tbuckley/cabot-search huggingface dataset:
Abstract B67: IG-001: A non-biologic nanoparticle paclitaxel for the treatment of ovarian cancer
Authors: Larn Hwang, Catherine Cheng, Vuong Trieu
Journal: Clinical Cancer Research (2013)

Abstract Introduction: IG-001(Genexol-PM), like nab-paclitaxel, is a polymer bound nanoparticle paclitaxel. IG-001 utilizes biodegradable di-block copolymer composed of methoxy poly (ethylene glycol)-poly (lactide) to form nanoparticles with Paclitaxel containing hydrophobic core and a hydrophilic shell. IG-001 is being developed for difficult to perfuse hypoxic tumors such as pancreatic cancer and ovarian cancer. Methods: Clinical efficacy was evaluated across multiple cancer indications including metastatic breast cancer (MBC), non small cell lung cancer (NSCLC), pancreatic cancer and ovarian cancer. Phase I ovarian trial design: six patients/dose level were treated with IG-001 at 220, 260, and 300 mg/m2. Phase II ovarian trial design: randomized, two-arm trial, primary advanced epithelial ovarian cancer consisting of 100 pts (50/each arm). Control Arm: Solvent based paclitaxel 175mg/m2 IV + Carboplatin 5 AUC IV, 3 weeks, 6 cycles and Experimental Arm: IG-001 260mg/m2 IV + Carboplatin 5 AUC IV 3 weeks, 6 cycles. Phase III ovarian trial design- planning phase to consist of therapeutic drug monitoring and biomarker testing. Results: Clinical trials conducted with IG-001 demonstrated significant antitumor activities comparable to historical data for Abraxane. Across three cancer indications (MBC, NSCLC, and Pancreatic Cancer), IG-001 was more active than historical Taxol. Since Pancreatic Cancer is known to be poorly-perfused, IG-001 activity in this indication is consistent with it being able to penetrate poorly-perfused tumors. Conclusions: IG-001 is effective across multiple cancer indications. Clinical development of IG-001 in ovarian cancer is ongoing. Phase I data was encouraging and phase II data forthcoming. IG-001 could be considered to be superior to Cremophore based paclitaxel because of the possibilities of delivering higher paclitaxel dose without additional toxicities. Phase III trial design incorporating therapeutic drug monitoring and biomarker testing should further improve on IG-001 clinical activities. Citation Format: Larn Hwang, Catherine Cheng, Vuong Trieu. IG-001: A non-biologic nanoparticle paclitaxel for the treatment of ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B67.
Two kinds of theory-laden cognitive processes: Distinguishing intransigence from dogmatism
Authors: Elias L. Khalil
Journal: Behavioral and Brain Sciences (2013)

The brain is involved in theory-laden cognitive processes. But there are two different theory-laden processes. In cases where the theory is based on facts, more facts can either falsify or confirm a theory. In cases where the theory is about the choice of a benchmark or a standard, more facts can only make a theory either more or less warranted.
Carbon monoxide in breath in relation to smoking and carboxyhaemoglobin levels.
Authors: N J Wald, M Idle, J Boreham, A Bailey
Journal: Thorax (1981)

Carboxyhaemoglobin (COHb) levels were studied in 11 249 men. The distribution among the 2613 men who smoked cigarettes was well separated from that in 6641 non-smokers (including ex-smokers). The distribution for 2005 cigar and pipe smokers was intermediate, though some of the highest COHb levels occurred in cigar smokers. Using a COHb cut-off level of 2%, 81% of cigarette smokers, 35% of cigar and pipe smokers, and 1.0% of non-smokers had raised COHb levels. In a subsidiary experiment alveolar air samples were collected from 162 smokers and 25 non-smokers using a simple breath sampling technique. Carbon monoxide concentrations in alveolar breath were highly correlated with COHb levels (r = 0.97) indicating that COHb levels can be estimated reliably by measuring the concentration of carbon monoxide in breath. Alveolar carbon monoxide measurement is thus a simple method of estimating whether a person is likely to be a smoker.
The Use of Alternate, Non–Cross-Resistant Adjuvant Chemotherapy on the Basis of Pathologic Response to a Neoadjuvant Doxorubicin-Based Regimen in Women With Operable Breast Cancer: Long-Term Results From a Prospective Randomized Trial
Authors: Eva Thomas, Frankie A. Holmes, Terry L. Smith, Aman U. Buzdar, Debra K. Frye, Giuseppe Fraschini, S. Eva Singletary, Richard L. Theriault, Marsha D. McNeese, Frederick Ames, Ronald Walters, Gabriel N. Hortobagyi
Journal: Journal of Clinical Oncology (2004)

Purpose To evaluate the use of an alternate, non–cross-resistant adjuvant chemotherapy regimen in women with a poor pathologic response to a preoperative doxorubicin-based regimen. Patients and Methods Patients with locally advanced breast cancer received three cycles of vincristine, doxorubicin, cyclophosphamide, and prednisone (VACP) every 21 days followed by surgery. Patients with less than 1 cm 3 residual tumor at mastectomy received an additional five cycles of VACP. Those with more than 1 cm 3 residual tumor were randomly assigned to receive an additional five cycles of VACP or five cycles of vinblastine, methotrexate with calcium leucovorin rescue, and fluorouracil (VbMF). Results One hundred ninety-three patients were evaluable. Overall clinical response was seen in 83.4% after three cycles of VACP, whereas the pathologic complete response was 12.2%. One hundred six patients were randomly assigned to VACP or VbMF. Those receiving VbMF achieved higher relapse-free survival (RFS) and overall survival (OS) than those who received additional VACP, although the differences did not reach statistical significance. Initial stage of tumor, clinical complete response, and pathologic complete response were all associated with statistically superior survival rates. Conclusion Clinical and pathologic response to preoperative doxorubicin-based chemotherapy predicted for improved survival in women with operable breast cancer. For those with a poor response to initial neoadjuvant chemotherapy, treatment with VbMF was associated with a trend toward improved RFS and OS compared with those continuing with the doxorubicin regimen.
Adolescent body mass index and erythrocyte sedimentation rate in relation to colorectal cancer risk
Authors: Elizabeth D Kantor, Ruzan Udumyan, Lisa B Signorello, Edward L Giovannucci, Scott Montgomery, Katja Fall
Journal: Gut (2015)

Adult obesity and inflammation have been associated with risk of colorectal cancer (CRC); however, less is known about how adolescent body mass index (BMI) and inflammation, as measured by erythrocyte sedimentation rate (ESR), relate to CRC risk. We sought to evaluate these associations in a cohort of 239 658 Swedish men who underwent compulsory military enlistment examinations in late adolescence (ages 16-20 years).At the time of the conscription assessment (1969-1976), height and weight were measured and ESR was assayed. By linkage to the national cancer registry, these conscripts were followed for CRC through 1 January 2010. Over an average of 35 years of follow-up, 885 cases of CRC occurred, including 501 colon cancers and 384 rectal cancers. Cox regression was used to estimate adjusted HRs and corresponding 95% CIs.Compared with normal weight (BMI 18.5 to <25 kg/m(2)) in late adolescence, upper overweight (BMI 27.5 to <30 kg/m(2)) was associated with a 2.08-fold higher risk of CRC (95% CI 1.40 to 3.07) and obesity (BMI 30+ kg/m(2)) was associated with a 2.38-fold higher risk of CRC (95% CI 1.51 to 3.76) (p-trend: <0.001). Male adolescents with ESR (15+ mm/h) had a 63% higher risk of CRC (HR 1.63; 95% CI 1.08 to 2.45) than those with low ESR (<10 mm/h) (p-trend: 0.006). Associations did not significantly differ by anatomic site.Late-adolescent BMI and inflammation, as measured by ESR, may be independently associated with future CRC risk. Further research is needed to better understand how early-life exposures relate to CRC.
Extracellular MUC3 mucin secretion follows adherence of Lactobacillus strains to intestinal epithelial cells in vitro
Authors: D R Mack, S Ahrne, L Hyde, S Wei, M A Hollingsworth
Journal: Gut (2003)

Mucins are large complex glycoproteins that protect intestinal mucosal surfaces by limiting access of environmental matter to their epithelial cells. Several mucin genes have been described, including MUC3 that is a membrane associated mucin of the small intestine. Increased MUC3 mRNA transcription is induced by incubation of intestinal epithelial cells with a Lactobacillus strain known to be adherent to them.To determine whether increased epithelial cell MUC3 mucin expression in response to Lactobacillus strains results in increased extracellular secretion of MUC3 mucins and the importance of epithelial cell adherence in modulation of MUC3 mucin expression.HT29 cells grown to enhance expression of MUC3 mucins were incubated with selected Lactobacillus strains. Spent cell culture medium was collected for detection of secreted MUC3 mucins using dot blot immunoassay with a generated MUC3 antibody. Post-incubation HT29 cell RNA was collected for analysis of MUC3 expression by northern blot analysis using a MUC3 cDNA probe. In vitro binding studies using Lactobacillus strains incubated alone or coincubated with enteropathogenic Escherichia coli strain E2348/69 were used for adherence and inhibition of adherence studies, respectively.Lactobacillus strains with minimal ability to adhere to HT29 cells failed to induce upregulation of mucin gene expression. There was a direct correlation between upregulation of MUC3 mucin mRNA expression and extracellular secretion of MUC3 mucin. The same Lactobacillus strains that increased extracellular secretion of MUC3 mucin led to reduced adherence of enteropathogen E coli E2348/69 during coincubation experiments.Probiotic microbes induce MUC3 mucin transcription and translation with extracellular secretion of the MUC3 mucins. Epithelial cell adherence enhances the effects of probiotics on eukaryotic mucin expression.
Cyclosporin A, apoptosis of BAL T-cells and expression of Bcl-2 inasthmatics
Authors: S. Ying, L.N. Khan, Q. Meng, N.C. Barnes, A.B. Kay
Journal: European Respiratory Journal (2003)

The late asthmatic reaction is characterised by elevated numbers of interleukin‐4/interleukin‐5/CD4‐positive T‐helper cells type 2 in bronchoalveolar lavage fluid (BALF). Cyclosporin A (CsA) is known to inhibit T‐cell proliferation, induce apoptosis of CD4‐positive T‐cells and downregulate cytokine gene expression. It was assessed whether CsA‐induced inhibition of the late asthmatic reaction was associated with apoptosis of BALF T‐lymphocytes and other cell types, as well as expression of the antiapoptotic protein B‐cell leukaemia/lymphoma 2 gene product (Bcl‐2). BALF cells were obtained from asthmatics at baseline and 24 h after allergen-inhalation challenge following prior administration of CsA (n=13) or placebo (n=11). The number of apoptotic CD3‐positive T‐lymphocytes increased in the CsA but not the placebo group. The numbers of Bcl‐2‐positive cells were significantly reduced in the CsA but not the placebo group. The majority of Bcl‐2‐positive cells were CD3‐positive T‐lymphocytes. The beneficial effect of cyclosporin A in asthma may be related to its inhibitory effect on the late asthmatic reaction via induction of T‐cell apoptosis and decreased B‐cell leukaemia/lymphoma 2 gene product levels.
Thoracoscopy in the diagnosis of pleural effusion.
Authors: A Canto, E Blasco, M Casillas, A G Zarza, J Padilla, J Pastor, V Tarazona, F Paris
Journal: Thorax (1977)

The technique, indications, and complications of diagnostic thoracoscopy are described. Two hundred and eight explorations have been performed in our service in the last seven years. From 137 pleural malignancies we have obtained an unequivocal positive biopsy in 129 (94%) with a minimum number of complications and no mortality. From our experience we conclude that thoracoscopy, when porperly performed, is diagnostic in most pleural conditions.
Too much of a good thing is bad: proteasome inhibition induces stressed hearts to fail
Authors: L. Carrier
Journal: Cardiovascular Research (2010)

This editorial refers to ‘Proteasome functional insufficiency activates the calcineurin–NFAT pathway in cardiomyocytes and promotes maladaptive remodelling of stressed mouse hearts’ by M. Tang et al ., pp. 424–433, this issue.

A fine balance between protein synthesis and protein degradation regulates cellular homeostasis. Cardiac remodelling is a common response of the heart to changes in physiological or pathological demand. Hypertrophic growth is the primary mechanism through which the heart normalizes ventricular wall stress. It is characterized by an increase in the volume of individual cardiac myocytes, which can be the result of an acceleration of synthesis or a reduced degradation rate of proteins. However, while the synthesis rate has always been shown to be increased, protein degradation has been shown to be either accelerated or unchanged in hypertrophic hearts and inhibited by induction of cardiac work or high aortic pressure in Langendorff preparations.1

The ubiquitin–proteasome system (UPS) is one of the two major proteolytic systems that degrade most cellular, nuclear, and myofibrillar proteins in cells, as recently reviewed in a Spotlight issue of Cardiovascular Research .2 A main function of the UPS is to prevent accumulation of damaged, misfolded, and mutant proteins. Over the past two decades, the UPS has been increasingly recognized as a main player in regulating a multitude of cellular processes and dynamics. Two consecutive steps characterize the UPS. The first one is ubiquitination, which consists of the addition of several ubiquitin moieties onto a target intended for degradation and which involves the concerted action of at least three … 

*Corresponding author. Tel: +49 40 7410 57208; fax: +49 40 7410 55925, Email: l.carrier{at}uke.uni-hamburg.de
Interrogating causal pathways linking genetic variants, small molecule metabolites, and circulating lipids
Authors: So-Youn Shin, Ann-Kristin Petersen, Simone Wahl, Guangju Zhai, Werner Römisch-Margl, Kerrin S Small, Angela Döring, Bernet S Kato, Annette Peters, Elin Grundberg, Cornelia Prehn, Rui Wang-Sattler, H-Erich Wichmann, Martin de Angelis, Thomas Illig, Jerzy Adamski, Panos Deloukas, Tim D Spector, Karsten Suhre, Christian Gieger, Nicole Soranzo
Journal: Genome Medicine (2014)

Emerging technologies based on mass spectrometry or nuclear magnetic resonance enable the monitoring of hundreds of small metabolites from tissues or body fluids. Profiling of metabolites can help elucidate causal pathways linking established genetic variants to known disease risk factors such as blood lipid traits.We applied statistical methodology to dissect causal relationships between single nucleotide polymorphisms, metabolite concentrations, and serum lipid traits, focusing on 95 genetic loci reproducibly associated with the four main serum lipids (total-, low-density lipoprotein-, and high-density lipoprotein- cholesterol and triglycerides). The dataset used included 2,973 individuals from two independent population-based cohorts with data for 151 small molecule metabolites and four main serum lipids. Three statistical approaches, namely conditional analysis, Mendelian randomization, and structural equation modeling, were compared to investigate causal relationship at sets of a single nucleotide polymorphism, a metabolite, and a lipid trait associated with one another.A subset of three lipid-associated loci (FADS1, GCKR, and LPA) have a statistically significant association with at least one main lipid and one metabolite concentration in our data, defining a total of 38 cross-associated sets of a single nucleotide polymorphism, a metabolite and a lipid trait. Structural equation modeling provided sufficient discrimination to indicate that the association of a single nucleotide polymorphism with a lipid trait was mediated through a metabolite at 15 of the 38 sets, and involving variants at the FADS1 and GCKR loci.These data provide a framework for evaluating the causal role of components of the metabolome (or other intermediate factors) in mediating the association between established genetic variants and diseases or traits.
Capillary perfusion of the rat brain cortex. An in vivo confocal microscopy study.
Authors: A Villringer, A Them, U Lindauer, K Einhäupl, U Dirnagl
Journal: Circulation Research (1994)

Confocal laser-scanning microscopy was used to visualize subsurface cerebral microvessels labeled with intravascular fluorescein in a closed cranial window model of the anesthetized rat. In noninvasive optical sections up to 250 microns beneath the brain surface, plasma perfusion and blood cell perfusion of individual capillaries were studied. Under resting conditions, in all cerebral capillaries the presence of plasma flow as demonstrated by the appearance of an intravenously injected fluorescent tracer within 20 seconds after injection. Plasma flow was verified even in capillaries that contained stationary erythrocytes or leukocytes; 91.1% of the capillaries contained flowing blood cells, 5.2% contained stationary blood cells, and no blood cells were seen in 3.6%. Mean blood cell velocity was 498.3 +/- 443.9 microns/s, and the mean blood cell supply rate was 35.75 +/- 28.01 cells per second. When capillaries were continuously observed for 1 minute, "on" and "off" periods of blood cell flow were noted. During hypercapnia (increase of PCO2 from 33.25 to 50.26 mm Hg), mean blood cell flux increased from 38.6 +/- 17.2 to 55.5 +/- 12.2 per second (P &lt; .005, paired t test of mean values in six animals), and blood cell velocity increased from 519.5 +/- 254.8 to 828.5 +/- 460.8 microns/s (P = .074, paired t test of mean values in six animals). Homogeneity of blood cell flux increased as indicated by the coefficient of variation decreasing from 44.6% to 22.0%, and the portion of poorly perfused capillaries (blood cell flux, &lt; 40 per second) decreased from 59.2% to 22.4%.(ABSTRACT TRUNCATED AT 250 WORDS)
Lymphocyte Ontogeny and Activation in Gene Targeted Mutant Mice
Authors: K. Pfeffer, T. W. Mak
Journal: Annual Review of Immunology (1994)

Gene targeting by homologous recombination in pluripotent embryonic stem cells enabled the systematic creation of mouse strains with defined genetic alterations. During the past few years a rapidly growing number of gene targeted mice has provided new insights into development, selection, activation, and signaling of T and B cells, as well as into the functions of cytokines. Here we discuss the present state of targeting technology and summarize the phenotypic changes observed in gene targeted mouse strains of immunological interest. These data allow us for the first time to define genetic checkpoints in lymphocyte development that are crucial for the orderly progression of T and B cells through ontogeny and for the generation of an immune response.
Leptospirosis in Reunion Island (Indian Ocean): analysis of factors associated with severity in 147 confirmed cases
Authors: Fabrice Paganin, Arnaud Bourdin, Cécile Dalban, Jean-Paul Courtin, Patrice Poubeau, Gianandrea Borgherini, Alain Michault, Jean-Claude Sally, François Tixier, Robert Genin, Claude Arvin-Berod
Journal: Intensive Care Medicine (2007)
Significant associations of antidrug antibody levels with serum drug trough levels and therapeutic response of adalimumab and etanercept treatment in rheumatoid arthritis
Authors: Der-Yuan Chen, Yi-Ming Chen, Wen-Chan Tsai, Jui-Cheng Tseng, Yi-Hsing Chen, Chia-Wei Hsieh, Wei-Ting Hung, Joung-Liang Lan
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objective</h3> To evaluate the associations between (1) antidrug antibody (ADAb) and therapeutic response, (2) ADAb and serum drug trough levels and (3) serum drug levels and therapeutic responses in rheumatoid arthritis (RA) patients receiving adalimumab or etanercept. Secondarily, we aim (1) to evaluate the concordance between radioimmunoassay and bridging ELISA for ADAb assessment and to evaluate the correlation between two different ELISA methods for detecting drug levels, and (2) to determine the optimal cut-off drug levels for good European League Against Rheumatism (EULAR) response. <h3>Methods</h3> ADAb levels were determined by bridging ELISA and radioimmunoassay, and drug levels evaluated using sandwich ELISA among 36 adalimumab-treated patients and 34 etanercept-treated patients at the 6th and 12th month. The optimal cut-off drug levels for EULAR responses were determined by receiver-operating characteristic curve analysis. <h3>Results</h3> ADAb was detected in 10 (27.8%) and 13 (36.1%) of adalimumab-treated patients after 12-month therapy using bridging ELISA and radioimmunoassay respectively, but not detected in any of etanercept-treated patients. The presence of ADAb was associated with lower EULAR response and lower drug levels compared with those without ADAb (both p&lt;0.001). Drug trough levels were positively associated with DAS28 decrement (ΔDAS28) (all p&lt;0.001). The optimal cut-off trough levels for adalimumab were 1.274 μg/mL and 1.046 μg/mL, and those for etanercept were 1.242 μg/mL and 0.800 μg/mL for good EULAR response assessed at the 6th and 12th month, respectively. <h3>Conclusions</h3> ADAb levels were inversely correlated with therapeutic response and drug levels. The positive correlation between drug levels and ΔDAS28 indicates that drug monitoring would be useful to evaluate therapeutic response of TNF-α inhibitors.
Cardiac bioimpedance as a non-invasive tool in patients with pulmonary hypertension
Authors: Christian Lensch, Ralf Kaiser, Christian Frantz, Robert Bals, Heinrike Wilkens
Journal: European Respiratory Journal (2011)

Background:  Pulmonary hypertension (PH) is a serious disease diagnosed by echocardiography and right heart catheterization. Left ventricular dysfunction and decreased cardiac output is a common feature in pulmonary hypertension. The aim of this study was to evaluate cardiac bioimpedance (CBI) as a possible non-invasive tool in hemodynamic monitoring.   Methods:  19 patients (19-76 years) with IPAH or CTEPH (PAPm 48±14,4 mmHg; PVR 799±497 dyn s cm -5 ) and 6 healthy volunteers were measured simultaneously by thoracic echocardiography and non-invasive cardiac bioimpedance (CBI) using a BoMed NCCOM3. Parameters were standardized by body surface area. Linear regression analysis and F-Test were performed.   Results:  Left ventricular end diastolic volume index in CBI correlated with echocardiography measurements in both M-Mode (r=0,6181; p=0,002) and B-Mode (Simpson, r=0,8431, p   Conclusions:  In patients with IPAH or CTEPH, cardiac bioimpedance might be a useful non-invasive tool in monitoring left ventricular hemodynamics including left ventricular preload and cardiac output.