tbuckley/cabot-search huggingface dataset:
Multicenter Randomized Phase II Study of Two Schedules of Docetaxel, Estramustine, and Prednisone Versus Mitoxantrone Plus Prednisone in Patients With Metastatic Hormone-Refractory Prostate Cancer
Authors: Stéphane Oudard, Eugeniu Banu, Philippe Beuzeboc, Eric Voog, Louis Marie Dourthe, Anne Claire Hardy-Bessard, Claude Linassier, Florian Scotté, Adela Banu, Yvan Coscas, François Guinet, Marie-France Poupon, Jean-Marie Andrieu
Journal: Journal of Clinical Oncology (2005)

Mitoxantrone-corticosteroid is currently the standard palliative treatment in hormone-refractory prostate cancer (HRPC) patients. Recent clinical trials documented the high activity of the docetaxel-estramustine combination. We conducted a randomized phase II study to evaluate prostate-specific antigen (PSA) response (primary end point) and safety of two docetaxel-estramustine-prednisone (DEP) regimens and mitoxantrone-prednisone (MP).One hundred thirty metastatic HRPC patients were randomly assigned to receive docetaxel (70 mg/m2 on day 2 or 35 mg/m2 on days 2 and 9 of each 21-day cycle) and estramustine (280 mg p.o. tid on days 1 through 5 and 8 through 12) or mitoxantrone 12 mg/m2 every 3 weeks; all patients received prednisone (10 mg daily).One hundred twenty-seven patients were assessable for PSA response and safety. A > or = 50% PSA decline was found in a greater percentage of patients in the docetaxel arms (67% and 63%) compared with MP (18%; P = .0001). Median time to PSA progression was five times longer with DEP than with MP (8.8 and 9.3 v 1.7 months, respectively; P = .000001). Overall survival was better in the docetaxel arms (18.6 and 18.4 months) compared with the MP arm (13.4 months), but not significantly so (P = .3). Crossover rates differed significantly among treatment arms (16%, 10%, and 48% in arms A, B, and C, respectively; P = .00001). Treatment-related toxicities were mild and mainly hematologic.The results of this randomized phase II study showed significantly higher PSA decline < or = 50% and longer times to progression in HRPC patients receiving DEP-based chemotherapy than MP, and that DEP could be proposed in this setting.
Regulation and mechanisms of macrophage cholesterol efflux
Authors: Alan R. Tall, Philippe Costet, Nan Wang
Journal: Journal of Clinical Investigation (2002)

The accumulation of cholesterol in macrophage foam cells results from the uptake of retained and modified apoB lipoproteins (1) and is a central event in atherogenesis.Although it has long been known that HDL and its apolipoproteins can stimulate cholesterol efflux from macrophage foam cells (2, 3) and reduce atherogenesis in animal models (4, 5), this area of research has been enlivened by the elucidation of the genetic defect in Tangier disease, a condition in which there is a defect in apolipoprotein-mediated cholesterol efflux (6) and in which the hallmark pathology is the accumulation of macrophage foam cells in various tissues.Tangier disease is caused by mutations in the ATP-binding cassette transporter A1 (ABCA1).This cell surface transporter facilitates the efflux of phospholipids and cholesterol onto lipid-poor apolipoproteins, initiating the formation of HDL particles.This Perspective will focus on recent studies on the regulation and role of ABCA1 in cellular cholesterol efflux, lipoprotein physiology, and atherogenesis, attempting to place this work in the broader context of studies on cellular cholesterol efflux, centripetal cholesterol transport, and ABC transporter structure and function.
Different Effect of Paclitaxel on Primary Tumor Mass, Tumor Cell Contents, and Metastases for Four Experimental Human Prostate Tumors Expressing Luciferase
Authors: Nadia El Hilali, Nuria Rubio, Jerónimo Blanco
Journal: Clinical Cancer Research (2005)

Primary tumor growth is usually assessed by measuring tumor mass or volume, under the assumption that such variables correlate with the contents of tumor cells. However, tumors are complex interacting mixtures of tumor cells and host components. The different sensitivity of such components to cytostatic agents should be taken into consideration when evaluating the effectiveness of antineoplastic agents. We evaluate the effect of the antineoplastic agent paclitaxel on primary tumors expressing luciferase and their metastases using a sensitive luminescence-based procedure to directly asses the number tumor cells, in comparison with traditionally used tumor mass measurement.Nude mice bearing human prostate tumors expressing the luciferase gene, LNCaP.Sluc, DU 145.Sluc, and PC-3.Sluc, i.m. inoculated, and PC-3M.Sluc, orthotopically inoculated, were subjected to a 10-day treatment with either 10 mg/kg/d paclitaxel or saline solution. At the end of the treatment period, primary tumors as well as metastasis target organs were harvested, weighed, and homogenized. The presence of tumor cells in the tissue homogenates was evaluated using a luminometer, following the addition of luciferin. Tumor cell equivalent is defined as the amount of light produced by a single tumor cell in culture.Paclitaxel had a different effect on the primary tumor mass and the contents of tumor cells for each tumor type. Whereas LNCaP.Sluc, PC-3.Sluc, and PC-3M.Sluc primary tumor masses were significantly reduced by the action of paclitaxel, their contents in tumor cell equivalents were not significantly affected. In contrast, paclitaxel only reduced significantly the number of tumor cell equivalents in DU 145 primary tumors. In the lymph nodes, paclitaxel reduced the number of DU 145.Sluc metastases significantly, by a factor of 10(3), but had no significant effect on the rest of tumor cells. However, in lungs and muscle, paclitaxel treatment reduced significantly the number of metastatic PC-3.Sluc and PC-3M.Sluc tumor cell equivalents. In the bones, no tumor cell type was significantly affected by paclitaxel.Some components of tumor stroma seem to be more sensitive to antineoplastic agents than the tumor cells themselves and may also contribute to modulate the response to therapy. Our results caution against the use of a single general variable, such as tumor mass, to evaluate the effectiveness of antineoplastic agents and emphasize the effect of the tumor cell environment in their sensitivity to treatment.
Neck soft tissue and fat distribution: comparison between normal men and women by magnetic resonance imaging
Authors: A. T Whittle, I. Marshall, I. L Mortimore, P. K Wraith, R. J Sellar, N. J Douglas
Journal: Thorax (1999)

<h3>BACKGROUND</h3> Obesity and increased neck circumference are risk factors for the obstructive sleep apnoea/hypopnoea syndrome (SAHS). SAHS is more common in men than in women, despite the fact that women have higher rates of obesity and greater overall body fat. One factor in this apparently paradoxical sex distribution may be the differing patterns of fat deposition adjacent to the upper airway in men and women. A study was therefore undertaken to compare neck fat deposition in normal men and women. <h3>METHODS</h3> Using T1 weighted magnetic resonance imaging, the fat and tissue volumes in the necks of 10 non-obese men and 10 women matched for age (men mean (SE) 36 (3) years, women 37 (3) years, p = 0.7), body mass index (both 25 (0.6) kg/m<sup>2</sup>, p&gt;0.9), and Epworth Sleepiness Score (both 5 (1), p = 0.9) were assessed; all denied symptoms of SAHS. <h3>RESULTS</h3> Total neck soft tissue volume was greater in men (1295 (62) vs 928 (45) cm<sup>3</sup>, p&lt;0.001), but the volume of fat did not differ between the sexes (291 (29) vs 273 (18) cm<sup>3</sup>, p = 0.6). The only regions impinging on the pharynx which showed a larger absolute volume of fat in men (3.2 (0.7) vs 1.1 (0.3) cm<sup>3</sup>, p = 0.01) and also a greater proportion of neck fat in men (1.3 (0.3)% vs 0.4 (0.1)%, p = 0.03) were the anterior segments inside the mandible at the palatal level. <h3>CONCLUSIONS</h3> There are differences in neck fat deposition between the sexes which, together with the greater overall soft tissue loading on the airway in men, may be factors in the sex distribution of SAHS.
Sensitivity and specificity of HAT Sero-K-SeT, a rapid diagnostic test for serodiagnosis of sleeping sickness caused by Trypanosoma brucei gambiense: a case-control study
Authors: Philippe Büscher, Pascal Mertens, Thierry Leclipteux, Quentin Gilleman, Diane Jacquet, Dieudonné Mumba-Ngoyi, Patient Pati Pyana, Marleen Boelaert, Veerle Lejon
Journal: The Lancet Global Health (2014)

Human African trypanosomiasis (HAT) is a life-threatening infection affecting rural populations in sub-Saharan Africa. Large-scale population screening by antibody detection with the Card Agglutination Test for Trypanosomiasis (CATT)/Trypanosoma brucei (T b) gambiense helped reduce the number of reported cases of gambiense HAT to fewer than 10 000 in 2011. Because low case numbers lead to decreased cost-effectiveness of such active screening, we aimed to assess diagnostic accuracy of a rapid serodiagnostic test (HAT Sero-K-SeT) applicable in primary health-care centres.In our case-control study, we assessed participants older than 11 years who presented for HAT Sero-K-SeT and CATT/T b gambiense at primary care centres or to mobile teams (and existing patients with confirmed disease status at these centres) in Bandundu Province, DR Congo. We defined cases as patients with trypanosomes that had been identified in lymph node aspirate, blood, or cerebrospinal fluid. During screening, we recruited controls without previous history of HAT or detectable trypanosomes in blood or lymph who resided in the same area as the cases. We assessed diagnostic accuracy of three antibody detection tests for gambiense HAT: HAT Sero-K-SeT and CATT/T b gambiense (done with venous blood at the primary care centres) and immune trypanolysis (done with plasma at the Institute of Tropical Medicine, Antwerp, Belgium).Between June 6, 2012, and Feb 25, 2013, we included 134 cases and 356 controls. HAT Sero-K-SeT had a sensitivity of 0·985 (132 true positives, 95% CI 0·947-0·996) and a specificity of 0·986 (351 true negatives, 0·968-0·994), which did not differ significantly from CATT/T b gambiense (sensitivity 95% CI 0·955, 95% CI 0·906-0·979 [128 true positives] and specificity 0·972, 0·949-0·985 [346 true negatives]) or immune trypanolysis (sensitivity 0·985, 0·947-0·996 [132 true positives] and specificity 0·980, 0·960-0·990 [349 true negatives]).The diagnostic accuracy of HAT Sero-K-SeT is adequate for T b gambiense antibody detection in local health centres and could be used for active screening whenever a cold chain and electricity supply are unavailable and CATT/T b gambiense cannot be done.
Transepithelial exit of leucocytes: inflicting, reflecting or resolving airway inflammation?
Authors: C. Persson, L. Uller
Journal: Thorax (2010)

The passage of infiltrated tissue granulocytes across airway epithelium into airway lumen is generally considered to be a pathogenic process in asthma and chronic obstructive pulmonary disease (COPD). An alternative hypothesis is proposed here—namely that the transepithelial egression of infiltrated leucocytes acts to rid diseased airway tissues of proinflammatory cells efficiently and non-injuriously. Several clinical observations previously discussed as 'unexpected' and 'puzzling' support this hypothesis. In acutely resolving allergen challenge-induced inflammation, in patients with mild asthma, airway wall eosinophils disappear without evidence of apoptosis but with evidence of a developing airway lumen eosinophilia. In the same postchallenge resolution phase, lymphocytes, neutrophils and mast cells exhibit peak numbers in airway lumen of individuals with asthma. In severe asthma requiring intubation, clinical improvement is similarly parallelled by a marked increase over several days in airway lumen neutrophils. Increased numbers of sputum neutrophils and lymphocytes also occur as symptoms improve in COPD over several months after smoking cessation. Conversely, when the transepithelial exit of leucocytes has been inhibited in inflamed animal airways the inflammation in the airway wall has been much aggravated. Finally, transepithelial egression of numerous granulocytes and lymphocytes clearly can occur without any harm to airway epithelial barriers. The present hypothesis of 'resolution through egression' provides a novel interpretation of common airway lumen data, cautions against administration of agents that impede leucocyte egression in inflammatory airway diseases and infers new approaches in disease resolution research.
Level of galactosylation determines cryoglobulin activity of murine IgG3 monoclonal rheumatoid factor
Authors: Aki Kuroki, Yasuhiro Kuroda, Shuichi Kikuchi, Frédéric Lajaunias, Thierry Fulpius, Yves Pastore, Liliane Fossati-Jimack, Luc Reininger, Toho Toda, Munehiro Nakata, Naoya Kojima, Tsuguo Mizuochi, Shozo Izui
Journal: Blood (2002)
Localization of gamma/delta T cells to the intestinal epithelium is independent of normal microbial colonization.
Authors: A Bandeira, T Mota-Santos, S Itohara, S Degermann, C Heusser, S Tonegawa, A Coutinho
Journal: The Journal of Experimental Medicine (1990)

Using monoclonal antibodies identifying all gamma/delta and alpha/beta T cell receptors in cytofluorometric analysis, we have compared the composition of intestinal intraepithelial lymphocytes (i-IEL) in euthymic and athymic germ-free (GF) and conventional (SPF) mice. The results show a marked influence of microbial colonization in the numbers of single-positive (CD4+ or CD8+) alpha/beta i-IEL, but little effect in the pool size or characteristics of gamma/delta i-IEL. In young athymic mice, virtually no alpha/beta i-IEL are detected, while considerable numbers of gamma/delta i-IEL remain, though reduced in GF animals.
Graphene‐Based Electroresponsive Scaffolds as Polymeric Implants for On‐Demand Drug Delivery
Authors: Ania Servant, Veronica Leon, Dhifaf Jasim, Laura Methven, Patricia Limousin, Ester Vazquez Fernandez‐Pacheco, Maurizio Prato, Kostas Kostarelos
Journal: Advanced Healthcare Materials (2014)

Stimuli‐responsive biomaterials have attracted significant attention in the field of polymeric implants designed as active scaffolds for on‐demand drug delivery. Conventional porous scaffolds suffer from drawbacks such as molecular diffusion and material degradation, allowing in most cases only a zero‐order drug release profile. The possibility of using external stimulation to trigger drug release is particularly enticing. In this paper, the fabrication of previously unreported graphene hydrogel hybrid electro‐active scaffolds capable of controlled small molecule release is presented. Pristine ball‐milled graphene sheets are incorporated into a three dimensional macroporous hydrogel matrix to obtain hybrid gels with enhanced mechanical, electrical, and thermal properties. These electroactive scaffolds demonstrate controlled drug release in a pulsatile fashion upon the ON/OFF application of low electrical voltages, at low graphene concentrations (0.2 mg mL –1 ) and by maintaining their structural integrity. Moreover, the in vivo performance of these electroactive scaffolds to release drug molecules without any “resistive heating” is demonstrated. In this study, an illustration of how the heat dissipating properties of graphene can provide significant and previously unreported advantages in the design of electroresponsive hydrogels, able to maintain optimal functionality by overcoming adverse effects due to unwanted heating, is offered.
Early screening for reperfusionand CTEPH after acute pulmonary embolism – Early screening for reperfusion and CTEPH after acutepulmonary embolism
Authors: Birgit Fuchs, Helene Vogelsinger, Christian M. Kaehler
Journal: European Respiratory Journal (2014)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease with high mortality and few treatment options. The percentage of patients with acute PE who develop CTEPH is unknown but is believed to range from 0.6% to 8.8%. In this prospective, observational study we were interested in the reperfusion rate under routine anticoagulation therapy after acute central PE.  128 patients with acute PE were screened and 19 patients (mean age 63±18 yrs, 47% male/53% females) with central PE finally included in this observational study between 2011 and 2013. 4 patients had an idiopathic event while 15 patients presented with thrombosis at the time of diagnosis. 2 patients presented with a second hit. All patients received standard anticoagulation with accenocoumarol (INR 2-3). CT scans were performed at time of diagnosis and after 3-4 (4.0±1.43) months. At diagnosis the mean D-dimer was 8212±6077 µg/L and the NT-pro BNP levels elevated in 9 patients. After at least 3 months of standard anticoagulation a complete reperfusion was achieved in 10 patients (53%). In 9 patients no or only partial reperfusion was documented. 3 out of them presented with an elevated sPAP in the echo which was confirmed by right heart cathetherisation.  After 3-4 months of anticoagulation resolution of central emboli was observed in 58% of cases. 16% of patients initially presenting with central emboli developed CTEPH after this short observation period. Thus, screening of this special PE population might be helpful to detect CTPEH early.
<i>p53-Inducible Ribonucleotide Reductase</i> (<i>p53R2/RRM2B</i>) Is a DNA Hypomethylation–Independent Decitabine Gene Target That Correlates with Clinical Response in Myelodysplastic Syndrome/Acute Myelogenous Leukemia
Authors: Petra A. Link, Maria R. Baer, Smitha R. James, David A. Jones, Adam R. Karpf
Journal: Cancer Research (2008)

Abstract While the therapeutic activity of the deoxycytidine analogue decitabine is thought to reflect its ability to reactivate methylation-silenced genes, this agent is also known to trigger p53-dependent DNA damage responses. Here, we report that p53-inducible ribonucleotide reductase (p53R2/RRM2B) is a robust transcriptional target of decitabine. In cancer cells, decitabine treatment induces p53R2 mRNA expression, protein expression, and promoter activity in a p53-dependent manner. The mechanism of p53R2 gene induction by decitabine does not seem to be promoter DNA hypomethylation, as the p53R2 5′ CpG island is hypomethylated before treatment. Small interfering RNA (siRNA) targeting of DNA methyltransferase 1 (DNMT1) in wild-type p53 cells leads to genomic DNA hypomethylation but does not induce p53R2, suggesting that DNMT/DNA adduct formation is the molecular trigger for p53R2 induction. Consistent with this idea, only nucleoside-based DNMT inhibitors that form covalent DNA adducts induce p53R2 expression. siRNA targeting of p53R2 reduces the extent of cell cycle arrest following decitabine treatment, supporting a functional role for p53R2 in decitabine-mediated cellular responses. To determine the clinical relevance of p53R2 induction, we measured p53R2 expression in bone marrow samples from 15 myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML) patients undergoing decitabine therapy. p53R2 mRNA and protein were induced in 7 of 13 (54%) and 6 of 9 (67%) patients analyzed, respectively, despite a lack of methylation changes in the p53R2 promoter. Most notably, there was a significant association (P = 0.0047) between p53R2 mRNA induction and clinical response in MDS/AML. These data establish p53R2 as a novel hypomethylation-independent decitabine gene target associated with clinical response. [Cancer Res 2008;68(22):9358–66]
C-Terminal Truncation of Connexin43 Changes Number, Size, and Localization of Cardiac Gap Junction Plaques
Authors: Karen Maass, Junko Shibayama, Sharon E. Chase, Klaus Willecke, Mario Delmar
Journal: Circulation Research (2007)

Haplodeficient mice expressing carboxyl-terminally truncated Cx43 (K258stop/KO), instead of the wild-type Cx43 isoform, reach adulthood and reveal no abnormalities in heart morphology. Here, we have analyzed the expression of K258stop protein and the morphology of gap junctions in adult hearts of these mice. Coimmunofluorescence analysis revealed reduced juxtaposition of K258stop with other junctional proteins at the intercalated disc. Immunoprecipitation studies documented changes in the interaction with previously described Cx43 binding proteins. Quantitative transmission electron and confocal microscopy confirmed the localization of K258stop gap junctions to the periphery of the intercalated disc and further revealed an increase in the size of K258stop gap junction plaques and a reduction in their number. Dual whole cell patch clamp analysis confirmed that K258stop gap junctions were functional, with single channel properties similar to those described in exogenous systems. We conclude that the carboxyl-terminal domain of Cx43 (Cx43CT) is involved in regulating the localization, number and size of Cx43 plaques in vivo. Conversely, protein interactions or posttranslational modifications taking place within the Cx43CT are not required for the assembly of functional gap junctions in the intercalated disc.
p66Shc Is Indispensable for Phenethyl Isothiocyanate–Induced Apoptosis in Human Prostate Cancer Cells
Authors: Dong Xiao, Shivendra V. Singh
Journal: Cancer Research (2010)

Naturally occurring phenethyl isothiocyanate (PEITC) selectively inhibits growth of cancer cells by causing apoptosis, but the mechanism of cell death induction is not fully understood. We now show, for the first time, that growth factor adapter protein p66(Shc) is indispensable for PEITC-induced apoptosis. Mouse embryonic fibroblasts derived from p66(Shc) knockout mice were significantly more resistant to PEITC-mediated growth inhibition, cytoplasmic histone-associated apoptotic DNA fragmentation, and caspase-3 activation compared with wild-type fibroblasts. The PEITC treatment resulted in induction as well as increased Ser(36) phosphorylation of p66(Shc) in PC-3 and LNCaP human prostate cancer cells. Knockdown of p66(Shc) protein conferred significant protection against PEITC-mediated cytoplasmic histone-associated DNA fragmentation as well as production of reactive oxygen species in both PC-3 and LNCaP cells. The PEITC-treated PC-3 and LNCaP cells exhibited increased binding of p66(Shc) with prolyl isomerase Pin1, a protein implicated in translocation of p66(Shc) to mitochondria. Consistent with these results, treatment of PC-3 cells with PEITC resulted in translocation of p66(Shc) to the mitochondria as judged by immunoblotting using cytosolic and mitochondrial fractions and immunofluorescence microscopy. Growth suppression and apoptosis induction in tumor xenografts in vivo by oral administration of PEITC to the PC-3 tumor-bearing male athymic mice were accompanied by statistically significant increase in the level of Ser(36)-phosphorylated p66(Shc). Collectively, these results provide novel insight into the critical role of p66(Shc) in regulation of PEITC-induced apoptotic cell death in human prostate cancer cells.
Strength-Duration Curves for Ventricular Defibrillation in Dogs
Authors: L. A. GEDDES, W. A. TACKER, J. MCFARLANE, J. BOURLAND
Journal: Circulation Research (1970)

The threshold voltage and current necessary for ventricular defibrillation was measured in dogs using capacitor-discharge and half-sinusoidal pulses of current of various durations. From these quantities the electrical strength required for defibrillation was determined and expressed as energy, peak current, and charge per gram of heart. The optimum current duration depends on the criterion selected. It was found that with half-sinusoidal current, less energy, current, and charge were required; this type of waveform approximates that delivered by capacitor-inductor defibrillators. For minimum energy with this waveform, the optimum duration range is 1.25 to 8.3 msec and the energy required is approximately 7 mw-sec per gram of heart. For minimum current, the optimum duration is 8.3 msec; with this duration the peak half-sinusoidal current is about 30 mamp per gram of heart. There is no clearly defined duration for minimum charge for capacitor-discharge or half-sinusoidal current.