tbuckley/cabot-search huggingface dataset:
Pharmacogenomic association between genetic polymorphism of UGT1A1 and serious toxicities occurring in the cancer patients receiving irinotecan-containing chemotherapy
Authors: Jin-Hyoung Kang, Jeong-Oh Kim, Jeong-Young Shin, Ji-Ryeon Jang, Myung-Ah Lee, Hiun Suk Chae, In-Kyung Kim, Chul-Ho Lee, Hwan-Seok Rhee
Journal: Cancer Research (2006)

1313   Background: Irinotecan (CPT-11) is one of the widely used anti-cancer drugs, especially for colorectal and lung cancers, whereas it causes severe neutropenia and diarrhea limiting dose escalation in clinical practice. It undergoes drug metabolism to form an active SN-38, which is further converted to its beta-glucuronide by UDP-glucuronosyltransferase (UGT) 1A1. Pharmacogenomic associations between genetic variants on several specific sites including UGT1A1*28 and toxicities of irinotecan have been reported. Purpose: The aim of our study was to investigate comprehensive allelic frequency and haplotype of UGT1A1 gene in healthy Koreans and to determine the significance of UGT1A1 variants (-3279T>G, -3156G>A, promoter TA indel, 211G>A, 686C>A) on the serious toxicities induced by irinotecan in a prospective pharmacogenomic study. Method: Genotypes were identified by gene scan analysis on the ABI3730XL sequencer for variants in UGT1A1 (-3279T>G, -3156G>A, -53TA 5-8 , 211G>A, 686C>A) in blood samples from 218 healthy volunteers and 33 patients (pts) with advanced colorectal and lung cancer receiving irinotecan-containing chemotherapy. Toxicities have been graded according to NCI common toxicity criteria (ver 3.0). Results: In 218 healthy Koreans, the allelic frequencies of -3279T>G, -3156G>A, TATA indel, 211G>A, and 686C>A were 26%, 12%, 8%, 15% and 1%, respectively. The median age of cancer pts was 58 years (range: 43-73 years). Serious gastrointestinal or/and hematological toxicities were observed in 16 of 33 pts: diarrhea ≥ G2 in 11 cases (33.3%); neutropenia ≥ G3 in 5 cases (15.2%). Interestingly, it was identified that genetic polymorphisms of three different promotor sites, -3279T>G, -3156G>A, and (TA) indel existed simultaneously. Of eleven pts experiencing ≥ G2 diarrhea, one had polymorphisms on three different sites and another three had 211G>A. However, no polymorphisms were observed on all five variant sites in the other seven pts. Of five pts experiencing ≥ G3 neutropenia, two showed -3279T>G, -3156G>A, and heterozygotes (TA) 7  mutation and another two had 211G>A mutation. No polymorphism of 686C>A was detected in all pts. Conclusion: This preliminary results indicate that genotyping of 211G>A polymorphism as well as the heterozygotes (TA) 7  and promoter (-3279, -3156) polymorphisms might predict the occurrence of serious toxicities by irinotecan in genetically predisposed cancer pts.
Abstract 15908: Association of Heart Rate Turbulence, Deceleration Capacity and Morphologic Variability with Sudden Cardiac Death Following Non-ST-Elevation Acute Coronary Syndrome: Results from the MERLIN-TIMI 36 Trial
Authors: Zeeshan Syed, Benjamin M Scirica, Satishkumar Mohanavelu, David A Morrow, Collin M Stultz, John Guttag
Journal: Circulation (2010)

Background: Electrocardiographic (ECG) parameters such as heart rate turbulence (HRT), deceleration capacity (DC) and morphologic variability (MV) have previously been shown to identify patients at...
Abstract 1783: Pro-Apoptotic Bnip3 Mediates Permeabilization of Mitochondria and Release of Cytocrome c via a Novel Mechanism
Authors: Melissa N Quinsay, Shivaji Rikka, M Richard Sayen, Jeffery D Molkentin, Roberta A Gottlieb, Asa B Gustafsson
Journal: Circulation (2008)

Bnip3 is a member of the BH3-only subfamily of pro-apoptotic Bcl-2 proteins and is associated with mitochondrial dysfunction and cell death in the myocardium. The pro-apoptotic Bcl-2 proteins mediate mitochondrial dysfunction independent of the mitochondrial permeability transition pore (mPTP). However, Bnip3 has been reported to mediate cell death via the mPTP. In this study, we investigated the mechanism(s) by which Bnip3 causes mitochondrial dysfunction. Using a mitochondrial swelling assay to assess pore opening, we found that addition of 200 microM Ca2+ to mitochondria isolated from rat hearts induced rapid swelling of mitochondria and release of cytochrome c (cyto c). Bnip3 also induced mitochondrial swelling and cyto c release, but always at a slower rate and to a greater degree, suggesting that Bnip3 mediates swelling via a different mechanism. Cyclosporin A (CsA), an inhibitor of mPTP opening, prevented Ca2+-induced swelling and cyto c release, but had no effect on Bnip3. Another BH3-only protein, tBid, caused release of cyto c but failed to induce swelling of mitochondria. Interestingly, Bnip3, but not Ca2+ and tBid, induced release of the matrix protein MnSOD. Cyclophilin D (cycD) is an essential component of the mPTP and heart mitochondria isolated from cycD−/− mice were resistant to Ca2+-, but not to Bnip3-induced swelling and cyto c release. Also, tBid caused cyto c release without mitochondrial swelling in the absence of cycD. To further explore the mPTP as a downstream effector of Bnip3-mediated cell death, we assessed cell death in mouse embryonic fibroblasts (MEFs) isolated from wild type (wt) and cycD−/− mice. Infection with an adenovirus expressing Bnip3 caused significant cell death in wt (52.8±1.8%) and cycD−/− (61.8±6.1%) MEFs as measured by LDH release. In addition, both Bnip3 and opening of the mPTP have been reported to initiate upregulation of autophagy. Monitoring of GFP-LC3 incorporation into autophagosomes by fluorescence microscopy revealed that Bnip3 infection induced autophagy in wt (86.5±6.6%) and cycD−/− (96.4±1.4%) MEFs (n=3, p&lt;0.05). Thus, these studies suggest that Bnip3 mediates permeabilization of the inner and outer mitochondrial membranes via a novel mechanism that is different from other BH3-only proteins. This research has received full or partial funding support from the American Heart Association, AHA National Center.
Interhospital Transfers by Helicopter: The First 50 Patients of the Careflight Project
Authors: S S Kee, C M H Ramage, P Mendel, A S E Bristow
Journal: Journal of the Royal Society of Medicine (1992)

An interhospital helicopter transfer service was set up using a dedicated helicopter fitted with medical equipment and staffed by anaesthetists. The system proved to be safe and practical. Fifty patients were referred from 38 hospitals throughout the UK, with 84% of transfers preplanned. Patients were transferred a mean distance of 118 miles (range 35–397 miles) and there was no deterioration during transfer as measured by pre and post transfer sickness scores. Twenty-eight per cent of cases could not have been practically transferred by conventional means. The death rate of 20% was lower than that reported for specially equipped and staffed land transfer systems, which may indicate less physiological deterioration in the critically ill compared to road transfer. Dedicated helicopter transfer resulted in a 50% survival rate in patients with a sickness score over 18, a group found not to survive after land transfer. There was no correlation between distance moved and outcome. A helicopter transfer system using suitable equipment and staff is a practical and safe method of moving critically ill patients between hospitals, and may be preferable to land transfer for distances in excess of 25 miles.
Chromogenic in situ hybridization (CISH) for X- and Y-chromosomes in sex determination of anatomic pathology specimens
Authors: Aloisio S. Silva, Mauricio Palau, Maria J. Merino
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4214 

Introduction: Sex identification of tissues may be useful in the pathology laboratory in mislabeled cases, mix-up and tissue contamination of blocks and slides if they come from people of different sex. It can also be useful in identification of donor cells in cases of sex-mismatched bone marrow transplantation. The specific utilization of X and Y chromosomes CISH in tissue specimens has been rare. We evaluated the reliability of distinguishing male from female tissues in formalin-fixed paraffin-embedded (FFPE) pathology material using CISH for sex chromosomes. We also present one case of sex-mismatched bone-marrow stem cells transplantation in which this technique was successfully used in identification of male donor cells in a female patient. experimental procedures: Tissue samples from males and females were studied. Blocks were randomly selected and anonymized, in order to provide blind evaluation. On each sample, X- and Y-chromosomes hybridization protocols were performed separately in different slides. Sex identification of tissues was interpreted from X- and Y-chromosomes CISH slides separately and then jointly for each case. Sex identification by CISH results were compared with patients’ real sexes obtained from medical charts. Results: Six male and five female slides were identified by CISH, using each probe. When analyzed in pairs, all the samples matched. All cases were correctly sex identified using X- and Y-chromosomes CISH, whether slides were interpreted together or separately. Y-chromosome CISH of rectal biopsies from a male to female transplanted patient showed clear hybridization in stromal and mononuclear cells in the lamina propria, recognizing the transplanted male cells. Conclusions: In the present study, CISH for sexual chromosomes reliably identified male and female FFPE anatomic pathology samples. Sex identification of tissues and cells by CISH may be a practical alternative in the recognition of questionable tissues as well as the identification of transplanted cells.
Abstract 255: Therapeutic Hypothermia Ameliorates Sepsis-Induced Myocardial Mitochondrial Dysfunction
Authors: Chiung-Yuan Hsu, Chien-Hua Huang, Min-Shan Tsai, Huei-Wen Chen, Wen-Jone Chen
Journal: Circulation (2011)

Introduction: Mitochondrial dysfunction play an important roles during the sepsis induce organ failure. Therapeutic hypothermia can protect mitochondrial dysfunction during injury. How the therapeutic hypothermia acts on septic myocardial mitochondria is still not well explored. Hypothesis: Therapeutic hypothermia is beneficial sepsis induced myocardial mitochondrial dysfunction and survival. Methods: Sepsis was induced in 10-12 week specific-pathogen-free bred male adult Sprague-Dawley rats by cecal ligation and tube insertion. Rats were randomized into controlled normothermia (36-37.5°C) or therapeutic hypothermia (32-34°C) at sepsis induced 6 hours later. The animal heart was harvested at 1 hour after temperature control and mitochondrial was isolated by differential centrifugation. Results: Therapeutic Hypothermia group (n=18) can significantly improve 72 hours survival than the Normothermia group (n=20, p= 0.0031&lt; 0.05). Mitochondrial membrane potential has trend to deteriorat in sepsis (n=13) compared to Sham.( n=18, p=0.062 &gt;0.05). Temperature management did not maintained the membrane potential (Normothermia n= 7, Hypothermia n=5, sepsis vs. normothermia p= 0.98; sepsis vs. hypothermia p=0.88). Myocardial mitochondria oxidative phosphorylation complexes activity including Complex I+III, Complex II+III and Complex IV were worse in sepsis (n=9) compared to Sham (n=14) group. Temperature control can significantly improved the activity either in therapeutic hypothermia ( n=4) and normothermia groups (n=6) except Complex I+II in therapeutic hypothermia group. (Figure) Conclusion: Therapeutic hypothermia preserves mitochondrial oxidative phosphorylation complexes activity in sepsis myocardium and indeed benefit for sepsis prognosis.
Ionizing radiation induces mast cell degranulation and may contribute to fibrosis in patients undergoing radiation therapy
Authors: Nicole L. Simone, Benjamin P. Soule, Jared Brown, Dean Metcalf, James M. Mitchell
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

575 

Purpose: Mast cells have been thought to play a role in various side effects of radiation such as acute radiation sickness (ARS) and fibrosis. It is well known that radiation has numerous effects on immune system effector cells ranging from induction of cytokines to the down-regulation of immune surveillance. This study examines the effect of ionizing radiation on mast cells in culture. Methods: Bone marrow stem cells were grown in culture to produce mature mast cells which were collected at 6 weeks and exposed to gamma irradiation from a 60Co source at six doses ranging from 12.5 to 400cGy. A Beta-hexosaminidase degranulation assay was performed within 15 minutes following irradiation. The cells were collected at 24, 48 and 72 hours post-irradiation to assess the extent of apoptosis and total cell number and cell viability determinations were made by direct visualization with Trypan Blue stain. Results: The Beta-hexosaminidase assay revealed that mast cell degranulation was related to radiation dose and ranged from 30-45% with a peak detected between 25 -100cGy. Apoptosis increased continuously with increasing doses of radiation. Furthermore, cell viability assessment revealed linear dose and time dependent cell death. These results confirm that the dose-dependent degranulation of the mast cells was not simply the result of cell death. Discussion: We found that ionizing radiation induces mast cell degranulation in a non-linear, dose-dependent fashion with a peak degranulation between 25-100cGy, a dose which normal tissue may be subjected to during standard radiotherapy. This pattern of cytokine release is consistent with historic data for other cell types however the underlying mechanism is currently being further investigated. Release of mast cell contents has been shown to have local as well as systemic effects. Early studies of ARS implicated histamine release and mast cell contents are felt to play a role in the development of fibrosis. Therefore, the results of this preliminary study suggest for the first time that modulation of the mast cell response through pharmacologic intervention may modulate the injury incurred by normal tissue from gamma irradiation.



![Figure][1]  [1]: pending:yes
What to Expect From the Evolving Field of Geriatric Cardiology
Authors: Susan P. Bell, Nicole M. Orr, John A. Dodson, Michael W. Rich, Nanette K. Wenger, Kay Blum, John Gordon Harold, Mary E. Tinetti, Mathew S. Maurer, Daniel E. Forman
Journal: Journal of the American College of Cardiology (2015)
Course: The RCSE SELECT Programme
Authors: J. G Temple
Journal: BMJ (1998)

Royal College of Surgeons of Edinburgh Available from RCSE (free introductory sample of 3 modules, £400 for all 43 modules Rating: ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img> Set at a level sufficient for the basic examinations of the UK Royal Colleges of Surgeons, The RCSE SELECT Programme is a new and innovative distance learning package that comprises 43 modules. It is suggested that this programme will also be of use to higher surgical trainees in … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif
A Syndrome of Peripheral Blood T-Cell Infection With Epstein-Barr Virus (EBV) Followed by EBV–Positive T-Cell Lymphoma
Authors: Hirokazu Kanegane, Kishor Bhatia, Marina Gutierrez, Hisashi Kaneda, Taizo Wada, Akihiro Yachie, Hidetoshi Seki, Takashi Arai, Sei-ichi Kagimoto, Minoru Okazaki, Tsutomu Oh-ishi, Amir Moghaddam, Fred Wang, Giovanna Tosato
Journal: Blood (1998)
Lymphocyte glucocorticoid receptor number in posttraumatic stress disorder
Authors: R Yehuda, M T Lowy, S M Southwick, D Shaffer, E L Giller
Journal: American Journal of Psychiatry (1991)

The authors' objective was to investigate the possibility that glucocorticoid receptor changes may be involved in the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in posttraumatic stress disorder (PTSD).They measured the number of lymphocyte cytosolic glucocorticoid receptors and plasma cortisol concentrations in 15 consecutively admitted male combat Vietnam veterans with PTSD and in a normal comparison group of 11 subjects.Both the patients and the normal comparison subjects showed a morning-to-afternoon decline in glucocorticoid receptor concentrations, paralleling the normal diurnal decline in cortisol levels. The number of glucocorticoid receptors was 63% greater in the morning and 26% greater in the afternoon in the patients with PTSD than in the normal subjects. No group differences in cortisol levels were observed, nor were glucocorticoid receptor number and cortisol levels correlated. The number of morning glucocorticoid receptors was positively correlated with symptoms of PTSD and anxiety.These results provide further evidence for a dysregulation of the HPA axis in PTSD. The finding that patients with PTSD had a substantially greater number of lymphocyte glucocorticoid receptors than normal comparison subjects is consistent with the authors' previous observations of low 24-hour urinary cortisol excretion in subjects with PTSD. Furthermore, the receptor changes observed are opposite of those reported in major depressive disorder. The present data, along with other findings of HPA abnormalities in PTSD, support the possibility of a greater negative feedback sensitivity at one or more levels of the HPA axis.
MMP14 enhances tumour growth and invasion in hepatocellular carcinoma
Authors: Ying-Chi Ip, Siu-Tim Cheung, Sheung-Tat Fan
Journal: Cancer Research (2004)

1826  Matrix metalloproteinase (MMP) family consists of more than 25 zinc-dependent endopeptidases. While most of them are secretory zymogens, MMP14 is a transmembrane protein. It is involved in tissue remodeling and embryonic development. It also contributes to metastasis (Nat Rev Cancer, 2:161-174, 2002) and angiogenesis by increasing vascular endothelial growth factor (VEGF) (FASEB, 16:555-564, 2002). MMP14 directly participates in tumour invasion through activation of MMP2, which degrades components of the ECM. In our microarray study (Mol Biol Cell, 13:1929-39, 2002), it was identified to be up-regulated specifically in hepatocellular carcinoma (HCC) with histological evidence of venous invasion, a microscopic feature that demonstrated presence of tumor cells in the vascular space lined by endothelial cells. Venous invasion associated with metastasis and recurrence, but the underlying mechanism is still unclear. In the current study, we observed that both the active 60kD and catalytically inactive 45kD forms in the tumour revealed an increased level compared to its adjacent non-tumour by western blot. The 45kD form was the result of autocatalytic mechanism of the active MMP14, which would be internalized and recycled for rapid relocation of fresh enzymes at the leading invasive front (J Cell Sci 116:3905-3916, 2003). Therefore, its presence in HCC tumor but not in non-tumor indirectly reflects the existence of active MMP14 on cell surface and the ability to activate pro-MMP2 (Cancer Sci 94:569-574, 2003). By immunohistochemistry study on clinical specimens, MMP14 demonstrated heterogeneous expression in the tumor tissues while hepatocytes surrounding the veins in the non-tumour tissues showed positive signal. The difference in MMP14 localization and species between tumour and non-tumour suggests this protein may act as determinant in different steps of cell invasion process. To further understand how MMP14 functionally affect the process of tumour invasion, we have cloned the MMP14 cDNA. The gene was overexpressed in a HCC cell line, Hep3B, and the performance was analyzed in various steps of cell invasion. Compared with the control transfectants, overexpression of MMP14 promoted cell growth, increased cell invasion, adhesion efficiency and migration ability of the HCC cells in vitro. The effect of MMP14 overexpression was also examined in vivo by implantation of transfectants into the liver of nude mice. MMP14-transfected xenografts showed enhanced growth rate and increased frequency of intrahepatic metastasis, compared with the control transfectants. All these data support the role of MMP14 in HCC invasion. Invasion and metastasis are the principal causes of death in HCC patients. They also have a profound impact on prognosis and disease recurrence after tumour resection. The current study provided evidence that MMP14 is involved in tumour invasion and MMP14 could be essential as a novel targets for HCC treatment.
Abstract 2087: Factors Associated With Thrombotic Complications in the First 2 Years After the Fontan Procedure: A Multicentre Prospective Study
Authors: Brian W McCrindle, Andrew Cochrane, Robin Roberts, Barbara Szechtman, Michael Gent, Cedric Manlhiot, Robert Weintraub, Maureen Andrew, Paul Monagle
Journal: Circulation (2009)

Thrombosis (TE) is an important complication for children with single ventricle and Fontan procedure, contributing to mortality and morbidity. Many associated factors have been proposed, but there ...
Abstract 14201: ANX-042, a Novel Natriuretic Peptide (NP), is Safe and Stimulates Cyclic Guanosine Monophosphate (cGMP) in Healthy Volunteers
Authors: Horng H Chen, Robert D Simari, Stephen P Youngberg, Donna R Grogan, Jeffrey W Miller, John C Burnett
Journal: Circulation (2013)

Background: We identified an alternatively spliced mRNA for B-type natriuretic peptide (ASBNP) that includes a unique and distinct longer carboxyl-terminus. Based on this mRNA, we biodesigned a tru...
O119 : Stopping tenofovir disoproxil fumarate (TDF) treatment after long term virologic suppression in HBeAg-negative CHB: Week 48 interim results from an ongoing randomized, controlled trial (“finite CHB”)
Authors: T. Berg, K.-G. Simon, S. Mauss, E. Schott, R. Heyne, D. Klass, C. Eisenbach, T.M. Welzel, R. Zachoval, G. Felten, J. Schulze zur Wiesch, M. Cornberg, E.B. Martins, L. Gallo, T. Warger, J. Petersen
Journal: Journal of Hepatology (2015)
The Hygiene of Marriage: A Detailed Consideration of Sex and Marriage.
Authors: Millard S. Everett
Journal: JAMA (1933)

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First case of Echinococcus vogeli infection imported to the Netherlands, January 2013
Authors: C Stijnis, A Bart, L Brosens, T Van Gool, M Grobusch, T van Gulik, J Roelfsema, P van Thiel
Journal: Eurosurveillance (2013)

In January 2013 in the Netherlands, a man in his 50s from Suriname underwent hemihepatectomy because of a cystic liver mass, assumed to be a cystadenoma. Pathology revealed an echinococcal infection. PCR analysis of cyst material identified Echinococcus vogeli, causing polycystic hydatid disease. This echinococcus species is rarely diagnosed outside South America. The patient received adequate treatment, but this case emphasises the importance of awareness of this infection when treating patients with cystic tumours from endemic areas.