVC) after prednisolone, but nearly all had improvements in at least one psychological test. There were no detectable associations between changes in objective measurements and changes in psychological test ratings. This study suggests that in patients with chronic obstructive lung disease significant psychological changes are no more likely to follow treatment with a corticosteroid than treatment with a placebo and that physiological improvement after corticosteroid treatment is not tied to psychological changes.
The influence of age and the level of arterial blood pressure on the changes in forearm blood flow resulting from sudden alterations in local vascular transmural pressure
Authors: P. H. FENTEM, J. M. YATES
Journal: Cardiovascular Research (1975)

Forearm blood flow was measured by venous occlusion plethysmography in normotensive subjects of various ages and in patients with treated or untreated hypertension. Brief exposure of one forearm to pressures below atmospheric was used to study the transient local changes in arterial inflow which occurred with changes in transmural pressure induced in this way. The increase in initial arterial inflow with such an exposure to suction in a group of young normotensive women was only slightly reduced in two groups of older women. However, a group of subjects with untreated hypertension showed a significantly smaller initial inflow during the suction. There was some indication that adequate treatment of high blood pressure might reverse this effect.
Alloantibody and Complement Promote T Cell–Mediated Cardiac Allograft Vasculopathy Through Noncanonical Nuclear Factor-κB Signaling in Endothelial Cells
Authors: Dan Jane-wit, Thomas D. Manes, Tai Yi, Lingfeng Qin, Pamela Clark, Nancy C. Kirkiles-Smith, Parwiz Abrahimi, Julie Devalliere, Gilbert Moeckel, Sanjay Kulkarni, George Tellides, Jordan S. Pober
Journal: Circulation (2013)

Cardiac allograft vasculopathy is the major cause of late allograft loss after heart transplantation. Cardiac allograft vasculopathy lesions contain alloreactive T cells that secrete interferon-γ, a vasculopathic cytokine, and occur more frequently in patients with donor-specific antibody. Pathological interactions between these immune effectors, representing cellular and humoral immunity, respectively, remain largely unexplored.We used human panel reactive antibody to form membrane attack complexes on allogeneic endothelial cells in vitro and in vivo. Rather than inducing cytolysis, membrane attack complexes upregulated inflammatory genes, enhancing the capacity of endothelial cells to recruit and activate allogeneic interferon-γ--producing CD4(+) T cells in a manner dependent on the activation of noncanonical nuclear factor-κB signaling. Noncanonical nuclear factor-κB signaling was detected in situ within endothelial cells both in renal biopsies from transplantation patients with chronic antibody-mediated rejection and in panel-reactive antibody--treated human coronary artery xenografts in immunodeficient mice. On retransplantation into immunodeficient hosts engrafted with human T cells, panel-reactive antibody--treated grafts recruited more interferon-γ--producing T cells and enhanced cardiac allograft vasculopathy lesion formation.Alloantibody and complement deposition on graft endothelial cells activates noncanonical nuclear factor-κB signaling, initiating a proinflammatory gene program that enhances alloreactive T cell activation and development of cardiac allograft vasculopathy. Noncanonical nuclear factor-κB signaling in endothelial cells, observed in human allograft specimens and implicated in lesion pathogenesis, may represent a target for new pharmacotherapies to halt the progression of cardiac allograft vasculopathy.
Bevacizumab in combination with paclitaxel for HER-2 negative metastatic breast cancer: an economic evaluation.
Authors: KJ Dedes, K Matter-Walstra, M Schwenkglenks, BC Pestalozzi, D Fink, TT Szucs
Journal: Cancer Research (2009)

Abstract Abstract #6104 Background: The addition of bevacizumab to weekly paclitaxel as primary chemotherapy for HER-2 negative metastatic breast cancer (MBC) prolongs progression-free survival without relevant increase of toxicity. However, the health economic implications of this costly treatment option have not yet been assessed.&amp;#x2028; Material and Methods: We constructed a Markov model comprising three health-states: stable or responsive disease, disease progression and death. Markov cohort simulation was used to follow the clinical course of typical patients with MBC. Cycle length was one month. Information on response rates, major adverse effects was derived, and transition probabilities were estimated, based on the results of the E2100 clinical trial. Direct costs of treatment, major adverse events, laboratory tests, and disease progression were assessed from the perspective of a Swiss statutory health insurance perspective. Utilities for health states were obtained from the literature. Costs are reported in 2008 Euros (EUR).&amp;#x2028; Results: Over the patients' lifetime, the addition of bevacizumab to weekly paclitaxel until disease progression is estimated to cost an additional 35'564 EUR and to yield a gain of 0.22 quality-adjusted life years (QALYs), resulting in an incremental cost-utility ratio of 164'921 EUR/QALY. In univariate and probabilistic sensitivity analyses, results showed a 95% CI from 117'998 to 484'251 EUR/QALY and were most sensitive to the cost of bevacizumab. Subgroup analysis indicated a more favourable cost-utility ratio (136'177 EUR/QALY, 95 % CI 97'999-435'823) in the age group &amp;lt; 50 years.&amp;#x2028; Discussion: Compared with commonly accepted willingness to pay thresholds in oncology, the addition 10 mg of bevacizumab per kilogram [body weight] to paclitaxel in MBC patients is expensive given the clinical benefit in terms of QALYs gained. Further research should consider patient age and alternative dosages for a more cost-effective utilisation of bevacizumab. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6104.
Farnesyltransferase Inhibitors Induce DNA Damage via Reactive Oxygen Species in Human Cancer Cells
Authors: Jingxuan Pan, Miaorong She, Zhi-Xiang Xu, Lily Sun, Sai-Ching Jim Yeung
Journal: Cancer Research (2005)

Abstract Farnesyltransferase inhibitors (FTIs) possess antitumor activity. Based on recent findings, we hypothesized that FTIs induce reactive oxygen species (ROS) that damage DNA, leading to DNA damage responses. To test this hypothesis, we investigated the effects of FTIs on the generation of ROS, DNA double-strand breaks (DSB), DNA damage responses, and RhoB, and the effects of quenching ROS on these FTI effects. We evaluated four FTIs in human cancer cell lines of different tissue origins. We found that FTIs induced ROS and DSBs. Suppressing expression of the β-subunit of farnesyltransferase with siRNA did not induce ROS, but slightly attenuated the ROS induced by FTIs. N-acetyl-l-cysteine (NAC), but not caspase inhibitors, blocked FTI-induced DSBs, suggesting that the DSBs were caused by ROS and did not result from apoptosis. The DSBs led to DNA damage responses. H2AX became phosphorylated and formed nuclear foci. The DNA-damage-sensing molecules involved were probably ataxia-telangiectasia mutated protein (ATM) and DNA-dependent protein kinase (DNA-PK) but not ATM- and Rad3-related protein (ATR). Key components of the homologous recombination and nonhomologous end joining repair pathways (DNA-PK, BRCA1, and NBS1) underwent phosphorylation and formed nuclear foci. RhoB, a mediator of the antineoplastic effect of FTIs and a protein inducible by DNA damage, was increased by FTIs. This increase was blocked by NAC. We concluded that FTIs induced oxidative DNA damage by inducing ROS and initiated DNA damage responses, including RhoB induction, and there was a complex relationship among FTIs, farnesyltransferase, ROS, and RhoB. Our data also imply that inhibitors of DNA repair may accentuate the clinical efficacy of FTIs.
Extracellular Nucleotides Induce Arterial Smooth Muscle Cell Migration Via Osteopontin
Authors: Hervé Chaulet, Claude Desgranges, Marie-Ange Renault, Françoise Dupuch, Gérome Ezan, Franck Peiretti, Gervaise Loirand, Pierre Pacaud, Alain-Pierre Gadeau
Journal: Circulation Research (2001)

Migration and proliferation of arterial smooth muscle cells (SMCs) play a prominent role in the development of atherosclerotic plaques and restenosis lesions. Most of the growth-regulatory molecules potentially involved in these pathological conditions also demonstrate chemotactic properties. Extracellular purine and pyrimidine nucleotides have been shown to induce cell cycle progression and to elicit growth of cultured vascular SMCs. Moreover, the P2Y 2 ATP/UTP receptor was overexpressed in intimal thickening, suggesting a role of these nucleotides in vascular remodeling. Using the Transwell system migration assay, we demonstrate that extracellular ATP, UTP, and UDP exhibit a concentration-dependent chemotactic effect on cultured rat aortic SMCs. UTP, the most powerful nucleotide inducer of migration, elicited significant responses from 10 nmol/L. In parallel, UTP increased osteopontin expression dose-dependently. The blockade of osteopontin or its integrin receptors α v β 3 /β 5 by specific antibodies or antagonists inhibited UTP-induced migration. Moreover, the blockade of ERK-1/ERK-2 MAP kinase or rho protein pathways led to the inhibition of both UTP-induced osteopontin increase and migration, demonstrating the central role of osteopontin in this process. Taken together, these results suggest that extracellular nucleotides, and particularly UTP, can induce arterial SMC migration via the action of osteopontin.
A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model
Authors: Rolf Postina, Anja Schroeder, Ilse Dewachter, Juergen Bohl, Ulrich Schmitt, Elzbieta Kojro, Claudia Prinzen, Kristina Endres, Christoph Hiemke, Manfred Blessing, Pascaline Flamez, Antoine Dequenne, Emile Godaux, Fred van Leuven, Falk Fahrenholz
Journal: Journal of Clinical Investigation (2004)

Alzheimer disease (AD) is characterized by excessive deposition of amyloid beta-peptides (A beta peptides) in the brain. In the nonamyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by the alpha-secretase within the A beta peptide sequence. Proteinases of the ADAM family (adisintegrin and metalloproteinase) are the main candidates as physiologically relevant alpha-secretases, but early lethality of knockout animals prevented a detailed analysis in neuronal cells. To overcome this restriction, we have generated transgenic mice that overexpress either ADAM10 or a catalytically inactive ADAM10 mutant. In this report we show that a moderate neuronal overexpression of ADAM10 in mice transgenic for human APP([V717I]) increased the secretion of the neurotrophic soluble alpha-secretase-released N-terminal APP domain (APPs alpha), reduced the formation of A beta peptides, and prevented their deposition in plaques. Functionally, impaired long-term potentiation and cognitive deficits were alleviated. Expression of mutant catalytically inactive ADAM10 led to an enhancement of the number and size of amyloid plaques in the brains of double-transgenic mice. The results provide the first in vivo evidence for a proteinase of the ADAM family as an alpha-secretase of APP, reveal activation of ADAM10 as a promising therapeutic target, and support the hypothesis that a decrease in alpha-secretase activity contributes to the development of AD.
Patients with gastro-oesophageal reflux disease and cough have impaired laryngopharyngeal mechanosensitivity
Authors: S Y Phua
Journal: Thorax (2005)

In the second of four articles, the authors discuss the "estimation" approach to interpreting study results. Whereas, in hypothesis testing, study results lead the reader to reject or accept a null hypothesis, in estimation the reader can assess whether a result is strong or weak, definitive or not. A confidence interval, based on the observed result and the size of the sample, is calculated. It provides a range of probabilities within which the true probability would lie 95% or 90% of the time, depending on the precision desired. It also provides a way of determining whether the sample is large enough to make the trial definitive. If the lower boundary of a confidence interval is above the threshold considered clinically significant, then the trial is positive and definitive, if the lower boundary is somewhat below the threshold, the trial is positive, but studies with larger samples are needed. Similarly, if the upper boundary of a confidence interval is below the threshold considered significant, the trial is negative and definitive. However, a negative result with a confidence interval that crosses the threshold means that trials with larger samples are needed to make a definitive determination of clinical importance.
Efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis and a previous inadequate response to disease-modifying antirheumatic drugs: the ROSE study
Authors: Yusuf Yazici, Jeffrey R Curtis, Akgun Ince, Herbert Baraf, Raymond L Malamet, Lichen L Teng, Arthur Kavanaugh
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> To evaluate efficacy of tocilizumab in US patients with moderate to severe active rheumatoid arthritis (RA) and inadequate clinical response to disease-modifying antirheumatic drugs (DMARD). Safety-related outcomes were also analysed. <h3>Methods</h3> The rapid onset and systemic efficacy study was a 24-week, randomised, double-blind trial. Patients were randomly assigned 2:1 to tocilizumab 8 mg/kg (n=412) or placebo (n=207) every 4 weeks while continuing background DMARD in both groups. <h3>Results</h3> The primary efficacy endpoint, percentage of patients achieving ACR50 response at week 24, was higher with tocilizumab versus placebo (30.1% vs 11.2%; p&lt;0.0001). Percentages of ACR20 and ACR50 responders were significantly higher with tocilizumab versus placebo as early as week 4 and continued to week 24; more patients in the tocilizumab versus placebo group also achieved ACR70 responses beginning at week 8 (p&lt;0.01). Significant improvements associated with tocilizumab versus placebo were seen in routine assessment of patient index data responses, EULAR good response, DAS28 and percentages of patients achieving low disease activity and clinical remission (based on DAS28). A substudy examining early response to therapy showed improved patient global assessment of disease activity (p=0.005) and pain (p=0.01) and DAS28 (p=0.007) with tocilizumab versus placebo at day 7. Safety findings were consistent with the known tocilizumab safety profile; rates of serious infections (per 100 patient-years) were 7.87 (95% CI 4.30 to 13.2) and 1.20 (95% CI 0.03 to 6.66) in the tocilizumab and placebo groups, respectively. <h3>Conclusions</h3> This study demonstrated the efficacy of tocilizumab in improving measures of disease activity in patients with RA who failed to respond adequately to DMARD therapy. Rapid improvement in clinical outcomes was demonstrated in a substudy as early as week 1 as shown by DAS28 scores, patient measures and C-reactive protein. <h3>Trial Registry no</h3> NCT00531817