tbuckley/cabot-search huggingface dataset:
Caspase-3 Activity Predicts Local Recurrence in Rectal Cancer
Authors: Pieter de Heer, Elza C. de Bruin, Elma Klein-Kranenbarg, Remco I.J.M. Aalbers, Corrie A.M. Marijnen, Hein Putter, Hans J. de Bont, J. Fred Nagelkerke, J. Han J.M. van Krieken, Hein W. Verspaget, Cornelis J.H. van de Velde, Peter J.K. Kuppen
Journal: Clinical Cancer Research (2007)

Radiotherapy followed by total mesorectal excision surgery has been shown to significantly reduce local recurrence rates in rectal cancer patients. Radiotherapy, however, is associated with considerable morbidity. The present study evaluated the use of biochemical detection of enzymatic caspase-3 activity as preoperative marker for apoptosis to preselect patients that are unlikely to develop a local recurrence to spare these patients from overtreatment and the negative side effects of radiotherapy.Nonirradiated freshly frozen tissue samples from 117 stage III rectal cancer patients were collected from a randomized clinical trial that evaluated preoperative radiotherapy in total mesorectal excision surgery. Additional frozen archival tissues from 47 preoperative biopsies and corresponding resected colorectal tumors were collected. Level of apoptosis was determined by measuring the enzymatic activity of caspase-3 in a biochemical assay.In tumor tissue, caspase-3 activity lower than the median was predictive of 5-year local recurrence (hazard ratio, 7.4; 95% confidence interval, 1.7-32.8; P = 0.008), which was unaffected by adjustment for type of resection, tumor location, and T status (adjusted hazard ratio, 7.5; 95% confidence interval, 1.7-34.1; P = 0.009). Caspase-3 activity in preoperative biopsies was significantly correlated with caspase-3 activity in corresponding resected tumors (r = 0.56; P < 0.0001).Detection of tumor apoptosis levels by measuring caspase-3 activity, for which a preoperative biopsy can be used, accurately predicted local recurrence in rectal cancer patients. These findings indicate that caspase-3 activity is an important denominator of local recurrence and should be evaluated prospectively to be added to the criteria to select rectal cancer patients in which radiotherapy is redundant.
"Deeply disappointing" public health cuts will increase demand on NHS,says expert
Authors: C. White
Journal: BMJ (2015)

A large three-generation family with autosomal dominant type 1 porencephaly from southern Italy was studied. A high rate of miscarriages was observed. Of the nine affected individuals, four displayed a severe phenotype, and five had slight pyramidal signs or mild cognitive abnormalities. The MRI study disclosed unilateral porencephalic cyst, or colpocephaly. A genome-wide screen resulted in suggestive evidence for linkage to chromosome 13qter with a maximum logarithm-of-the-odds score of 3.16, from multipoint analysis, with marker D13S285.
Benefit of interferon therapy in hepatocellular carcinoma prevention for individual patients with chronic hepatitis C
Authors: H Yoshida
Journal: Gut (2004)

<b>Background:</b> An increase in the incidence of hepatocellular carcinoma (HCC) in Japan since the 1980s suggests an imminent outbreak in other countries where viral spread occurred more recently. Interferon therapy for chronic hepatitis C, in general, has been shown to prevent HCC. <b>Aims:</b> To determine the scale of benefit in individual patients. <b>Subjects:</b> Histologically proven chronic hepatitis C patients in the Inhibition of Hepatocarcinogenesis by Interferon Therapy (IHIT) cohort (Ann Intern Med1999;131:174), as updated in March 2003. <b>Methods:</b> The lifetime risk for HCC was calculated based on HCC incidence rates, stratified by sex, age, fibrosis stage, and outcome of interferon therapy. The gain in HCC free survival was defined as the difference between expected HCC free survival with sustained virological response and that without. <b>Results:</b> The gain in HCC free survival was greater when a patient was younger and fibrosis was more advanced. For example, a 30 year old male with F3 fibrosis gained 12.4 years by attaining sustained response while a patient with F1 fibrosis older than 60 years gained less than one year. For a treatment protocol with a given sustained response rate, prior estimation of the gain can be obtained by multiplying the calculated HCC free survival for responders by the response rate. <b>Conclusions:</b> The gain in HCC free survival may serve as an indicator of the benefit of interferon therapy in terms of HCC prevention and be useful in the consideration of indication and selection of treatment protocol for individual patients.
IT-19 * TEMOZOLAMIDE RESISTANT INNATE LYMPHOCYTES ADMINISTERED DURING CHEMOTHERAPY IMPROVE SURVIVAL IN HIGH-GRADE GLIOMA
Authors: L. Lamb, L. Pereboeva, G. Gillespie, S. Langford, G. Cloud, H. Spencer
Journal: Neuro-Oncology (2014)

Conventional treatment strategies for high-grade primary brain tumors have failed to consistently extend median survival beyond two years. Using a human/mouse xenograft model, we report improved survival using a combination of Temozolomide (TMZ) chemotherapy with a Drug Resistant Cellular Immunotherapy (DRI) consisting of activated MGMT-transduced γδ T cells and NK cells. MGMT genetic engineering enables cytotoxic lymphocyte function in a chemotherapy-rich environment at a time when the tumor is maximally stressed. Intracranial (IC) glioma xenografts were established using either unmodified (P) or a TMZ-resistant clone (T) of human GBM-X12 primary explants propagated in mice. Tumor-bearing mice were treated i.p. with 60mg/kg TMZ on days 6, 8,13, and 15 post-tumor placement and received IC injection of 1 x 106 MGMT-modified DRI on post-injection days 7 and 14. Control mice received non-modified cells, TMZ alone or no therapy. Survival was assessed using Kaplan-Meier analysis. Both GBM-X12P and X12T express stress antigens MIC-A, MIC-B, and ULBP-4 with only ULBP-4 slightly upregulated on X12T upon exposure to TMZ. Both tumors were killed by expanded/activated γδ T cells in vitro at approximately 80% at an effector : target ratio of 20:1. Cell therapy alone did not improve survival beyond that of untreated mice for either tumor. For the unmodified tumor X12P, both TMZ therapy and TMZ + DRI significantly improved survival over untreated controls (p < 0.001), and the combined therapy increased median survival from 57 to 75 days over TMZ alone. Combined therapy with TMZ + DRI also improved survival for X12T (p = 0.0147) over untreated controls, and showed a marginal improvement over TMZ alone (p = 0.0966) and improvement in median survival from 22 to 25 days. In summary, the combination of chemotherapy-induced stress antigen expression and targeted DRI significantly increases time to progression and improves survival in tumor-bearing immunodeficient mice.
Seasonal Childhood Anaemia in West Africa Is Associated with the Haptoglobin 2-2 Genotype
Authors: Sarah H Atkinson, Kirk Rockett, Giorgio Sirugo, Philip A Bejon, Anthony Fulford, Maria A O'Connell, Robin Bailey, Dominic P Kwiatkowski, Andrew M Prentice
Journal: PLoS Medicine (2006)

Background Anaemia is a major cause of morbidity and mortality for children in Africa. The plasma protein haptoglobin (Hp) binds avidly to free haemoglobin released following malaria-induced haemolysis. Haptoglobin polymorphisms result in proteins with altered haemoglobin-binding capacity and different antioxidant, iron-recycling, and immune functions. Previous studies examined the importance of haptoglobin polymorphism in malaria and iron homeostasis, but it is unknown whether haptoglobin genotype might be a risk factor for anaemia in children in a malaria-endemic area. Methods and Findings A cohort of 780 rural Gambian children aged 2–6 y was surveyed at the start and end of the malaria season. Samples were taken to assess haemoglobin (Hb) concentration, iron status (ferritin, zinc protoporphyrin, transferrin saturation, and soluble transferrin receptor concentration), haptoglobin concentration, α-1-antichymotrypsin (a measure of inflammation), and malaria parasites on blood film. We extracted DNA and genotyped for haptoglobin, sickle cell, and glucose-6-phosphate (G6PD) deficiency. Mean Hb levels fell over the malaria season. Children with the haptoglobin 2-2 genotype (17%) had a greater mean drop in Hb level over the malaria season (an 8.9 g/l drop; confidence interval [CI] 5.7, 12.1) compared to other children (a 5.1 g/l drop; CI 3.8, 6.4). In multivariate regression analysis, controlling for baseline Hb level, age group, village, malaria parasites on blood film, iron status, haptoglobin concentration, and G6PD deficiency, haptoglobin genotype predicted Hb level at the end of the malaria season ( p = 0.0009, coefficient = −4.2). Iron status was not influenced by haptoglobin genotype. Conclusions The finding that haptoglobin 2-2 genotype is a risk factor for anaemia in children in a malaria-endemic area may reflect the reduced ability of the Hp2-2 polymer to scavenge free haemoglobin-iron following malaria-induced haemolysis. The magnitude of the effect of haptoglobin genotype (4 g/l Hb difference, p = 0.0009) was comparable to that of G6PD deficiency or HbAS (3 g/l difference, p = 0.03; and 2 g/l difference, p = 0.68, respectively).
PET imaging of CXCR4 using copper-64 labeled peptide antagonist
Authors: Orit Jacobson, Ido D. Weiss, Lawrence P. Szajek, Gang Niu, Ying Ma, Dale O. Kiesewetter, Joshua M. Farber, Xiaoyuan Chen
Journal: Theranostics (2011)

Expression of CXCR4 in cancer has been found to correlate with poor prognosis and resistance to chemotherapy. In this study we developed a derivative of the CXCR4 peptide antagonist, T140-2D, that can be labeled easily with the PET isotope copper-64, and thereby enable in vivo visualization of CXCR4 in tumors. T140 was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono (N-hydroxysuccinimide ester) (DOTA-NHS) to give T140-2D, which contains a DOTA molecule on each of the two lysine residues. (64)Cu-T140-2D was evaluated in vitro by migration and binding experiments, and in vivo by microPET imaging and biodistribution, in mice bearing CXCR4-positive and CXCR4-negative tumor xenografts. T140-2D was labeled with copper-64 to give (64)Cu-T140-2D in a high radiochemical yield of 86 ± 3% (not decay-corrected) and a specific activity of 0.28 - 0.30 mCi/µg (10.36 - 11.1 MBq/µg). (64)Cu-T140-2D had antagonistic and binding characteristics to CXCR4 that were similar to those of T140. In vivo, (64)Cu-T140-2D tended to bind to red blood cells and had to be used in a low specific activity form. In this new form (64)Cu-T140-2D enabled specific imaging of CXCR4-positive, but not CXCR4-negative tumors. Undesirably, however, (64)Cu-T140-2D also displayed high accumulation in the liver and kidneys. In conclusion, (64)Cu-T140-2D was easily labeled and, in its low activity form, enabled imaging of CXCR4 in tumors. It had high uptake, however, in metabolic organs. Further research with imaging tracers targeting CXCR4 is required.
Simvastatin Depresses Blood Clotting by Inhibiting Activation of Prothrombin, Factor V, and Factor XIII and by Enhancing Factor Va Inactivation
Authors: Anetta Undas, Kathleen E. Brummel, Jacek Musial, Kenneth G. Mann, Andrew Szczeklik
Journal: Circulation (2001)

Background —The mechanism of the antithrombotic action of statins is unclear. The aim of this study was to evaluate the effects of simvastatin on the coagulation process at sites of microvascular injury. Methods and Results —Tissue factor–initiated coagulation was assessed in blood samples collected every 30 seconds from bleeding-time wounds of 17 patients who had advanced coronary artery disease and total cholesterol levels of 224.6±11.8 mg/dL (mean±SEM). Quantitative Western blotting for time courses of fibrinogen depletion and activation of prothrombin, factor V, and factor XIII was performed before and after 3 months of simvastatin treatment (20 mg/d). Simvastatin induced reductions in total cholesterol (23%) and LDL-cholesterol (36%), which were accompanied by significant decreases in the rates of prothrombin activation (16.2±2.1%; P =0.004), formation of α-thrombin B-chain (27.4±1.8%; P =0.001), generation of factor Va heavy chain (29.7±3.1%; P =0.007) and factor Va light chain (18.9±1.2%; P =0.02), factor XIII activation (19.8±1.3%; P =0.001), and fibrinogen conversion to fibrin (72.2±3%; P =0.002). Posttreatment fibrinopeptides A and B concentrations, determined by using high-performance liquid chromatography, were reduced within the last 30 seconds of bleeding. The 30-kDa fragment of the factor Va heavy chain (residues 307 to 506), produced by activated protein C, and the 97-kDa fragment of the factor Va heavy chain (residues 1 to 643) were released more rapidly after simvastatin treatment. The antithrombotic actions of simvastatin showed no relationship to its cholesterol-lowering action. Conclusions —Simvastatin treatment depresses blood clotting, which leads to reduced rates of prothrombin activation, factor Va generation, fibrinogen cleavage, factor XIII activation, and an increased rate of factor Va inactivation. These effects are not related to cholesterol reduction.
Phosphorylation of Thr18 and Ser20 of p53 in Ad-p53–induced apoptosis
Authors: Akira Nakamizo, Toshiyuko Amano, Wei Zhang, Xin-Qiao Zhang, Latha Ramdas, Ta-Jen Liu, B. Nebiyou Bekele, Tadahisa Shono, Tomio Sasaki, William F. Benedict, Raymond Sawaya, Frederick F. Lang
Journal: Neuro-Oncology (2008)

The p53 protein plays a critical role in inducing cell cycle arrest or apoptosis. Because p53 is inactivated in human gliomas, restoring p53 function is a major focus of glioma therapy. The most clinically tested strategy for replacing p53 has been adenoviral-mediated p53 gene therapy (Ad-p53). In addition to their therapeutic implications, investigations into Ad-p53 provide model systems for understanding p53's ability to induce cell cycle arrest versus apoptosis, particularly because wild-type p53 cells are resistant to Ad-p53–induced apoptosis. Here we use Ad-p53 constructs to test the hypothesis that simultaneous phosphorylation of p53 at threonine 18 (Thr18) and serine 20 (Ser20) is causally associated with p53-mediated apoptosis. Studies using phosphorylation-specific antibodies demonstrated that p53-induced apoptosis correlates with phosphorylation of p53 at Thr18 and Ser20 but not with carboxy-terminal phosphorylation (Ser392). To prove a causal relationship between apoptosis and Thr18 and Ser20 phosphorylation of p53, the effects of an adenoviral p53 construct that was not phosphorylated (Ad-p53) was compared with a Thr18/Ser20 phosphomimetic construct (Ad-p53-18D20D) in wild-type p53 gliomas. Whereas treatment with Ad-p53 resulted only in cell cycle arrest, treatment with Ad-p53-18D20D induced dramatic apoptosis. Microarray and Western blot analyses showed that only Ad-p53-18D20D was capable of inducing expression of apoptosis-inducing proteins. Chromatin immunoprecipitation assays indicated that the protein product of Ad-p53-18D20D, but not Ad-p53, was capable of binding to apoptosis-related genes. We thus conclude that phosphorylation of Thr18 and Ser20 is sufficient for inducing p53-mediated apoptosis in glioma cells. These results have implications for p53 gene therapy and inform other strategies that aim to restore p53 function.
CUTANEOUS VASOCONSTRICTORS, PRIMARY PIGMENTATION AND THE GREY-BLUE REACTION.
Authors: G. H. FINDLAY
Journal: British Journal of Dermatology (1961)

Journal Article CUTANEOUS VASOCONSTRICTORS, PRIMARY PIGMENTATION AND THE GREY‐BLUE REACTION. Get access G. H. FINDLAY G. H. FINDLAY Section of Dermatology, University of Pretoria, Transvaal, and Photobiology Research Group, Council for Scientific and Industrial Research Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 73, Issue 6, 1 June 1961, Pages 238–243, https://doi.org/10.1111/j.1365-2133.1961.tb14438.x Published: 01 June 1961
Adenovirus-Mediated p14ARF Gene Transfer in Human Mesothelioma Cells
Authors: C.-T. Yang, L. You, C.-C. Yeh, J. W.-C. Chang, F. Zhang, F. McCormick, D. M. Jablons
Journal: JNCI Journal of the National Cancer Institute (2000)

The p14(ARF) protein encoded by the INK4a/ARF locus promotes degradation of the MDM2 protein and thus prevents the MDM2-mediated inhibition of p53. Homozygous deletion of the INK4a/ARF locus is common in human mesothelioma and may result in the loss of p14(ARF) and the inactivation of p53. We designed this study to evaluate the biologic and potential therapeutic roles of p14(ARF) expression in mesothelioma cells.We constructed Adp14, an adenoviral vector carrying human p14(ARF) complementary DNA, and used it to transfect human mesothelioma cell lines H28, H513, H2052, and MSTO-211H. Overexpression of p14(ARF) led to increased amounts of p53 and the p21(WAF) proteins and dephosphorylation of the retinoblastoma protein. The growth rate of mesothelioma cells was inhibited markedly by infection with Adp14 compared with mock infection or infection with a control adenovirus vector, AdCtrl. Overexpression of p14(ARF) induced G(1)-phase cell cycle arrest and apoptotic cell death. Cytotoxicity assays showed that Adp14 had a statistically significantly (P =.002) greater effect on colon cancer (HCT116) cell lines containing two copies of the wild-type p53 gene than on p53-null cells, suggesting that functional p53 is a critical determinant of p14(ARF)-mediated cytotoxicity.The transfection of p14(ARF) into mesothelioma cells led to the overexpression of p14(ARF), which resulted in G(1)-phase arrest and apoptotic cell death. These results suggest that this gene therapy-based approach may be of use in the treatment of mesothelioma.
Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial
Authors: Jayant S Vaidya, Frederik Wenz, Max Bulsara, Jeffrey S Tobias, David J Joseph, Mohammed Keshtgar, Henrik L Flyger, Samuele Massarut, Michael Alvarado, Christobel Saunders, Wolfgang Eiermann, Marinos Metaxas, Elena Sperk, Marc Sütterlin, Douglas Brown, Laura Esserman, Mario Roncadin, Alastair Thompson, John A Dewar, Helle M R Holtveg, Steffi Pigorsch, Mary Falzon, Eleanor Harris, April Matthews, Chris Brew-Graves, Ingrid Potyka, Tammy Corica, Norman R Williams, Michael Baum
Journal: The Lancet (2013)
Rhinitis Is Associated with Increased Systolic Blood Pressure in Men
Authors: Sabine Kony, Mahmoud Zureik, Catherine Neukirch, Bénédicte Leynaert, Daniel Vervloet, Françoise Neukirch
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

An association between impaired lower respiratory function and cardiovascular risk factors, such as hypertension, is often reported but it is unknown whether there is a relationship between upper airway disorders and cardiovascular risk factors, despite evidence that upper and lower respiratory tract disorders are closely linked. Our objective was to assess whether rhinitis is associated with arterial blood pressure and hypertension. In a population-based study of 330 adults aged 28–56 years, as part of the European Community Respiratory Health Survey, rhinitis was assessed by means of a questionnaire, and cardiovascular data were obtained using a questionnaire and by measuring blood pressure. Systolic blood pressure (SBP) was higher in men with rhinitis than in men without rhinitis (130.6 ± 12.7 mm Hg versus 123.5 ± 13.9 mm Hg; p = 0.002), and it was still the case after adjustment for cardiovascular and respiratory confounding factors. Hypertension was more frequent in men with rhinitis than in men without rhinitis, even after multivariate adjustment (odds ratio = 2.6, 95% confidence interval = [1.14–5.91]). The observation of SBP levels according to whether men have no rhinitis, seasonal rhinitis, or perennial rhinitis was compatible with a dose–response relationship (p for trend = 0.02). In conclusion, rhinitis is strongly associated with SBP and hypertension in men. Blood pressure should be regularly checked in men with rhinitis.
Progressive increase in conduction velocity across human mesenchymal stem cells is mediated by enhanced electrical coupling
Authors: D PIJNAPPELS, M SCHALIJ, J VANTUYN, D YPEY, A DEVRIES, E VANDERWALL, A VANDERLAARSE, D ATSMA
Journal: Cardiovascular Research (2006)

Objective: The purpose of the study was to investigate the development of electrical transmission across human adult bone marrow-derived mesenchymal stem cells (hMSCs) during long-term co-incubation with cardiomyocytes (CMCs). Methods: Neonatal rat CMCs were cultured in multi-electrode array dishes. A conduction block was induced by creating a central acellular channel, yielding two asynchronously beating CMC fields. Enhanced green fluorescent protein (eGFP)-labeled hMSCs from ischemic heart disease patients (n=8), eGFP-labeled hMSCs having RNA interference-mediated connexin43 (Cx43) knockdown (n=6), 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine (Dil)-labeled CMCs (n=6), or no cells (n=9) were seeded in the channel. Assessment of conduction velocity (CV), Cx expression and localization, gap junctional coupling, and intracellular electrical recordings were performed for up to 14 days. Results: Resynchronization of the two CMC fields occurred within 24 h after seeding of hMSCs. CV across hMSCs increased from 1.4±0.4 cm/s at day 7 to 3.5±0.1 cm/s (p<0.05) at day 14. CV across seeded CMCs was 16.8±0.2 cm/s throughout this period. No resynchronization occurred in the absence of seeded cells. Knockdown of Cx43 in hMSCs abolished conduction across the channel completely. Time-dependent increase of CV across hMSCs was associated with increased Cx43 mRNA and protein expression resulting in increased gap junctional coupling. Intracellular recordings in coupled hMSCs showed increased conducted action potential (AP) amplitude, lower resting membrane potential, and decreased duration of conducted AP (p<0.05, day 14 versus day 1). Conclusions: CV across hMSCs increases progressively after 7 days of co-incubation with CMCs, most likely via improved electrotonic interaction. This is associated with increased Cx43 expression, increased functional gap junctional coupling, and enhanced intercellular electrical coupling between hMSCs and CMCs.
Clinical Significance of Urinary Liver-Type Fatty Acid–Binding Protein in Patients With Diabetic Nephropathy
Authors: Kumi Suzuki, Tetsuya Babazono, Hidekazu Murata, Yasuhiko Iwamoto
Journal: Diabetes Care (2005)

Tubulointerstitial damage plays a crucial role in the progression of kidney diseases, including diabetic nephropathy (1). Among several distinct types of fatty acid–binding protein (FABP), liver-type FABP (l-FABP) is abundantly expressed in hepatocytes and constitutively expressed in proximal tubular cells of the kidney (2). l-FABP incorporates albumin-bound free fatty acids (FFAs) that are filtered through the glomeruli into proximal tubular cells and transports FFAs from the cytosol to the nucleus (3). In transgenic mice expressing human l-FAPB, protein overload, resulting in massive proteinuria, upregulated renal l-FABP expression and increased its urinary excretion (4), suggesting that urinary l-FABP may reflect tubulointerstitial damage. Recently, in patients with nondiabetic glomerular disease, urinary excretion of l-FABP increased in parallel with the severity of tubulointerstitial injury and correlated with proteinuria and the rate of progression of renal disease, suggesting that l-FABP may be a useful indicator for the progression of nondiabetic kidney disease (4,5). To determine the clinical significance of l-FABP in patients with diabetic nephropathy, we conducted a cross-sectional study comparing urinary l-FABP excretion in diabetic patients with serial stages of kidney disease.

Adult patients with type 2 diabetes were recruited from the outpatient clinic of the Division of Nephrology and Hypertension, Diabetes Center, Tokyo Women’s Medical University …