tbuckley/cabot-search huggingface dataset:
Current prodrug strategies for improving oral absorption of nucleoside analogues
Authors: Youxi Zhang, Yikun Gao, Xiaojing Wen, Haiying Ma
Journal: Asian Journal of Pharmaceutical Sciences (2014)

Nucleoside analogues are first line chemotherapy in various severe diseases: AIDS (acquired immunodeficiency disease syndrome), cytomegalovirus infections, cancer, etc. However, many nucleoside analogues exhibit poor oral bioavailability because of their high polarity and low intestinal permeability. In order to get around this drawback, prodrugs have been utilized to improve lipophilicity by chemical modification of the parent drug. Alternatively, prodrugs targeting transporters present in the intestine have been applied to promote the transport of the nucleoside analogues. Valacyclovir and valganciclovir are two classic valine ester prodrugs transported by oligopeptide transporter 1. The ideal prodrug achieves delivery of a parent drug by attaching a non-toxic moiety that is stable during transport, but is readily degraded to the parent drug once at the target. This article presents advances of prodrug approaches for enhancing oral absorption of nucleoside analogues.
Genome Nucleotide Composition Shapes Variation in Simple Sequence Repeats
Authors: X. Tian, J. E. Strassmann, D. C. Queller
Journal: Molecular Biology and Evolution (2010)

Simple sequence repeats (SSRs) or microsatellites are a common component of genomes but vary greatly across species in their abundance. We tested the hypothesis that this variation is due in part to AT/GC content of genomes, with genomes biased toward either high AT or high CG generating more short random repeats that are long enough to enhance expansion through slippage during replication. To test this hypothesis, we identified repeats with perfect tandem iterations of 1–6 bp from 25 protists with complete or near-complete genome sequences. As expected, the density and the frequency are highly related to genome AT content, with excellent fits to quadratic regressions with minima near a 50% AT content and rising toward both extremes. Within species, the same trends hold, except the limited variation in AT content within each species places each mainly on the descending (GC rich), middle, or ascending (AT rich) part of the curve. The base usages of repeat motifs are also significantly correlated with genome nucleotide compositions: Percentages of AT-rich motifs rise with the increase of genome AT content but vice versa for GC-rich subgroups. Amino acid homopolymer repeats also show the expected quadratic relationship, with higher abundance in species with AT content biased in either direction. Our results show that genome nucleotide composition explains up to half of the variance in the abundance and motif constitution of SSRs.
Dose-Response in Radiotherapy for Localized Prostate Cancer: Results of the Dutch Multicenter Randomized Phase III Trial Comparing 68 Gy of Radiotherapy With 78 Gy
Authors: Stephanie T.H. Peeters, Wilma D. Heemsbergen, Peter C.M. Koper, Wim L.J. van Putten, Annerie Slot, Michel F.H. Dielwart, Johannes M.G. Bonfrer, Luca Incrocci, Joos V. Lebesque
Journal: Journal of Clinical Oncology (2006)

Purpose To determine whether a dose of 78 Gy improves outcome compared with a conventional dose of 68 Gy for prostate cancer patients treated with three-dimensional conformal radiotherapy. Patients and Methods Between June 1997 and February 2003, stage T1b-4 prostate cancer patients were enrolled onto a multicenter randomized trial comparing 68 Gy with 78 Gy. Patients were stratified by institution, age, (neo)adjuvant hormonal therapy (HT), and treatment group. Four treatment groups (with specific radiation volumes) were defined based on the probability of seminal vesicle involvement. The primary end point was freedom from failure (FFF). Failure was defined as clinical failure or biochemical failure, according to the American Society of Therapeutic Radiation Oncology definition. Other end points were freedom from clinical failure (FFCF), overall survival (OS), and toxicity. Results Median follow-up time was 51 months. Of the 669 enrolled patients, 664 were included in the analysis. HT was prescribed for 143 patients. FFF was significantly better in the 78-Gy arm compared with the 68-Gy arm (5-year FFF rate, 64% v 54%, respectively), with an adjusted hazard ratio of 0.74 (P = .02). No significant differences in FFCF or OS were seen between the treatment arms. There was no difference in late genitourinary toxicity of Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer grade 2 or more and a slightly higher nonsignificant incidence of late gastrointestinal toxicity of grade 2 or more. Conclusion This multicenter randomized trial shows a significantly improved FFF in prostate cancer patients treated with a higher dose of radiotherapy.
An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels.
Authors: B Rigat, C Hubert, F Alhenc-Gelas, F Cambien, P Corvol, F Soubrier
Journal: Journal of Clinical Investigation (1990)

A polymorphism consisting of the presence or absence of a 250-bp DNA fragment was detected within the angiotensin I-converting enzyme gene (ACE) using the endothelial ACE cDNA probe. This polymorphism was used as a marker genotype in a study involving 80 healthy subjects, whose serum ACE levels were concomitantly measured. Allele frequencies were 0.6 for the shorter allele and 0.4 for the longer allele. A marked difference in serum ACE levels was observed between subjects in each of the three ACE genotype classes. Serum immunoreactive ACE concentrations were, respectively, 299.3 +/- 49, 392.6 +/- 66.8, and 494.1 +/- 88.3 micrograms/liter, for homozygotes with the longer allele (n = 14), and heterozygotes (n = 37) and homozygotes (n = 29) with the shorter allele. The insertion/deletion polymorphism accounted for 47% of the total phenotypic variance of serum ACE, showing that the ACE gene locus is the major locus that determines serum ACE concentration. Concomitant determination of the ACE genotype will improve discrimination between normal and abnormal serum ACE values by allowing comparison with a more appropriate reference interval.
Pak-1 Expression Increases with Progression of Colorectal Carcinomas to Metastasis
Authors: Julia H. Carter, Larry E. Douglass, James A. Deddens, Bruce M. Colligan, Tejal R. Bhatt, Jackson O. Pemberton, Susan Konicek, Joanne Hom, Mark Marshall, Jeremy R. Graff
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The p21-activated kinase-1 (Pak-1) promotes cell motility and invasiveness. Pak-1 is activated by the Rac, Rho, and Cdc42 small GTPases in response to a variety of stimuli including ras and phosphatidylinositol 3′-kinase/AKT pathway activation. Because Pak-1 plays a central role in regulating cell motility and invasiveness, we sought to determine whether Pak-1 may be involved in the malignant progression of colorectal carcinoma. Experimental Design: Pak-1 expression was examined by immunohistochemistry in archived tissues from normal human colons, tubular and tubulovillous adenomas, invasive adenocarcinomas (stages I-III/IV), and lymph node metastases (184 total specimens from 38 patients). Specific cytoplasmic immunostaining was evaluated for overall intensity and uniformity to derive a combined histoscore (stain intensity × percentage of epithelium stained). Results: Pak-1 expression was increased significantly with colorectal cancer progression from normal tissue to lymph node metastases (P &amp;lt; 0.0001). Furthermore, Pak-1 expression was increased significantly in adenomas, invasive carcinomas, and lymph node metastases compared with normal colon (P &amp;lt; 0.0001). Strikingly, Pak-1 expression was significantly higher in lymph node metastases than in invasive cancers, adenomas, or normal colon (P &amp;lt; 0.0001). Moreover, in patients with multiple lesions representing different stages of disease, Pak-1 expression was increased specifically in the most advanced lesions. Conclusions: This study demonstrates that Pak-1 expression is increased significantly with malignant progression of human colorectal carcinoma. These data, along with numerous functional studies demonstrating a central role for Pak-1 activity in tumor invasiveness and motility, implicate Pak-1 as an exciting target for therapy of colorectal carcinoma.
GPs, rather than the government, should be blamed for failures in new NHS, MPs are told
Authors: A. O'Dowd
Journal: BMJ (2011)

GPs on the new clinical commissioning groups (CCGs) in the NHS in England should take responsibility for any clinical failures and budget overspends rather than blaming the government, MPs have heard.

Responsibility should lie at the local level of the NHS once the reforms of the health service take effect, claimed Malcolm Grant, chairman of the NHS Commissioning Board, which will oversee England’s clinical commissioning groups.

Professor Grant, president and provost of University College London, was giving evidence to the health select committee on 18 October as a one off pre-appointment session to quiz him as the candidate chosen for the job by the health secretary Andrew Lansley. The Department of Health confirmed his appointment …
Immunoglobulin g lymphocytotoxic antibodies in clinical liver transplantation: Studies toward further defining their significance
Authors: Rafael Mañez, Robert H. Kelly, Makoto Kobayashi, Shunichi Takaya, Oscar Bronsther, David Kramer, Rene J. Duquesnoy, Yuichi Iwaki, John J. Fung, Thomas E. Starzl, Anthony J. Demetris
Journal: Hepatology (1995)

Twenty-two consecutive liver allograft recipients, who tested positive for immunoglobulin G (IgG) lympho-cytotoxicity were subjected to pretransplantion and posttransplantation immunologic monitoring of antidonor IgG lymphocytotoxic antibody titers, total hemolytic complement activity (CH100), circulating immune complexes (CIC), and platelet counts in an effort to improve our understanding of the preformed antibody state in clinical hepatic transplantation. Ten contemporaneous liver transplant recipients whose crossmatch results were negative and who experienced severe hepatocellular damage early after transplantation were included as controls. Crossmatch test results were negative 1 day after transplantation and during the 1 month follow-up remained negative in 14 of 22 (64%) sensitized recipients, most of whom had relatively low (≦ 1:16) antidonor IgG antibody titers before transplantation. After transplantation, this group and the control group experienced no thrombocytopenia, no increase of CIC, and a gradual increase in CH100 activity that reached normal levels within 1 week. A strong negative correlation between prothrombin time (PT) and CH100 activity in these groups of patients suggested that changes in CH100 activity (P < 0.0005) were tightly linked to liver synthetic function. In contrast, the crossmatch test results remained positive after transplantation in 8 of 22 (36%) sensitized recipients, all of whom had relatively high (> 1:32 to 1024) pretransplantation titers of antidonor IgG antibodies. After transplantation these patients developed a syndrome that was characterized by decreased CH100 activity and increased CIC compared with pretransplantation levels and refractory thrombocytopenia that was associated with a 50% allograft failure rate because of biopsy-proven humoral and acute (cellular) rejection. Moreover, the lack of a strong negative correlation between PT and CH100 activity (P = 0.1) in this group of patients suggested that the hypocomplementemia was not tightly linked to liver synthetic function. Before transplantation, determination of anti—donor antibody class (IgG) and titer alone showed a strong negative predictive value (100%) but less than optimal positive predictive value (67%) for identifying patients who experienced the posttransplantation syndrome described above. Therefore, evaluation of platelet counts, CH100 activity, CIC, persistence of anti-donor antibodies and results of a liver biopsy performed after transplantation assisted in identifying sensitized liver allograft recipients who suffered the adverse consequences of the preformed antibody state.
Fibroma of the Visceral Pleura
Authors: C. P. Thomas, C. E. Drew
Journal: Thorax (1953)

Intrathoracic fibromas are rare tumours, but as might be expected they have been described in many different situations within the chest in relation to areas of connective tissue.In a personal series of 198 primary intrathoracic neoplasms, excluding carcinoma of the lung and oesophagus, Harrington (1950) encountered 13 fibromas or lipofibromas, all of which arose in the posterior mediastinum, but most of those which have been fully described appear in single case reports.Study of the available literature suggests that these tumours may be classified in four groups depending upon their position.Some have been found in the larger bronchi and occasionally diagnosed after biopsy through a bronchoscope.Others have been identified in relation to the parietal pleura, although some of these are undoubtedly fibrous tumours of neural origin.The third gi oup occurs in the mediastinum and the fourth comprises those which appear to arise beneath the visceral pleura.The growth may assume giant size before the onset of symptoms referable to the chest, and may obtain additional blood supply through adhesion to neighbouring structures.It is then difficult-and sometimes impossible-to define its origin.Clagett and Hausmann (1944) claim the biggest fibroma yet removed from the chest, a mass weighing 5 kg., filling the lower part of the right pleural cavity and extending behind the heart to the left side.This was so densely adherent that it was not possible to decide whether it arose beneath the visceral or parietal pleura.This paper is intended to describe our findings in some examples which fall in the fourth group, i.e., those which we believe arise in close relation to the visceral pleura.CASE REPORTS CASE 1.-The patient was a man of 62 years of age when surgical operation was advised in 1947.At the age of 13 he developed right-sided pleurisy.When he was 21 years of age he spent two months in a sanatorium
Gene expression profiling reveals a downregulation in immune-associated genes in patients with AS
Authors: R. Duan, P. Leo, L. Bradbury, M. A. Brown, G. Thomas
Journal: Annals of the Rheumatic Diseases (2009)

<h3>Objective</h3> To identify differentially expressed genes in peripheral blood mononuclear cells (PBMCs) from patients with ankylosing spondylitis (AS) compared with healthy individuals. <h3>Methods</h3> RNA was extracted from PBMCs collected from 18 patients with active disease and 18 gender-matched and age-matched controls. Expression profiles of these cells were determined using microarray. Candidate genes with differential expressions were confirmed in the same samples using quantitative reverse transcription-PCR (qRT-PCR). These genes were then validated in a different sample cohort of 35 patients with AS and 18 controls by qRT-PCR. <h3>Results</h3> Microarray analysis identified 452 genes detected with 485 probes which were differentially expressed between patients with AS and controls. Underexpression of NR4A2, tumour necrosis factor AIP3 (TNFAIP3) and CD69 was confirmed. These genes were further validated in a different sample group in which the patients with AS had a wider range of disease activity. Predictive algorithms were also developed from the expression data using receiver-operating characteristic curves, which demonstrated that the three candidate genes have ∼80% power to predict AS according to their expression levels. <h3>Conclusions</h3> The findings show differences in global gene expression patterns between patients with AS and controls, suggesting an immunosuppressive phenotype in the patients. Furthermore, downregulated expression of three immune-related genes was confirmed. These candidate genes were also shown to be strong predictive markers for AS.
Hypothyroidism after Sunitinib Treatment for Patients with Gastrointestinal Stromal Tumors
Authors: Jayesh Desai, Leila Yassa, Ellen Marqusee, Suzanne George, Mary C. Frates, Ming Hui Chen, Jeffrey A. Morgan, Samuel S. Dychter, P. Reed Larsen, George D. Demetri, Erik K. Alexander
Journal: Annals of Internal Medicine (2006)

Background: Sunitinib malate is an oral tyrosine kinase inhibitor recently approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Because the ret proto-oncogene is also inhibited by this agent, clinical evaluation of thyroid function was performed. Objective: To describe the prevalence and clinical presentation of thyroid dysfunction related to sunitinib therapy. Design: Prospective, observational cohort study. Setting: Tertiary care hospital. Patients: 42 patients treated for a median of 37 weeks (range, 10 to 167 weeks). Measurements: Following analysis of serial thyroid-stimulating hormone (TSH) measurements collected prospectively during a clinical trial of sunitinib, the authors determined the proportion of patients with thyroid dysfunction. Results: Abnormal serum TSH concentrations were documented in 26 of 42 patients (62%): 15 (36%) developed persistent, primary hypothyroidism; 4 (10%) developed isolated TSH suppression; and 7 (17%) experienced transient, mild TSH elevations. The risk for hypothyroidism increased with the duration of sunitinib therapy. Six of 15 (40%) hypothyroid patients had suppressed TSH concentrations before developing hypothyroidism, suggesting thyroiditis. Two hypothyroid patients evaluated with thyroid ultrasonography had no visualized thyroid tissue despite normal baseline thyroid function. Limitations: The exploratory nature of this study precluded more frequent biochemical and sonographic analysis that may better define the mechanism of sunitinib-associated thyroid dysfunction. Conclusion: Hypothyroidism is a frequent complication of sunitinib therapy. Regular surveillance of thyroid function is warranted in patients receiving the drug. Although the mechanism by which this complication occurs is unknown, the observations of preceding TSH suppression and subsequent absence of visualized thyroid tissue in some patients suggest that sunitinib may induce a destructive thyroiditis through follicular cell apoptosis. This provides a rationale for further investigation of sunitinib treatment in patients with advanced thyroid cancer.
Nanoparticle-Aptamer Bioconjugates
Authors: Omid C. Farokhzad, Sangyong Jon, Ali Khademhosseini, Thanh-Nga T. Tran, David A. LaVan, Robert Langer
Journal: Cancer Research (2004)

Nucleic acid ligands (aptamers) are potentially well suited for the therapeutic targeting of drug encapsulated controlled release polymer particles in a cell- or tissue-specific manner. We synthesized a bioconjugate composed of controlled release polymer nanoparticles and aptamers and examined its efficacy for targeted delivery to prostate cancer cells. Specifically, we synthesized poly(lactic acid)-block-polyethylene glycol (PEG) copolymer with a terminal carboxylic acid functional group (PLA-PEG-COOH), and encapsulated rhodamine-labeled dextran (as a model drug) within PLA-PEG-COOH nanoparticles. These nanoparticles have the following desirable characteristics: (a) negative surface charge (-50 +/- 3 mV, mean +/- SD, n = 3), which may minimize nonspecific interaction with the negatively charged nucleic acid aptamers; (b) carboxylic acid groups on the particle surface for potential modification and covalent conjugation to amine-modified aptamers; and (c) presence of PEG on particle surface, which enhances circulating half-life while contributing to decreased uptake in nontargeted cells. Next, we generated nanoparticle-aptamer bioconjugates with RNA aptamers that bind to the prostate-specific membrane antigen, a well-known prostate cancer tumor marker that is overexpressed on prostate acinar epithelial cells. We demonstrated that these bioconjugates can efficiently target and get taken up by the prostate LNCaP epithelial cells, which express the prostate-specific membrane antigen protein (77-fold increase in binding versus control, n = 150 cells per group). In contrast to LNCaP cells, the uptake of these particles is not enhanced in cells that do not express the prostate-specific membrane antigen protein. To our knowledge, this represents the first report of targeted drug delivery with nanoparticle-aptamer bioconjugates.
MDM2 antagonists boost antitumor effect of androgen withdrawal: implications for therapy of prostate cancer
Authors: Christian Tovar, Brian Higgins, Kenneth Kolinsky, Mingxuan Xia, Kathryn Packman, David C Heimbrook, Lyubomir T Vassilev
Journal: Molecular Cancer (2011)

Abstract Background Hormone therapy is the standard of care for newly diagnosed or recurrent prostate cancers. It uses anti-androgen agents, castration, or both to eliminate cancer promoting effect of testicular androgen. The p53 tumor suppressor controls a major pathway that can block cell proliferation or induce apoptosis in response to diverse forms of oncogenic stress. Activation of the p53 pathway in cancer cells expressing wild-type p53 has been proposed as a novel therapeutic strategy and recently developed MDM2 antagonists, the nutlins, have validated this in preclinical models of cancer. The crosstalk between p53 and androgen receptor (AR) signaling suggest that p53 activation could augment antitumor outcome of androgen ablation in prostate cancer. Here, we test this hypothesis in vitro and in vivo using the MDM2 antagonist, nutlin-3 and the p53 wild-type prostate cancer cell line, LNCaP. Results Using charcoal-stripped serum as a cellular model of androgen deprivation, we show an increased apoptotic effect of p53 activation by nutlin-3a in the androgen-dependent LNCaP cells and to a lesser extent in androgen-independent but responsive 22Rv1 cell line. This effect is due, at least in part, to an enhanced downregulation of AR expression by activated p53. In vivo, androgen deprivation followed by two weeks of nutlin administration in LNCaP-bearing nude mice led to a greater tumor regression and dramatically increased survival. Conclusions Since majority of prostate tumors express wild-type p53, its activation by MDM2 antagonists in combination with androgen depletion may offer an efficacious new approach to prostate cancer therapy.