tbuckley/cabot-search huggingface dataset:
Reciprocal Relationship between <i>O</i>6-Methylguanine-DNA Methyltransferase P140K Expression Level and Chemoprotection of Hematopoietic Stem Cells
Authors: Michael D. Milsom, Moran Jerabek-Willemsen, Chad E. Harris, Axel Schambach, Emily Broun, Jeff Bailey, Michael Jansen, David Schleimer, Kalpana Nattamai, Jamie Wilhelm, Amanda Watson, Hartmut Geiger, Geoffrey P. Margison, Thomas Moritz, Christopher Baum, Jürgen Thomale, David A. Williams
Journal: Cancer Research (2008)

Abstract Retroviral-mediated delivery of the P140K mutant O6-methylguanine-DNA methyltransferase (MGMTP140K) into hematopoietic stem cells (HSC) has been proposed as a means to protect against dose-limiting myelosuppressive toxicity ensuing from chemotherapy combining O6-alkylating agents (e.g., temozolomide) with pseudosubstrate inhibitors (such as O6-benzylguanine) of endogenous MGMT. Because detoxification of O6-alkylguanine adducts by MGMT is stoichiometric, it has been suggested that higher levels of MGMT will afford better protection to gene-modified HSC. However, accomplishing this goal would potentially be in conflict with current efforts in the gene therapy field, which aim to incorporate weaker enhancer elements to avoid insertional mutagenesis. Using a panel of self-inactivating gamma-retroviral vectors that express a range of MGMTP140K activity, we show that MGMTP140K expression by weaker cellular promoter/enhancers is sufficient for in vivo protection/selection following treatment with O6-benzylguanine/temozolomide. Conversely, the highest level of MGMTP140K activity did not promote efficient in vivo protection despite mediating detoxification of O6-alkylguanine adducts. Moreover, very high expression of MGMTP140K was associated with a competitive repopulation defect in HSC. Mechanistically, we show a defect in cellular proliferation associated with elevated expression of MGMTP140K, but not wild-type MGMT. This proliferation defect correlated with increased localization of MGMTP140K to the nucleus/chromatin. These data show that very high expression of MGMTP140K has a deleterious effect on cellular proliferation, engraftment, and chemoprotection. These studies have direct translational relevance to ongoing clinical gene therapy studies using MGMTP140K, whereas the novel mechanistic findings are relevant to the basic understanding of DNA repair by MGMT. [Cancer Res 2008;68(15):6171–80]
The Joy of Medicine
Authors: Joseph Gascho
Journal: Annals of Internal Medicine (2014)

Ad Libitum17 June 2014The Joy of MedicineJoseph Gascho, MDJoseph Gascho, MDFrom Pennsylvania State University College of Medicine, Hershey, Pennsylvania.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M14-0941 Audio Reading - “The Joy of Medicine” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "The Joy of Medicine," by J. Gascho. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail It's about the manwho pilgrimages to Talladega every Octoberbecause you stented his widow makerand the couplecelebrating their 60thwho asked everybody to stand up and clapwhen you walked in to the VFW halland the time you were in the showerand you thought aboutwhat the wordy lady told you in the officethe day beforeand you ordered the blood testand prescribed the right pilland all was welland it would not have beenMaggie hit the ball to ... Author, Article, and Disclosure InformationAffiliations: From Pennsylvania State University College of Medicine, Hershey, Pennsylvania.Current Author Address: Joseph Gascho, MD; e-mail, [email protected]com. PreviousarticleNextarticle Advertisement Audio Reading - “The Joy of Medicine” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "The Joy of Medicine," by J. Gascho. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 17 June 2014Volume 160, Issue 12Page: 880KeywordsAortaGamesHematologic tests ePublished: 17 June 2014 Issue Published: 17 June 2014 Copyright & PermissionsCopyright © 2014 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
High rates of associated morbidity and mortality justify flu vaccination
Authors: J. R. Ortiz
Journal: BMJ (2014)

Screening services are a central feature of New Jersey’s new civil commitment law. This law, more commonly referred to as the screening law, exemplifies a nationwide trend in civil commitment legislation, attempting to balance liberty interests and the need to treat the mentally ill. Screening services, designated as the preferred process of entry into involuntary hospitalization, were expected to prevent unnecessary commitment and to provide community mental health services. When deemed necessary, commitment in local general hospitals rather than in state mental hospitals was to occur. This paper reports results of a study of screening centers that were already in operation in New Jersey prior to the implementation of the new law. It assesses the function of screening senices and their potential impact on the commitment process in light of the objectives of the law. Data were obtained from in-depth interviews with key informants from the screening centers as well as from their environment, and from statistical reports on hospitalizations in state hospitals, admissions to screening centers, and admissions to psychiatric inpatient units of general hospitals. Analysis suggests that without more resources for alternative community facilities, screening services cannot achieve their objectives and the new reform may not live up to expectations. Shortage of alternatives to hospitalization and lack of incentives to develop and use them appeared to be counterproductive to achieving the objectives of the law. The availability of screening service and psychiatric units in general hospitals for involuntary hospitalization, on one hand, and the lack of alternatives in the community, on the other, may actually lead to inappropriate commitments and an increase in the number of civil commitments. Furthermore, findings indicated that screeners encouraged hospitalization readily even if other, less restrictive environments could have been pursued. Screening centers may become “gate openers” instead of playing their expected role as “gate keepers.”
Effects of aging, sex, and physical training on cardiovascular responses to exercise.
Authors: T Ogawa, R J Spina, W H Martin, W M Kohrt, K B Schechtman, J O Holloszy, A A Ehsani
Journal: Circulation (1992)

BACKGROUND The relative contributions of decreases in maximal heart rate, stroke volume, and oxygen extraction and of changes in body weight and composition to the age-related decline in maximal oxygen uptake (VO2max) are unclear and may be influenced by sex and level of physical activity. METHODS AND RESULTS To investigate mechanisms by which aging, sex, and physical activity influence VO2max, we quantified VO2, cardiac output, and heart rate during submaximal and maximal treadmill exercise and assessed weight and fat-free mass in healthy younger and older sedentary and endurance exercise-trained men and women. For results expressed in milliliters per kilogram per minute, a three-to-four-decade greater age was associated with a 40-41% lower VO2max in sedentary subjects and a 25-32% lower VO2max in trained individuals (p less than 0.001). A smaller stroke volume accounted for nearly 50% of these age-related differences, and the remainder was explained by a lower maximal heart rate and reduced oxygen extraction (all p less than 0.001). Age-related effects on maximal heart rate and oxygen extraction were attenuated in trained subjects (p less than 0.05). After normalization of VO2max and maximal cardiac output to fat-free mass, age- and training-related differences were reduced by 24-47% but remained significant (p less than 0.05). For trained but not sedentary subjects, maximal cardiac output and stroke volume normalized to fat-free mass were greater in men than in women (p less than 0.05). CONCLUSIONS A lower stroke volume, heart rate, and arteriovenous oxygen difference at maximal exercise all contribute to the age-related decline in VO2max. Effects of age and training on VO2max, maximal cardiac output, and stroke volume cannot be fully explained by differences in body composition. In sedentary subjects, however, the sex difference in maximal cardiac output and stroke volume can be accounted for by the greater percentage of body fat in women than in men.
Clomiphene-Responsive Hypogonadism in Sickle Cell Anemia
Authors: C. SETH LANDEFELD
Journal: Annals of Internal Medicine (1983)

Two 19-year-old men with sickle cell anemia and hypogonadism had hypothalamic dysfunction that responded to oral clomiphene therapy. The patients had no nutritional deficiencies or anatomic lesions known to result in the hypogonadism associated with sickle cell anemia. Their sickle cell disease was characterized by infrequent crises, severe hemolytic anemia, urinary iron loss, and iron deficiency. Partial hypothalamic hypogonadism was shown by low levels of testosterone, low to low-normal levels of luteinizing hormone and follicle-stimulating hormone, and a nearly normal rise in gonadotropin levels in response to exogenous gonadotropin releasing hormone. Treatment with oral clomiphene raised luteinizing hormone, follicle-stimulating hormone, and testosterone levels to normal, and induced puberty in both patients. Treatment was discontinued in one patient because of the onset of priapism, but was continued for 10 months without side effects in the other. Severe hypogonadism in patients with sickle cell anemia should be thoroughly evaluated and clomiphene therapy considered in patients with hypothalamic dysfunction.
Atrial but Not Ventricular Fibrosis in Mice Expressing a Mutant Transforming Growth Factor-β <sub>1</sub> Transgene in the Heart
Authors: Hidehiro Nakajima, Hisako O. Nakajima, Olga Salcher, Andrea S. Dittiè, Klaus Dembowsky, Shaoliang Jing, Loren J. Field
Journal: Circulation Research (2000)

Abstract —Increased transforming growth factor (TGF)–β 1 activity has been observed during pathologic cardiac remodeling in a variety of animal models. In an effort to establish a causal role of TGF-β 1 in this process, transgenic mice with elevated levels of active myocardial TGF-β 1 were generated. The cardiac-restricted α–myosin heavy chain promoter was used to target expression of a mutant TGF-β 1 cDNA harboring a cysteine-to-serine substitution at amino acid residue 33. This alteration blocks covalent tethering of the TGF-β 1 latent complex to the extracellular matrix, thereby rendering a large proportion (&gt;60%) of the transgene-encoded TGF-β 1 constitutively active. Although similar levels of active TGF-β 1 were present in the transgenic atria and ventricles, overt fibrosis was observed only in the atria. Surprisingly, increased active TGF-β 1 levels inhibited ventricular fibroblast DNA synthesis in uninjured hearts and delayed wound healing after myocardial injury. These data suggest that increased TGF-β 1 activity by itself is insufficient to promote ventricular fibrosis in the adult mouse ventricle.
Concomitant Administration of Weekly Oxaliplatin, Fluorouracil Continuous Infusion, and Radiotherapy After 2 Months of Gemcitabine and Oxaliplatin Induction in Patients With Locally Advanced Pancreatic Cancer: A Groupe Coordinateur Multidisciplinaire en Oncologie Phase II Study
Authors: Laurence Moureau-Zabotto, Jean-Marc Phélip, Pauline Afchain, Laurent Mineur, Thierry André, Veronique Vendrely, Gerard Lledo, Olivier Dupuis, Florence Huguet, Emmanuel Touboul, Jacques Balosso, Christophe Louvet
Journal: Journal of Clinical Oncology (2008)

Background According to previously reported Groupe Coordinateur Multidisciplinaire en Oncologie (GERCOR) studies in locally advanced pancreatic cancer (LAPC), concomitant chemoradiotherapy (CCRT) may be recommended for patients who do not experience disease progression after systemic induction chemotherapy (CT). To further improve patient outcome with classical fluorouracil (FU)-based CCRT, this study was designed to prospectively investigate a CCRT with FU infusion and weekly oxaliplatin after 2 months of gemcitabine and oxaliplatin (GEMOX) induction chemotherapy. Patients and Methods Nonpretreated patients with LAPC having WHO performance status (PS) of 0 to 2 received four induction cycles of GEMOX (gemcitabine 1 g/m 2 on day 1 and oxaliplatin 100 mg/m 2 on day 2; day 1 of a 15-day cycle). One month after cycle 4, patients who did not experience disease progression with PS 0 to 2 received 45 Gy over 5 weeks + 10 Gy (as a concomitant boost during the last 2 weeks) of radiotherapy (RT), with daily 250 mg/m 2 FU as a continuous infusion and 60 mg/m 2 of oxaliplatin weekly. Results Of 59 patients, 50 patients (84.7%) received CCRT, whereas nine patients did not because of disease progression (seven patients), CT toxicity (one patient), or personal decision (one patient). Forty-four patients (74.5%) completed the fully planned CCRT. Median progression-free survival and overall survival durations were 7.6 and 12.2 months, respectively, for the whole population and 9.4 and 12.6 months, respectively, for patients who completed CCRT. CCRT grade 3 to 4 toxicities (National Cancer Institute Common Toxicity Criteria) were neutropenia (10.4%), thrombocytopenia (8.4%), nausea and vomiting (16.7%), and diarrhea (12.5%). Conclusion Concomitant administration of weekly oxaliplatin, continuous-infusion FU, and RT in patients with LAPC is feasible, with an acceptable acute and late safety profile. The encouraging results observed despite a nonoptimal patient selection (owing to the short induction time) indicates that further randomized evaluation to better define the specific role of oxaliplatin in CCRT is deserved.
The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: a meta-analysis
Authors: M.F.G. Verberg, M.J.C. Eijkemans, N.S. Macklon, E.M.E.W. Heijnen, E.B. Baart, F.P. Hohmann, B.C.J.M. Fauser, F.J. Broekmans
Journal: Human Reproduction Update (2008)

BACKGROUNDMilder ovarian stimulation protocols for in vitro fertilization (IVF) are being developed to minimize adverse effects. Mild stimulation regimens result in a decreased number of oocytes at retrieval. After conventional ovarian stimulation for IVF, a low number of oocytes are believed to represent poor ovarian reserve resulting in reduced success rates. Recent studies suggest that a similar response following mild stimulation is associated with better outcomes.
<i>PIK3CA</i> and <i>AKT1</i> Mutations Have Distinct Effects on Sensitivity to Targeted Pathway Inhibitors in an Isogenic Luminal Breast Cancer Model System
Authors: Julia A. Beaver, John P. Gustin, Kyung H. Yi, Anandita Rajpurohit, Matthew Thomas, Samuel F. Gilbert, D. Marc Rosen, Ben Ho Park, Josh Lauring
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Activating mutations in the phosphoinositide-3-kinase (PI3K)/AKT/mTOR pathway are present in the majority of breast cancers and therefore are a major focus of drug development and clinical trials. Pathway mutations have been proposed as predictive biomarkers for efficacy of PI3K-targeted therapies. However, the precise contribution of distinct PI3K pathway mutations to drug sensitivity is unknown. Experimental Design: We describe the creation of a physiologic human luminal breast cancer cell line model to study the phenotype of these mutations using the MCF-7 cell line. We used somatic cell gene targeting to “correct” PIK3CA E545K-mutant alleles in MCF-7 cells to wild-type sequence. The AKT1 E17K hotspot mutation was knocked in on this wild-type background. Results: Loss of mutant PIK3CA dramatically reduced phosphorylation of AKT proteins and several known AKT targets, but other AKT target proteins and downstream effectors of mTOR were not affected. PIK3CA wild-type cells exhibited reduced proliferation in vitro and in vivo. Knockin of the AKT1 E17K hotspot mutation on this PIK3CA wild-type background restored pathway signaling, proliferation, and tumor growth in vivo. PIK3CA, but not AKT1 mutation, increased sensitivity to the PI3K inhibitor GDC-0941 and the allosteric AKT inhibitor MK-2206. Conclusions: AKT1 E17K is a bona fide oncogene in a human luminal breast cancer context. Distinct PI3K pathway mutations confer differential sensitivity to drugs targeting the pathway at different points and by distinct mechanisms. These findings have implications for the use of tumor genome sequencing to assign patients to targeted therapies. Clin Cancer Res; 19(19); 5413–22. ©2013 AACR.
Association between apolipoprotein E phenotype and endogenous cholesterol synthesis as measured by deuterium uptake
Authors: R P Roe, P J Jones, J J Frohlich, D A Schoeller
Journal: Cardiovascular Research (1991)

Journal Article Association between apolipoprotein E phenotype and endogenous cholesterol synthesis as measured by deuterium uptake Get access Rebecca P Roe, Rebecca P Roe Search for other works by this author on: Oxford Academic PubMed Google Scholar Peter J H Jones, Peter J H Jones Search for other works by this author on: Oxford Academic PubMed Google Scholar Jiri J Frohlich, Jiri J Frohlich Search for other works by this author on: Oxford Academic PubMed Google Scholar Dale A Schoeller Dale A Schoeller Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 25, Issue 3, March 1991, Pages 249–255, https://doi.org/10.1093/cvr/25.3.249 Published: 01 March 1991 Article history Received: 06 July 1990 Accepted: 29 November 1990 Published: 01 March 1991
Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2
Authors: Maria-Céu Moreira, Sandra Klur, Mitsunori Watanabe, Andrea H Németh, Isabelle Le Ber, José-Carlos Moniz, Christine Tranchant, Patrick Aubourg, Meriem Tazir, Lüdger Schöls, Massimo Pandolfo, Jörg B Schulz, Jean Pouget, Patrick Calvas, Masami Shizuka-Ikeda, Mikio Shoji, Makoto Tanaka, Louise Izatt, Christopher E Shaw, Abderrahim M'Zahem, Eimear Dunne, Pascale Bomont, Traki Benhassine, Naïma Bouslam, Giovanni Stevanin, Alexis Brice, João Guimarães, Pedro Mendonça, Clara Barbot, Paula Coutinho, Jorge Sequeiros, Alexandra Dürr, Jean-Marie Warter, Michel Koenig
Journal: Nature Genetics (2004)
Tumor Dose Response to the Vascular Disrupting Agent, 5,6-Dimethylxanthenone-4-Acetic Acid, Using <i>In vivo</i> Magnetic Resonance Spectroscopy
Authors: Lesley D. McPhail, Yuen-Li Chung, Basetti Madhu, Simon Clark, John R. Griffiths, Lloyd R. Kelland, Simon P. Robinson
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To use 31P and 1H magnetic resonance spectroscopy (MRS) to assess changes in tumor metabolic profile in vivo in response to 5,6-dimethylxanthenone-4-acetic acid (DMXAA) with a view to identifying biomarkers associated with tumor dose response. Experimental Design: In vivo 31P and 1H MRS measurements of (a) tumor bioenergetics [β-nucleoside triphosphate/inorganic phosphate (β-NTP/Pi)], (b) the membrane-associated phosphodiesters and phosphomonoesters (PDE/PME), (c) choline (mmol/L), and (d) lactate/water ratio were made on murine HT29 colon carcinoma xenografts pretreatment and 6 or 24 hours posttreatment with increasing doses of DMXAA. Following in vivo MRS, the tumors were excised and used for high-resolution 31P and 1H MRS of extracts to provide validation of the in vivo MRS data, histologic analysis of necrosis, and high-performance liquid chromatography. Results: Both β-NTP/Pi and PDE/PME decreased in a dose-dependent manner 6 hours posttreatment with DMXAA, with significant decreases in β-NTP/Pi with 15 mg/kg (P &amp;lt; 0.001) and 21 mg/kg (P &amp;lt; 0.01). A significant decrease in total choline in vivo was found 24 hours posttreatment with 21 mg/kg DMXAA (P &amp;lt; 0.05); this was associated with a significant reduction in the concentration of the membrane degradation products glycerophosphoethanolamine and glycerophosphocholine measured in tissue extracts (P &amp;lt; 0.05). Conclusions: The reduction in tumor energetics and membrane turnover is consistent with the vascular-disrupting activity of DMXAA. 31P MRS revealed tumor response to DMXAA at doses below the maximum tolerated dose for mice. Both 31P and 1H MRS provide biomarkers of tumor response to DMXAA that could be used in clinical trials.
p53-Induced Up-Regulation of MnSOD and GPx but not Catalase Increases Oxidative Stress and Apoptosis
Authors: S. Perwez Hussain, Paul Amstad, Peijun He, Ana Robles, Shawn Lupold, Ichiro Kaneko, Masato Ichimiya, Sagar Sengupta, Leah Mechanic, Shu Okamura, Lorne J. Hofseth, Matthew Moake, Makoto Nagashima, Kathleen S. Forrester, Curtis C. Harris
Journal: Cancer Research (2004)

Abstract p53-mediated apoptosis may involve the induction of redox-controlling genes, resulting in the production of reactive oxygen species. Microarray expression analysis of doxorubicin exposed, related human lymphoblasts, p53 wild-type (WT) Tk6, and p53 mutant WTK1 identified the p53-dependent up-regulation of manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (GPx). Consensus p53 binding sequences were identified in human MnSOD and GPx promoter regions. A 3-fold increase in the MnSOD promoter activity was observed after the induction of p53 in Li-Fraumeni syndrome (LFS) fibroblast, TR9-7, expressing p53 under the control of a tetracycline-regulated promoter. An increased protein expression of endogenous MnSOD and GPx also positively correlated with the level of p53 induction in TR9-7 cells. However, catalase (CAT) protein expression remained unaltered after p53 induction. We also examined the expression of MnSOD, GPx, and CAT in a panel of normal or LFS fibroblasts, containing either WT or mutant p53. We found increased MnSOD enzymatic activity, MnSOD mRNA expression, and MnSOD and GPx protein in LFS fibroblasts carrying a WT p53 allele when compared with homozygous mutant p53 isogenic cells. The CAT protein level was unchanged in these cells. We observed both the release of cytochrome C and Ca2+ from the mitochondria into the cytoplasm and an increased frequency of apoptotic cells after p53 induction in the TR9-7 cells that coincided with an increased expression of MnSOD and GPx, and the level of reactive oxygen species. The increase in apoptosis was reduced by the antioxidant N-acetylcysteine. These results identify a novel mechanism of p53-dependent apoptosis in which p53-mediated up-regulation of MnSOD and GPx, but not CAT, produces an imbalance in antioxidant enzymes and oxidative stress.