tbuckley/cabot-search huggingface dataset:
In vivo response-adapted dose-dense (dd) doxorubicin and cyclophosphamide (AC) –&gt; weekly carboplatin and albumin-bound paclitaxel (nab-TC)/trastuzumab (H)/bevacizumab (B) in large and inflammatory breast cancer (BC): A phase II study
Authors: J. A. Bernstein, R. Mehta
Journal: Journal of Clinical Oncology (2007)

11078 Background: We showed high pathologic complete remission (pCR) rate with dd AC weekly (wkly) cremophor(c)-TCH in HER2+ BC in contrast to dd AC c-TC in HER2- BC (SABCS 2005). We substituted nab-T for c-T, and added B in HER2- BC to exploit the known synergy between the two in preclinical models. Methods: Pts received in vivo response-adapted 2–4 cycles of AC with G/GM-CSF followed by wkly 9–12 nab-T at 100 mg/m2 and C (AUC of 2), 3 wks on, 1 wk off. HER2+ patients (pts) received concurrent 12–16 wkly H (4mg/kg induction, 2mg/kg maintenance) and HER2- pts received 6–8 bi-wkly B (10 mg/kg). 37 of the proposed 43 pts with stage II-IV BC have been enrolled. Median age is 53 (range 32–76). Results: Median ejection fraction by echocardiogram was 67% (55–78) at baseline, 65% (55–80) after 2 cycles of dd AC and 66% (55–68) following nab-TCH. Additionally, no clinical cardiac dysfunction demonstrated. Adverse event with dd AC included neutropenic fever in 2 pts. 8 of 88 dd AC cycles administered were delayed by =1 wk. Of the 37 pts evaluated, 30 were switched to nab-TCH/TCB after 2 cycles of AC for less than 50% tumor reduction and 7 completed 4 cycles. Adverse event with nab- TCH/TCB included grade III arthralgia in 2 pts and TIA in 1 pt. pCR was documented in 5 of 8 HER2+ after nab-TCH, and 3 of 10 HER2- tumors after nab-TCB. Across the spectrum of stage II-IV, inflammatory and lobular carcinoma, tumors were reduced to ≤ 5 mm in first 7 of 8 (87.5%) HER2+ and 8 of 10 (80%) HER2- BC. Progression free survival at a median follow-up of 6 months (range 2–15 month) remains 100%. Conclusion: Induction chemotherapy with dd AC followed by wkly targeted chemotherapy is well tolerated. Additionally, limiting the exposure of AC to 2 cycles in resistant BC may reduce the known cumulative cardiac toxicity and yet allow the targeting of different clones in a heterogeneous BC population. [Table: see text]
Airway gene expression in COPD is dynamic with inhaled corticosteroid treatment and reflects biological pathways associated with disease activity
Authors: Maarten van den Berge, Katrina Steiling, Wim Timens, Pieter S Hiemstra, Peter J Sterk, Irene H Heijink, Gang Liu, Yuriy O Alekseyev, Marc E Lenburg, Avrum Spira, Dirkje S Postma
Journal: Thorax (2013)

<h3>Background</h3> A core feature of chronic obstructive pulmonary disease (COPD) is the accelerated decline in forced expiratory volume in one second (FEV<sub>1</sub>). The recent Groningen and Leiden Universities study of Corticosteroids in Obstructive Lung Disease (GLUCOLD) study suggested that particular phenotypes of COPD benefit from fluticasone±salmeterol by reducing the rate of FEV<sub>1</sub> decline, yet the underlying mechanisms are unknown. <h3>Methods</h3> Whole-genome gene expression profiling using the Affymetrix Gene ST array (V.1.0) was performed on 221 bronchial biopsies available from 89 COPD patients at baseline and after 6 and 30 months of fluticasone±salmeterol and placebo treatment in GLUCOLD. <h3>Results</h3> Linear mixed effects modelling revealed that the expression of 138 genes decreased, whereas the expression of 140 genes significantly upregulated after both 6 and 30 months of treatment with fluticasone±salmeterol versus placebo. A more pronounced treatment-induced change in the expression of 50 and 55 of these 278 genes was associated with a lower rate of decline in FEV<sub>1</sub> and Saint George Respiratory Questionnaire, respectively. Genes decreasing with treatment were involved in pathways related to cell cycle, oxidative phosphorylation, epithelial cell signalling, p53 signalling and T cell signalling. Genes increasing with treatment were involved in pathways related to focal adhesion, gap junction and extracellular matrix deposition. Finally, the fluticasone-induced gene expression changes were enriched among genes that change in the airway epithelium in smokers with versus without COPD in an independent data set. <h3>Conclusions</h3> The present study suggests that gene expression in biological pathways of COPD is dynamic with treatment and reflects disease activity. This study opens the gate to targeted and molecular phenotype-driven therapy of COPD.
Combination of Bevacizumab and Chemotherapy for Platinum-Resistant Recurrent Ovarian Cancer: Some Observations About the AURELIA Trial
Authors: Federica Tomao, Silverio Tomao, Pierluigi Benedetti Panici
Journal: Journal of Clinical Oncology (2014)

the authors stated that AURELIA (A Study of Bevaczumab [Avastin] Added to Chemotherapy in Patients With Platinum-Resistant Ovarian Cancer) is the first trial to demonstrate a significant progression-free survival benefit of either a combination regimen or a biologic agent in platinum-resistant ovarian cancer.This attractive result confirms that combining single-agent chemotherapy with biologic agents could be a novel strategy in the treatment of platinum-resistant disease.In our opinion, using the same bevacizumab dose (10 mg) in all three arms would have been preferable to administering the drug every 14 days, even in the topotecan arm (or 15 mg every 3 weeks in all three arms).A recent meta-analysis indicated that there was no significative difference between the high and low doses of bevacizumab, indicating that dose regimens may not alter the association of bevacizumab with risk of fatal adverse effects. 2 In the AURELIA trial, patients who had received more than two prior anticancer regimens were ineligible.It is likely that almost all of the patients had received one or two lines of treatment with taxanes; therefore, we believe that in the study it would have been better to exclude the arm with paclitaxel, perhaps using another drug active in ovarian cancer.Moreover, a meta-analysis by Huang et al 2 and another study 3 found significant difference in risk of fatal adverse effects with bevacizumab when used in different chemotherapeutic regimens.Treatment with bevacizumab in combination with taxanes resulted in more toxic effects than bevacizumab combined with other agents.A randomized clinical trial comparing bevacizumab plus paclitaxel with bevacizumab plus capecitabine reported that the risk of chemotherapy discontinuation for adverse effects was twice as high with paclitaxel compared with capecitabine. 4The RIBBON-1 study (Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Chemotherapy With or Without Bevacizumab for First-Line Treatment of Human Epidermal Growth Factor Receptor 2-Negative, Locally Recurrent or Metastatic Breast Cancer) 5 and a recent meta-analysis 6 also confirmed that the use of bevacizumab significantly increased the risk of GI perforation when used in conjunction with taxanes.These data should advise against the use of taxanes in association with bevacizumab in second-or third-line chemotherapy schedules for platinum-resistant recurrent ovarian cancer.Also, if the safety data of AURELIA trial are favorable, it nevertheless would be interesting in this context to know, for example, what drugs and regimens caused the occurrence of fatal adverse effects in the two treatment arms (five deaths in each arm).
Effects of inhaled human insulin on airway lining fluid composition in adults with diabetes
Authors: M. C. Liu, R. J. Riese, K. Van Gundy, P. Norwood, B. E. Sullivan, P. F. Schwartz, J. G. Teeter
Journal: European Respiratory Journal (2008)

Inhaled human insulin (Exubera® (human insulin of rDNA origin) Inhalation Powder) causes small, early and reversible changes in pulmonary function in subjects with diabetes mellitus. The present study assessed whether changes occur in cellular and soluble constituents of airway lining fluid consistent with inflammation as a possible cause for Exubera®-associated lung function alterations. Two 31-week, open-label, sequential design phase 2 studies were conducted, one with 20 subjects with type 1 and one with 24 subjects with type 2 diabetes. After run-in, all subjects received subcutaneous insulin for 12 weeks, followed after 1 week by 12 weeks of Exubera®. Bronchoalveolar lavage fluid cell counts and protein constituents were determined at baseline, after 12 weeks of subcutaneous insulin and after 12 weeks of Exubera®. Baseline cellular and soluble constituents of lavage fluid were similar to those reported for nondiabetic adults. Exubera® produced no consistent clinically or statistically significant changes in total or differential lavage fluid cell counts or protein concentrations, even though Exubera®-associated changes in pulmonary function are known to be fully manifest within 12 weeks. Therefore, 12 weeks of Exubera® treatment is not associated with evidence of pulmonary inflammation. The treatment effects on lung function observed in Exubera® trials are not caused by lung inflammation.
Ionic Mechanisms Responsible for the Electrocardiographic Phenotype of the Brugada Syndrome Are Temperature Dependent
Authors: Robert Dumaine, Jeffrey A. Towbin, Pedro Brugada, Matteo Vatta, Dmitri V. Nesterenko, Vladislav V. Nesterenko, Josep Brugada, Ramon Brugada, Charles Antzelevitch
Journal: Circulation Research (1999)

Abstract —The Brugada syndrome is a major cause of sudden death, particularly among young men of Southeast Asian and Japanese origin. The syndrome is characterized electrocardiographically by an ST-segment elevation in V1 through V3 and a rapid polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation. Our group recently linked the disease to mutations in SCN5A , the gene encoding for the α subunit of the cardiac sodium channel. When heterologously expressed in frog oocytes, electrophysiological data recorded from the Thr1620Met missense mutant failed to adequately explain the electrocardiographic phenotype. Therefore, we sought to further characterize the electrophysiology of this mutant. We hypothesized that at more physiological temperatures, the missense mutation may change the gating of the sodium channel such that the net outward current is dramatically augmented during the early phases of the right ventricular action potential. In the present study, we test this hypothesis by expressing Thr1620Met in a mammalian cell line, using the patch-clamp technique to study the currents at 32°C. Our results indicate that Thr1620Met current decay kinetics are faster when compared with the wild type at 32°C. Recovery from inactivation was slower for Thr1620Met at 32°C, and steady-state activation was significantly shifted. Our findings explain the features of the ECG of Brugada patients, illustrate for the first time a cardiac sodium channel mutation of which the arrhythmogenicity is revealed only at temperatures approaching the physiological range, and suggest that some patients may be more at risk during febrile states.
Initial antibiotic therapy for lower respiratory tract infection in the community: a European survey
Authors: GJ Huchon, G Gialdroni-Grassi, P Leophonte, F Manresa, T Schaberg, M Woodhead
Journal: European Respiratory Journal (1996)

A survey of first-line antibiotic prescription in community-acquired lower respiratory tract infection (LRTI) by general practitioners (GP) was carried out simultaneously, using the same methodology in France, Germany, Italy, Spain and the UK. Data were obtained from 2,056 patients and 605 GPs. There was no antibiotic prescription in 17% of all LRTIs and 13% of community-acquired pneumonia (CAP) in the five countries taken together; and in 32% of all LRTIs and in 23% of CAP in Germany. Of patients with acute bronchitis, exacerbation of chronic bronchitis and viral lower respiratory tract infection, 87, 92 and 71% received antibiotics, respectively. The most frequent prescriptions were penicillins in France and the UK, third-generation cephalosporin in Italy, tetracycline in Germany and macrolide in Spain. The daily dosage of aminopenicillin prescribed was: 41% &lt;1.5 g; 49% &gt; or = 1.5 g and &lt;3 g; and 10% &gt; or = 3 g. In Italy, 53% of all antibiotics were injected in all LRTIs, and 71% in CAP; in contrast, antibiotic injection was lower than 2% both in the UK and Germany, with an average of 14% in the five countries combined. We conclude that there are variations in antibiotic prescription by GPs in Western Europe; differences are likely to be multifactorial, but could, in part, be explained by differences in health systems and sources of information available to GPs.
Bile acid-induced modifications in DNA synthesis by the regenerating perfused rat liver
Authors: Jose J. G. Marin, Emilio R. Barbero, Maria C. Herrera, Arantxa Tabernero, Maria J. Monte
Journal: Hepatology (1993)

Liver cell proliferation is a complex process that can be affected by a large number of factors such as bile acids, which have been reported to be associated to the pathogenesis of liver cancer. In this work, bile acid-induced modifications in DNA synthesis by regenerating perfused rat liver were investigated. Two-thirds hepatectomy was carried out 24 hr before perfusion of liver with recirculating, erythrocyte-free Krebs-Henseleit solution. The viability of the preparations was maintained under all experimental conditions, as indicated by bile flow, oxygen uptake, perfusion pressure, perfusion flow and release of lactate dehydrogenase and potassium into the perfusate. Livers received (min 10 to min 60) bile acid infusion at a rate of 25 nmol/min/gm liver (i.e., maximal secretion rate/2) in regenerating livers as calculated for taurocholate in separate experiments). Trace amounts of [methyl-14C]thymidine were added to the perfusate at min 30. At the end of the experiments (min 60) the livers were washed, removed, weighed and homogenized to determine radioactivity in whole tissue, in DNA and in non-DNA-related fractions. Taurocholate and, to a lesser extent, taurodeoxycholate and dehydrocholate (but not ursodeoxycholate) were found to reduce 14C incorporation into DNA. This was not due to changes in the content of 14C in whole, regenerating liver tissue. Taurocholate, taurodeoxycholate, dehydrocholate and ursodeoxycholate had no effect on thymidine uptake; moreover, the proportion of 14C found in bile was negligible. However, bile acid-induced modification in the fate of intracellular thymidine was observed. In regenerating livers receiving no bile acid, the 14C carried by thymidine metabolites accounted for about 60% of 14C in whole liver tissue. Taurocholate markedly increased this proportion to about 80%. Reverse-phase high-pressure liquid chromatography revealed that most of this 14C (about 80%) was recovered at the elution time, corresponding to thymidine catabolites rather than to DNA precursors. These results suggest that bile acids induce enhancement of thymidine catabolism that reduces its incorporation into DNA; inhibition in the process of DNA synthesis itself, leading to a subsequent increase in the metabolism of DNA precursors; or both. Moreover, from the diversity in this property for bile acid species it might be inferred that changes in the composition and size of the bile acid pool during liver carcinogenesis or regeneration play a role in the modulation of the proliferative process.
Monocyte chemotactic protein 1 is a potent activator of human basophils.
Authors: S C Bischoff, M Krieger, T Brunner, C A Dahinden
Journal: The Journal of Experimental Medicine (1992)

Cytokines belonging to the RANTES/SIS family are highly induced in a number of pathophysiological processes such as autoimmune disorders, cancers, atherosclerosis, and chronic inflammation. However, apart from their chemotactic activity on monocytes and particular lymphocyte types, the biological activities in the human system of this recently discovered cytokine family are largely unknown. Here we report that one family member, described as monocyte chemotactic protein 1 (MCP-1), strongly activates mature human basophils in a pertussis toxin-sensitive manner. MCP-1 causes a rise in the cytosolic free calcium level in basophils and monocytes, but not in other blood leukocyte types, and triggers basophil degranulation at low concentrations (ED50 = 3-10 nM). Thus, MCP-1 is a cytokine capable of directly inducing histamine release by basophils. Furthermore, MCP-1 promotes the formation of leukotriene C4 by basophils pretreated with interleukin 3 (IL-3), IL-5, or granulocyte/macrophage colony-stimulating factor. MCP-1-induced basophil mediator release may play an important role in allergic inflammation and other pathologies expressing MCP-1.
Association Between a Functional Catechol <i>O</i>-Methyltransferase Gene Polymorphism and Schizophrenia: Meta-Analysis of Case-Control and Family-Based Studies
Authors: Stephen J. Glatt, Stephen V. Faraone, Ming T. Tsuang
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: There is strong evidence for a genetic contribution to schizophrenia, but efforts to identify susceptibility genes have been largely unsuccessful because of the low power of individual studies. The authors' goal was to evaluate the collective evidence for an association between the Val158/108Met polymorphism of the catechol O-methyltransferase (COMT) gene and schizophrenia. METHOD: They performed separate meta-analyses of existing case-control and family-based association studies. RESULTS: Overall, case-control studies showed no indication of an association between either allele and schizophrenia, and family-based studies found modest evidence implicating the Val allele in schizophrenia risk. The pooled analyses of studies from diverse geographical regions may have obscured ethnic differences in patterns of genetic risk for schizophrenia. Stratification of the studies by ethnicity of the subjects yielded evidence for an association with the Val allele in case-control studies of European samples and, especially, in family-based studies of European samples. Case-control and family-based studies of Asian samples produced mixed results and, overall, little evidence for association. CONCLUSIONS: The results of the two types of association studies diverged somewhat, but the evidence from the family-based studies, although based on fewer reports, may be more accurate. The Val allele may be a small but reliable risk factor for schizophrenia for people of European ancestry, but the influence of this polymorphism on risk in Asian populations remains unclear. These results call for more family-based studies to confirm the association between COMT and schizophrenia in European samples and to clarify its contribution to risk in Asian samples. They also suggest that case-control studies should use methods of genomic control to avoid being confounded by population stratification.
The metabolic basis of dual periodicity of feeding in rats
Authors: Jacques Le Magnen
Journal: Behavioral and Brain Sciences (1981)

Abstract This article examines how the depletion and replenishment of various energy stores give rise to periodic eating and how constant body-energy levels are maintained over time. Measures of the energy expended throughout the 24-hour feeding pattern in rats indicate that two different energy stores (one of small capacity and one of large) determine two superimposed feeding periodicities: one from meal to meal (prandial), the other from day to night (nycthemeral). The article reviews how experimental overrepletion or overdepletion of gastrointestinal content, blood glucose, or body fats affect food intake. These data suggest that gastrointestinal content determines both meal size and meal-to-meal periodicity. Other evidence indicates that glucose uptake rate in tissues, which is modulated by fat synthesis and fat mobilization, affects the periodic onset of feeding and the difference between nocturnal and diurnal postprandial satiety. There follows an examination of the neuroendocrine bases for the interacting mechanisms governing energy input and output balance and of the role of the ventromedial hypothalamus in body-fat regulation and the lateral hypothalamus in feeding.
Strategic Approach to Fit-for-Purpose Biomarkers in Drug Development
Authors: John A. Wagner
Journal: The Annual Review of Pharmacology and Toxicology (2007)

The strategic, fit-for-purpose use of the combination of robust target engagement and well-qualified disease-related biomarkers enhances understanding of the mechanism of action, ties together preclinical and clinical data, enables the assessment of target engagement, facilitates early proof of concept and dose focusing, and increases the efficiency of early clinical development with improved quality of decision making. Significant progress in biomarker discovery, validation, and qualification has increased drug-development decision making and regulatory applications. Target engagement biomarkers are present early in a pathophysiologic cascade and inform on physical or biological interactions with the molecular target of the drug. Disease-related biomarkers are present late in the pathophysiologic cascade and are linked to clinical benefit; thus, they assess a drug's effect on a particular disease. Together, these concepts lay the groundwork for high-quality drug-development decision making and a framework for the acceptance and qualification of biomarkers for regulatory use.
Immunity to Citrullinated Proteins in Rheumatoid Arthritis
Authors: Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, Lars Alfredsson
Journal: Annual Review of Immunology (2008)

Antibodies to citrullinated proteins (ACPA), i.e., to peptides posttranslationally modified by the conversion of arginine to citrulline, are specific serological markers for rheumatoid arthritis (RA). Studies on anticitrulline immunity, summarized in this review, demonstrate that the criterion-based syndrome RA should be subdivided into at least two distinct subsets (ACPA-positive and ACPA-negative disease). A new etiological model is proposed for ACPA-positive RA, built on MHC class II–dependent activation of adaptive immunity. Fundamentals of this model include the following: (a) ACPA antedate onset of arthritis; (b) ACPA may aggravate arthritis in rodents; (c) ACPA are triggered in the context of genes that confer susceptibility to RA (HLA-DRB1 SE) and by environmental agents triggering RA (smoking or bacterial stimuli); (d) ACPA may complex with citrullinated proteins present in target tissue as part of a multistep process for arthritis development. The model provides a new basis for molecular studies on the pathogenesis of ACPA-positive arthritis.