tbuckley/cabot-search huggingface dataset:
Liposomal Quercetin Efficiently Suppresses Growth of Solid Tumors in Murine Models
Authors: Zhi-ping Yuan, Li-juan Chen, Lin-yu Fan, Ming-hai Tang, Guang-li Yang, Han-su Yang, Xiao-bo Du, Guo-qing Wang, Wen-xiu Yao, Qu-mei Zhao, Bin Ye, Rui Wang, Peng Diao, Wei Zhang, Hong-bin Wu, Xia Zhao, Yu-Quan Wei
Journal: Clinical Cancer Research (2006)

Quercetin is a potent chemotherapeutic drug. Clinical trials exploring different schedules of administration of quercetin have been hampered by its extreme water insolubility. To overcome this limitation, this study is aimed to develop liposomal quercetin and investigate its distribution in vivo and antitumor efficacy in vivo and in vitro.Quercetin was encapsulated in polyethylene glycol 4000 liposomes. Biodistribution of liposomal quercetin i.v. at 50 mg/kg in tumor-bearing mice was detected by high-performance liquid chromatography. Induction of apoptosis by liposomal quercetin in vitro was tested. The antitumor activity of liposomal quercetin was evaluated in the immunocompetent C57BL/6N mice bearing LL/2 Lewis lung cancer and in BALB/c mice bearing CT26 colon adenocarcinoma and H22 hepatoma. Tumor volume and survival time were observed. The mechanisms underlying the antitumor effect of quercetin in vivo was investigated by detecting the microvessel density, apoptosis, and heat shock protein 70 expression in tumor tissues.Liposomal quercetin could be dissolved in i.v. injection and effectively accumulate in tumor tissues. The half-time of liposomal quercetin was 2 hours in plasma. The liposomal quercetin induced apoptosis in vitro and significantly inhibited tumor growth in vivo in a dose-dependent manner. The optimal dose of liposomal quercetin resulted in a 40-day survival rate of 40%. Quantitative real-time PCR showed that liposomal quercetin down-regulated the expression of heat shock protein 70 in tumor tissues. Immunohistochemistry analysis showed that liposomal quercetin inhibited tumor angiogenesis as assessed by CD31 and induced tumor cell apoptosis.Our data indicated that pegylated liposomal quercetin can significantly improve the solubility and bioavailability of quercetin and can be a potential application in the treatment of tumor.
A Dominant-Negative<i>GFI1B</i>Mutation in the Gray Platelet Syndrome
Authors: Davide Monteferrario, Nikhita A. Bolar, Anna E. Marneth, Konnie M. Hebeda, Saskia M. Bergevoet, Hans Veenstra, Britta A.P. Laros-van Gorkom, Marius A. MacKenzie, Cyrus Khandanpour, Lacramiora Botezatu, Erik Fransen, Guy Van Camp, Anthonie L. Duijnhouwer, Simone Salemink, Brigith Willemsen, Gerwin Huls, Frank Preijers, Waander Van Heerde, Joop H. Jansen, Marlies J.E. Kempers, Bart L. Loeys, Lut Van Laer, Bert A. Van der Reijden
Journal: New England Journal of Medicine (2013)

The gray platelet syndrome is a hereditary, usually autosomal recessive bleeding disorder caused by a deficiency of alpha granules in platelets. We detected a nonsense mutation in the gene encoding the transcription factor GFI1B (growth factor independent 1B) that causes autosomal dominant gray platelet syndrome. Both gray platelets and megakaryocytes had abnormal marker expression. In addition, the megakaryocytes had dysplastic features, and they were abnormally distributed in the bone marrow. The GFI1B mutant protein inhibited nonmutant GFI1B transcriptional activity in a dominant-negative manner. Our studies show that GFI1B, in addition to being causally related to the gray platelet syndrome, is key to megakaryocyte and platelet development.
Systemic sclerosis as prototypic disease with high levels of functional antibodies against angiotensin II type-1 and endothelin-1 type A receptor strongly predicting prognosis
Authors: G Riemekasten, A Philippe, I Lukitsch, T Slowinski, M Nather
Journal: Annals of the Rheumatic Diseases (2010)

Systemic sclerosis (SSc) features autoimmunity, vasculopathy and tissue fibrosis; the renin-angiotensin and endothelin systems have been implicated. The authors hypothesised a role for autoimmune receptor stimulation.

The authors tested sera of 478 SSc patients (298 in the study cohort and 180 from two independent cohorts), 372 …
Neoadjuvant docetaxel followed by adjuvant doxorubicin and cyclophosphamide in patients with stage III breast cancer
Authors: W.J. Gradishar, S.B. Wedam, M. Jahanzeb, J. Erban, S.A. Limentani, K.-T. Tsai, S.R. Olsen, S.M. Swain
Journal: Annals of Oncology (2005)

Background: To evaluate clinical and pathologic response to neoadjuvant docetaxel therapy in patients with stage III breast cancer.Patients and methods: Forty-five patients were planned to receive four cycles of docetaxel 100 mg/m2 every 3 weeks, followed by surgery, four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 (AC) every 3 weeks, radiation therapy (RT), and tamoxifen when indicated.Results: After four cycles of neoadjuvant docetaxel, the clinical response rate within the breast was 59% (95% CI 42% to 73%) and overall (breast and axilla) was 49% (95% CI 38% to 72%) in the intention-to-treat (ITT) population. At the time of surgery, 10% (n=4) of patients had a pathologic complete response (pCR) in the breast, 27% (n=11) had a pCR within the axillary lymph nodes, and 7% (n=3) had a pCR in the breast and axilla (95% CI 2% to 21%). An additional 5% (n=2) had minimal residual invasive tumor (<5 mm). The 5-year overall survival rate was 80%. The percentage of patients with grade 3/4 neutropenia was similar during docetaxel (93%) and AC (86%), while a greater percentage of patients had febrile neutropenia during docetaxel treatment (27%) compared with AC treatment (7%).Conclusions: Neoadjuvant docetaxel followed by surgery, adjuvant AC, hormonal therapy where indicated, and RT is an active regimen for patients with stage III breast cancer.
Pharmacokinetics of Gemcitabine in Japanese Cancer Patients: The Impact of a Cytidine Deaminase Polymorphism
Authors: Emiko Sugiyama, Nahoko Kaniwa, Su-Ryang Kim, Ruri Kikura-Hanajiri, Ryuichi Hasegawa, Keiko Maekawa, Yoshiro Saito, Shogo Ozawa, Jun-ichi Sawada, Naoyuki Kamatani, Junji Furuse, Hiroshi Ishii, Teruhiko Yoshida, Hideki Ueno, Takuji Okusaka, Nagahiro Saijo
Journal: Journal of Clinical Oncology (2006)

Gemcitabine is rapidly metabolized to its inactive metabolite, 2',2'-difluorodeoxyuridine (dFdU), by cytidine deaminase (CDA). We previously reported that a patient with homozygous 208A alleles of CDA showed severe adverse reactions with an increase in gemcitabine plasma level. This study extended the investigation of the effects of CDA genetic polymorphisms on gemcitabine pharmacokinetics and toxicities.Genotyping of CDA was performed by a direct sequencing of DNA obtained from the peripheral blood of Japanese gemcitabine-naïve cancer patients (n = 256). The patients recruited to the association study received a 30-minute intravenous infusion of gemcitabine at a dose of either 800 or 1,000 mg/m2, and eight blood samples were periodically collected (n = 250). Plasma levels of gemcitabine and dFdU were measured by high-performance liquid chromatography. Plasma CDA activities toward cytidine and gemcitabine were also measured (n = 121).Twenty-six genetic variations, including 14 novel ones and two known nonsynonymous single nucleotide polymorphisms (SNPs), were detected. Haplotypes harboring the nonsynonymous SNPs 79A>C (Lys27Gln) and 208G>A (Ala70Thr) were designated *2 and *3, respectively. The allelic frequencies of the two SNPs were 0.207 and 0.037, respectively. Pharmacokinetic parameters of gemcitabine and plasma CDA activities significantly depended on the number of haplotype *3. Haplotype *3 was also associated with increased incidences of grade 3 or higher neutropenia in the patients who were coadministered fluorouracil, cisplatin, or carboplatin. Haplotype *2 showed no significant effect on gemcitabine pharmacokinetics.Haplotype *3 harboring a nonsynonymous SNP, 208G>A (Ala70Thr), decreased clearance of gemcitabine, and increased incidences of neutropenia when patients were coadministered platinum-containing drugs or fluorouracil.
Influence of Antihypertensive Therapy on Development and Progression of Diabetic Glomerulopathy
Authors: Sharon Anderson, Barry M Brenner
Journal: Diabetes Care (1988)

Capillary hypertension is suggested to be the underlying cause of microvascular disease affecting the kidney, the retina, and other organs and tissues in diabetic patients and animals. Hyperglycemia causes an expansion of extracellular volume, which induces a vasodilatory response. Hemodynamic adaptation to vasodilation leads to an increase in intracapillary hydraulic pressure, which subs quently causes vascular damage. In experimental animals, restoration of capillary pressure to normal levels by ingestion of a low-protein diet or administration of an angiotensin l-converting enzyme inhibitor has been s own to prevent microvascular damage in the kidney, and dietary protein restriction limits injury in the retina as well. Atrial natriuretic peptide, which is secreted by atrial myocytes in response to volume expansion, may be involved in mediation of the hemodynamic adaptation (vasodilatory response) that results in diabetic microvascular disease.
Statin Use and Risk of Delirium in the Critically Ill
Authors: Valerie J. Page, Daniel Davis, Xiao B. Zhao, Samuel Norton, Annalisa Casarin, Thomas Brown, E. Wesley Ely, Daniel F. McAuley
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Rationale: Delirium is common in intensive care unit (ICU) patients and is a predictor of worse outcomes and neuroinflammation is a possible mechanism. The antiinflammatory actions of statins may reduce delirium.Objectives: To determine whether critically ill patients receiving statin therapy had a reduced risk of delirium than those not on statins.Methods: A prospective cohort analysis of data from consecutive ICU patients admitted to a UK mixed medical and surgical critical care unit between August 2011 and February 2012; the Confusion Assessment Method for ICU was used to determine the days each patient was assessed as being free of delirium during ICU admission.Measurements and Main Results: Delirium-free days, daily administration of statins, and serum C-reactive protein (CRP) were recorded. Four hundred and seventy consecutive critical care patients were followed, of whom 151 patients received statins. Using random-effects multivariable logistic regression, statin administration the previous evening was associated with the patient being assessed as free of delirium (odds ratio, 2.28; confidence interval, 1.01–5.13; P < 0.05) and with lower CRP (β = −0.52; P < 0.01) the following day. When the association between statin and being assessed as free of delirium was controlled for CRP, the effect size became nonsignificant (odds ratio, 1.56; confidence interval, 0.64–3.79; P = 0.32).Conclusions: Ongoing statin therapy is associated with a lower daily risk of delirium in critically ill patients. An ongoing clinical trial, informed by this study, is investigating if statins are a potential therapy for delirium in the critically ill.
Implications of late complications from adhesions for preoperative informed consent
Authors: Taufiek Konrad Rajab, Umar Naeem Ahmad, Edward Kelly
Journal: Journal of the Royal Society of Medicine (2010)

Summary The process of informed consent is a critical aspect of the doctor–patient relationship. Doctors have a professional duty to provide patients with sufficient information if a treatment is associated with a significant risk. NHS guidelines advise doctors to mention risks that occur more frequently than 1–2% or risks that are serious even if the likelihood is very small. In the case of abdominal and pelvic surgery, risks can broadly be divided into early and late complications. Early complications, such as bleeding and infection, have a close temporal relationship with the operation. Such complications are routinely mentioned during the consent process. In contrast, postoperative adhesions cause changes in the normal anatomy that can adversely affect function many years and even decades after the original operation, leaving patients at lifelong risk for late complications. These late adhesive complications, namely bowel obstruction, mechanical female infertility and chronic pain, are often neglected during the consent process. However, the risks to patients from late adhesive complications are serious and well in excess of the accepted threshold where it could be considered a breach in the duty of care not to inform patients. This is reflected by a number of claims against the NHS based on consent issues regarding late adhesive complications of surgery. Therefore, late complications of surgery from adhesions should be included in the pre-operative consent process. This would decrease litigation costs but more importantly also underpins the doctor–patient relationship.
GraphProt: modeling binding preferences of RNA-binding proteins
Authors: Daniel Maticzka, Sita J Lange, Fabrizio Costa, Rolf Backofen
Journal: Genome biology (2014)

Abstract We present GraphProt, a computational framework for learning sequence- and structure-binding preferences of RNA-binding proteins (RBPs) from high-throughput experimental data. We benchmark GraphProt, demonstrating that the modeled binding preferences conform to the literature, and showcase the biological relevance and two applications of GraphProt models. First, estimated binding affinities correlate with experimental measurements. Second, predicted Ago2 targets display higher levels of expression upon Ago2 knockdown, whereas control targets do not. Computational binding models, such as those provided by GraphProt, are essential for predicting RBP binding sites and affinities in all tissues. GraphProt is freely available at http://www.bioinf.uni-freiburg.de/Software/GraphProt .
Inhibition of 11β-HSD1 with RO5093151 for non-alcoholic fatty liver disease: a multicentre, randomised, double-blind, placebo-controlled trial
Authors: Norbert Stefan, Markus Ramsauer, Paul Jordan, Bettina Nowotny, Konstantinos Kantartzis, Jürgen Machann, Jong-Hee Hwang, Peter Nowotny, Sabine Kahl, Jürgen Harreiter, Silke Hornemann, Arun J Sanyal, Paul M Stewart, Andreas F Pfeiffer, Alexandra Kautzky-Willer, Michael Roden, Hans-Ulrich Häring, Sabine Fürst-Recktenwald
Journal: The Lancet Diabetes & Endocrinology (2014)
Outcome of Patients with Platelet-Derived Growth Factor Receptor Alpha–Mutated Gastrointestinal Stromal Tumors in the Tyrosine Kinase Inhibitor Era
Authors: Philippe A. Cassier, Elena Fumagalli, Piotr Rutkowski, Patrick Schöffski, Martine Van Glabbeke, Maria Debiec-Rychter, Jean-François Emile, Florence Duffaud, Javier Martin-Broto, Bruno Landi, Antoine Adenis, François Bertucci, Emmanuelle Bompas, Olivier Bouché, Serge Leyvraz, Ian Judson, Jaap Verweij, Paolo Casali, Jean-Yves Blay, Peter Hohenberger
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Platelet-derived growth factor receptor-alpha (PDGFRA) mutations are found in approximately 5% to 7% of advanced gastrointestinal stromal tumors (GIST). We sought to extensively assess the activity of imatinib in this subgroup. Experimental Design: We conducted an international survey among GIST referral centers to collect clinical data on patients with advanced PDGFRA-mutant GISTs treated with imatinib for advanced disease. Results: Fifty-eight patients were included, 34 were male (59%), and median age at treatment initiation was 61 (range, 19–83) years. The primary tumor was gastric in 40 cases (69%). Thirty-two patients (55%) had PDGFRA-D842V substitutions whereas 17 (29%) had mutations affecting other codons of exon 18, and nine patients (16%) had mutation in other exons. Fifty-seven patients were evaluable for response, two (4%) had a complete response, eight (14%) had a partial response, and 23 (40%) had stable disease. None of 31 evaluable patients with D842V substitution had a response, whereas 21 of 31 (68%) had progression as their best response. Median progression-free survival was 2.8 [95% confidence interval (CI), 2.6–3.2] months for patients with D842V substitution and 28.5 months (95% CI, 5.4–51.6) for patients with other PDGFRA mutations. With 46 months of follow-up, median overall survival was 14.7 months for patients with D842V substitutions and was not reached for patients with non-D842V mutations. Conclusions: This study is the largest reported to date on patients with advanced PDGFRA-mutant GISTs treated with imatinib. Our data confirm that imatinib has little efficacy in the subgroup of patients with D842V substitution in exon 18, whereas other mutations appear to be sensitive to imatinib. Clin Cancer Res; 18(16); 4458–64. ©2012 AACR.
Self-paced exercise is less physically challenging than enforced constant pace exercise of the same intensity: influence of complex central metabolic control
Authors: P J Lander, R J Butterly, A M Edwards
Journal: British Journal of Sports Medicine (2009)

Objective: To examine whether self-pacing reduces the physiological challenge of performing 5000 m rowing ergometry exercise in comparison with a matched-intensity exercise condition in which a constant effort pacing strategy is enforced. Methods: Nine healthy well-trained male participants volunteered to participate in three 5000 m rowing conditions (two submaximal and one maximal conditions) in an individualised order. In the submaximal conditions, participants were required to (1) perform 5000 m at a constant rating of perceived exertion (RPE 15-Hard) (SubRPE) or (2) perform 5000 m at an enforced constant pace equivalent to the mean power output (PO) of the SubRPE condition (SubEXT). A maximal condition (MaxTT) was included to disguise the purpose of the study and to facilitate an element of randomisation in the test sequence. Dynamic intratest responses were assessed every 30s: PO, V o 2 , iEMG, core (T c ) and skin temperatures (T sk ). Results: There was no difference between performance times of the two submaximal trials. The mean PO represented 83.83 (SD 8.88)% (SubRPE) and 83.40 (8.84)% (SubEXT) of the mean MaxTT power output. T c (SubRPE:38.46 (0.23)°C, SubEXT:38.72 (0.36)°C; p&lt;0.01), post-test BLa (SubRPE:5.24 (2.18), SubEXT:6.19 (2.51) mmol/l; p&lt;0.05) and iEMG (p&lt;0.05) were significantly elevated in SubEXT compared with SubRPE. There were no differences in the dynamics of HR or V o 2 between SubEXT and SubRPE. The intratest stroke-to-stroke variability of power output was significantly greater in the SubRPE condition compared with SubEXT (p&lt;0.01). Conclusions: Enforced constant paced exercise presents a significantly greater physiological challenge than self-paced exercise. The ability to dynamically self-pace effort via manipulations of power output during exercise is an important behavioural response to homeostatic challenges and thus forms an integral part of a complex central regulatory process.
Effects of Administration to Mice of Butylated Hydroxyanisole by Oral Intubation on Benzo[ a ]pyrene-Induced Pulmonary Adenoma Formation and Metabolism of Benzo[ a ]pyrene 2
Authors: Jennine L. Speier, Luke K. T. Lam, Lee W. Wattenberg
Journal: JNCI Journal of the National Cancer Institute (1978)

Administration of butylated hydroxyanisole (BHA) by oral intubation 4 hours before challenge with benzo[a]pyrene (BP) inhibited the formation of pulmonary adenomas in A/HeJ mice. Incubation of BP with liver microsomes from mice that received BHA 2,4, or 8 hours before being killed resulted in less binding of BP metabolites to added DNA than occurred with control microsomes. High-pressure liquid chromatography studies of the BP metabolite pattern produced by the incubation of BP with liver microsomes from mice given BHA by oral intubation showed a decrease in formation of BP-4,5-oxide and 9-hydroxybenzo[a]pyrene. In contrast, the formation of 3-hydroxybenzo[a]-pyrene was increased. The was increased. The short interval between the administration of BHA by oral intubation and the observed biochemical changes indicated that BHA could exert a direct effect on the microsomal metabolism of BP. These changes in metabolism of BP occurred under conditions of BHA administration that produced a decreased neoplastic response to this carcinogen.
An Ongoing Study of Anemia Correction in Chronic Kidney Disease
Authors: Marc A. Pfeffer
Journal: New England Journal of Medicine (2007)

To the Editor: Evidence-based medicine assimilates available data to direct decisions regarding the care of patients. Extrapolations from epidemiologic observations and laboratory or clinical markers of disease severity have supported new treatments that were subsequently found to be without value in randomized, controlled clinical trials.1 In addition, therapies considered to be beneficial and safe owing to their effect on surrogate markers have been found to be ineffective or harmful in such trials.1,2 Even the results of randomized, controlled trials can be misleading, especially when the trials are not adequately powered.3 The use of erythropoietic agents to treat anemia in . . .
Postprandial lipemia. A key for the conversion of high density lipoprotein2 into high density lipoprotein3 by hepatic lipase.
Authors: J R Patsch, S Prasad, A M Gotto, G Bengtsson-Olivecrona
Journal: Journal of Clinical Investigation (1984)

In this study, we have investigated the effects of alimentary lipemia in 15 normotriglyceridemic individuals on high density lipoproteins2 (HDL2) with respect to structure, composition, and substrate efficacy for hepatic lipase in vitro. In the study subjects, HDL2 levels ranged widely from 4.7 to 151.7 mg/dl plasma. HDL2 were isolated in the postabsorptive (pa) state and in the postprandial (pp) state, i.e., 7 h after ingestion of a standard fatty meal. In going from the pa state to the pp state, HDL2 exhibited higher flotation rates and lower densities due to a decreased proportion of protein (38.7----36.2%) and a higher abundance in phospholipid (32.5----34.9%). There was a variable increase in triglyceride at the expense of cholesteryl esters; this increase was correlated positively with the magnitude of pp lipemia (r = 0.69, P less than 0.01) and inversely with HDL2 levels (r = -0.72, P less than 0.01). Hdl2 fractions were incubated with human hepatic lipase in vitro. Product lipoproteins formed from lipolysis of pa-HDL2 and triglyceride-poorer pp-HDL2 were reduced in phospholipid content (by 25 and 50%, respectively) but remained in the size and density range of native HDL2. By contrast, a major fraction of triglyceride-richer pp-HDL2 was converted to particles with density, size, and apoprotein composition of native HDL3. Changes consistent with these findings in vitro were observed in vivo also, where 15 h postprandially, individuals with high-level lipemia showed a decrease in HDL2 and rise in HDL3, while those with lower-level lipemia did not. This study indicates that the magnitude of postprandial lipemia determines the proportion of triglyceride in pp-HDL2, which in turn determines whether or not HDL2 are converted to HDL3 by hepatic lipase action.