tbuckley/cabot-search huggingface dataset:
Convergence of Mutation and Epigenetic Alterations Identifies Common Genes in Cancer That Predict for Poor Prognosis
Authors: Timothy A Chan, Sabine Glockner, Joo Mi Yi, Wei Chen, Leander Van Neste, Leslie Cope, James G Herman, Victor Velculescu, Kornel E Schuebel, Nita Ahuja, Stephen B Baylin
Journal: PLoS Medicine (2008)

The identification and characterization of tumor suppressor genes has enhanced our understanding of the biology of cancer and enabled the development of new diagnostic and therapeutic modalities. Whereas in past decades, a handful of tumor suppressors have been slowly identified using techniques such as linkage analysis, large-scale sequencing of the cancer genome has enabled the rapid identification of a large number of genes that are mutated in cancer. However, determining which of these many genes play key roles in cancer development has proven challenging. Specifically, recent sequencing of human breast and colon cancers has revealed a large number of somatic gene mutations, but virtually all are heterozygous, occur at low frequency, and are tumor-type specific. We hypothesize that key tumor suppressor genes in cancer may be subject to mutation or hypermethylation.Here, we show that combined genetic and epigenetic analysis of these genes reveals many with a higher putative tumor suppressor status than would otherwise be appreciated. At least 36 of the 189 genes newly recognized to be mutated are targets of promoter CpG island hypermethylation, often in both colon and breast cancer cell lines. Analyses of primary tumors show that 18 of these genes are hypermethylated strictly in primary cancers and often with an incidence that is much higher than for the mutations and which is not restricted to a single tumor-type. In the identical breast cancer cell lines in which the mutations were identified, hypermethylation is usually, but not always, mutually exclusive from genetic changes for a given tumor, and there is a high incidence of concomitant loss of expression. Sixteen out of 18 (89%) of these genes map to loci deleted in human cancers. Lastly, and most importantly, the reduced expression of a subset of these genes strongly correlates with poor clinical outcome.Using an unbiased genome-wide approach, our analysis has enabled the discovery of a number of clinically significant genes targeted by multiple modes of inactivation in breast and colon cancer. Importantly, we demonstrate that a subset of these genes predict strongly for poor clinical outcome. Our data define a set of genes that are targeted by both genetic and epigenetic events, predict for clinical prognosis, and are likely fundamentally important for cancer initiation or progression.
461. Qualitative and Quantitative Luciferase Expression In Vivo of Transduced Hematopoietic Cell Populations Using Bioluminescent Imaging (BLI)
Authors: Henk Rozemuller, Ingrid F.H. Koggel, Robbert Spaapen, Anton Hagenbeek, Anton C.M. Martens
Journal: Molecular Therapy (2005)

The homing and outgrowth of luciferase gene-transduced hematopoietic cells can be visualized in live animals on sequential time points by bioluminescent imaging (BLI), using a highly sensitive liquid nitrogen cooled charge-coupled camera (CCCD). Luciferase might therefore be of value as a marker gene to monitor and be quantitative for the expression of therapeutic genes in vivo.
Efficacy at the Bedside
Authors: Henry Schneiderman
Journal: JAMA (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Postprandial Glucose: Marker or Risk Factor?
Authors: Angelo Avogaro
Journal: Diabetes Care (2011)

Postprandial glucose (PPG) has a noxious effect on the vascular endothelium, which is mainly mediated by oxidative stress. This condition leads to endothelial activation and dysfunction, two prerequisites for the onset of cardiovascular disease (CVD) (1). The importance of PPG is reflected in the creation of guidelines by the International Diabetes Federation (IDF) for the management of postmeal glucose (http://www.idf.org/guidelines/postmeal-glucose). In these guidelines, the statement “Postmeal and postchallenge hyperglycaemia are independent risk factors for macrovascular disease” was rated as Level 1+, i.e., the data were derived from well-conducted meta-analyses, systematic reviews of randomized controlled trials (RCTs), or RCTs with a low risk of bias. The relationship between postchallenge hyperglycemia and CVD has been addressed by several studies. In the Honolulu Heart Program, the risk of coronary heart disease was increased in Japanese American men aged 45–68 years who had an abnormal oral glucose tolerance test (2). Comparable results were observed in the Chicago Heart Association Detection Project in Industry Study (3), the Paris Prospective Study (4), the Baltimore Longitudinal Study of Aging (5), and the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study (6). Furthermore, two meta-analyses provided evidence that hyperglycemia in the nondiabetic range was associated with a higher risk of fatal and nonfatal CVD. They also showed that CVD events increased linearly, with no threshold, along with 2-h postmeal plasma glucose levels (7,8).

Relatively few studies have analyzed postmeal hyperglycemia as a risk factor in CVD development. In the Diabetes Intervention Study (DIS), in type 2 diabetic patients who were monitored for 11 years, postbreakfast glucose levels, rather than fasting glucose, were related to myocardial infarction and death (9). In this issue of Diabetes Care , Cavalot et al. (10) add further evidence of the harmful relationship between postmeal glucose levels and …
DNA repair is more important than catalase for Salmonella virulence in mice.
Authors: N A Buchmeier, S J Libby, Y Xu, P C Loewen, J Switala, D G Guiney, F C Fang
Journal: Journal of Clinical Investigation (1995)

Pathogenic microorganisms possess antioxidant defense mechanisms for protection from reactive oxygen metabolites such as hydrogen peroxide (H2O2), which are generated during the respiratory burst of phagocytic cells. These defense mechanisms include enzymes such as catalase, which detoxify reactive oxygen species, and DNA repair systems which repair damage resulting from oxidative stress. To determine the relative importance of these two potentially protective defense mechanisms against oxidative stress encountered by Salmonella during infection of the host, a Salmonella typhimurium double mutant unable to produce either the HPI or HPII catalase was constructed, and compared with an isogenic recA mutant deficient in DNA repair. The recA mutant was hypersusceptible to H2O2 at low cell densities in vitro, while the catalase mutant was more susceptible to high H2O2 concentrations at high cell densities. The catalase mutant was found to be resistant to macrophages and retained full murine virulence, in contrast to the recA mutant which previously was shown to be macrophage-sensitive and attenuated in mice. These observations suggest that Salmonella is subjected to low concentrations of H2O2 while at relatively low cell density during infection, conditions requiring an intact DNA repair system but not functional catalase activity.
STUDIES OF TUBERCLE BACILLUS-HISTIOCYTE RELATIONSHIPS
Authors: Jacob Fong, Dennis Chin, Herta M. Vickrey
Journal: The Journal of Experimental Medicine (1963)

Immunization of mice or guinea pigs with BCG rendered all or most of the histiocytes of these animals resistant to necrotization by virulent H37Rv; this cellular resistance was mediated by immune serum. Immune mouse histiocytes (from BCG-immunized animals) were able to induce cellular resistance in normal homologous and heterologous (rabbit) animal species; mouse histiocytic ribosomes were also tested in the homologous species and found to be active. Immune guinea pig histiocytes (from BCG-immunized guinea pigs) were ineffective in transferring cellular resistance to either homologous or heterologous (mouse and rabbit) animal species. Immune rabbit histiocytes were capable of inducing cellular resistance in mice and guinea pigs; rabbit histiocytic ribosomes were also tested in normal mice and found to be active in induction of cellular resistance. Recipient guinea pig histiocytes (from guinea pigs inoculated with immune rabbit histiocytes) were capable of inducing cellular resistance in normal guinea pigs and rabbits. Cultivation of lysed immune histiocytes of all three animal species on glycerol-blood agar medium failed to reveal any viable BCG; this provided one additional bit of evidence against the idea that induction of cellular resistance is due to viable bacilli.
An Epidemiologic Study of Mortality among Bereaved Parents
Authors: Itzhak Levav, Yehiel Friedlander, Jeremy D. Kark, Eric Peritz
Journal: New England Journal of Medicine (1988)

To study the health consequences of parental bereavement, we compared the mortality in two groups of bereaved Israeli parents with that in the general population. One cohort comprised the parents of all 2518 soldiers 18 to 40 years of age who were killed during the Yom Kippur War in 1973. The second consisted of the parents of 1128 men 18 to 30 years of age who died in accidents between 1971 and 1975. Both groups were followed through 1983. The comparison population was the entire population of Jewish Israelis for which sex-, age-, and calendar year–specific mortality rates were available. The 10-year age-adjusted life-table mortality was higher among fathers whose sons died in accidents rather than in war (P = 0.045), but mortality did not differ significantly between the two groups of mothers. Overall, we found no excess mortality among the bereaved parents as compared with the general population. The standardized mortality ratios for the fathers and mothers of sons killed at war were 0.91 and 0.90, respectively; for fathers and mothers whose sons died by accident, they were 1.04 and 0.91, respectively. None were significantly different from unity. There was no consistent evidence of an elevated risk of death, early or late, after the loss. Widowed and divorced parents who lost a son did have increased mortality, which was statistically significant in mothers. Our findings provide no support for the hypothesis that the loss of an adult son is associated with increased short-term or long-term mortality in married parents. (N Engl J Med 1988; 319:457–61.)
Addressing the Financial Burden of Cancer Treatment
Authors: Veena Shankaran, Scott Ramsey
Journal: JAMA Oncology (2015)

Patients with cancer spend a substantial amount of money on health care services and are at higher risk for financial hardship, including personal bankruptcy, than the general population. 1 Evidence that this so-called financial toxicity has a negative impact on clinical outcomes is emerging. High out-of-pocket spending on cancer treatment has been shown in recent studies to be associated with decreased treatment adherence and poorer quality of life. 2-4 The growing intersection between the financial and clinical aspects of cancer care represents an emerging challenge to the oncology community. In this article, we present 5 strategies to address the financial burden of cancer treatment.
A Few Personal Facts concerning Experiments on Animals Opposed to the False Fancies of the Persecutors of Vivisection
Authors: C. J. B. Williams
Journal: BMJ (1876)

THE BRITISH MEDICAL 7OURNAL. (JUly 2a, l5k6 pons and the pyramid, down to the lateral column of the spinal cd .Wben this condition has been fully developed, no kind of treatment is of any avail; and it appears, therefore, for this reason alone, that your therapeutical efforts should not be postponed a day longer than you can help it.Ergot, in the form of the liquid extract, for the cure of any miliary aneurisms which may be in the process of formation; phosphoru.s,for improving the nutrition and function of the injured nerve-cclls in the neighbourhoodl of the lesion; galvanisation and fara- disation, for the stimulation of the paralysel parts, are our sheet- anchors in the treatment of this condition ; and, if sagaciously usedl, will do infinitely more goo(l than the merely expectant plan of treat- ment, Which has hitherto been somewhat too much the fashion in these cases.
Welcome to Cardiovascular Research in 2015
Authors: K. R. Sipido, P. Holvoet, S. Janssens, A. Luttun, M. Sampaolesi
Journal: Cardiovascular Research (2014)

Research in cardiovascular biology and disease is influenced by the changing landscape in biomedical and health research. Increased demands for innovation, translation, and implementation of novel findings into patient care are reflected in growth of publications and journals with more clinical and translational content, and more emphasis on the potential impact of basic and preclinical research in basic science reports. At the same time there has been an exciting growth of pure exploratory basic research, related to technological innovation, e.g. advanced microscopy, rewarded with the 2014 Nobel …
Abstract 4498: Biological characterization of NVP-BKM120, a novel inhibitor of phosphoinosotide 3-kinase in Phase I/II clinical trials
Authors: charles F. Voliva, Sabina Pecchi, Matthew Burger, Tobi Nagel, Christian Schnell, christine Fritsch, saskia Brachmann, Daniel Menezes, Mark Knapp, Kevin Shoemaker, Marion Wiesmann, kay Huh, Isabel Zaror, Marion Dorsch, William R. Sellers, Carlos Garcia-Echeverria, Michel Maira
Journal: Cancer Research (2010)

Abstract The PI3K/Akt/mTor signaling pathway plays an important role in controlling cell growth, proliferation and survival. Through various mechanisms, the pathway is frequently dysregulated in human cancers, suggesting the use of PI3K inhibitors as novel targeted anticancer therapeutic agents. To this end, substantial drug discovery efforts have been devoted both in pharmaceutical companies and in academia to identify and develop therapeutic agents able to specifically down regulate PI3K or other components of this pathway in tumors cells. Following the discovery of NVP-BEZ235, our first dual pan-PI3K/mTOR clinical compound, we sought to identify additional PI3K inhibitors from different chemical classes with more stringent selectivity profiles. The key to achieve these objectives was to pursue a structure-based design approach coupled with intensive pharmacological evaluation of selected compounds during the medicinal chemistry optimization process. Here we report on the biological characterization of the pan-PI3K pyrimidine-derived inhibitor NVP-BKM120. This compound inhibits all four Class I PI3K isoforms (IC50 values in the 35 to 248 nM range) with at least 50-fold selectivity (compared to p110α) towards protein kinases. The compound is also active against the most common somatic PI3Kα mutations (H1047R, E542K and E545K). NVP-BKM120 does not significantly inhibit the related Class III (Vps34) and Class IV (mTOR, DNA-PK) PI3K kinases. Consistent with its mechanism of action, NVP-BKM120 decreases the cellular levels of p-Akt in mechanistic and relevant tumor cell lines (e.g., IC50 for S473P-Akt in Rat1-p110α cells of 93 nM). This biological activity correlates with inhibition of various Akt downstream signaling pathway components, and with its anti-proliferative activity. Thus, the compound demonstrates significant, concentration dependent cell growth inhibition and induction of apoptosis in a variety of tumor cancer cells, particularly for those harboring p110α mutants and/or over-expressing erbB2. In addition, NVP-BKM120 demonstrates significant, dose dependent in vivo pharmacodynamic activity as measured by inhibition of p-Akt in relevant xenograft models. The pharmacological, biological and preclinical safety profile of NVP-BKM120 supports its clinical development and the compound is currently undergoing Phase 1/II clinical trials in cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4498.
Organ Transplantation: A Proposal for Routine Salvaging of Cadaver Organs
Authors: Jesse Dukeminier, David Sanders
Journal: New England Journal of Medicine (1968)

NO medical advance in recent years has raised so much controversy as organ transplantation. Transplantation has given rise to unprecedented legal problems, often unrecognized and little discussed.1 One urgent problem that we shall discuss here is the creation of lifesaving resources (that is, cadaver kidneys and other organs for transplantation). By recognizing the claims of persons to cadaver organs, the law can either help or hinder the creation of an adequate supply of organs for transplantation. The law at present requires — to put it in a nutshell — that surgeons obtain consent of the next of kin before removing . . .
BRCA1 5083del19 Mutant Allele Selectively Up-Regulates Periostin Expression <i>In vitro</i> and <i>In vivo</i>
Authors: Barbara Quaresima, Francesco Romeo, Maria C. Faniello, Maddalena Di Sanzo, Chang-Gong Liu, Annamaria Lavecchia, Cristian Taccioli, Eugenio Gaudio, Francesco Baudi, Francesco Trapasso, Carlo M. Croce, Giovanni Cuda, Francesco Costanzo
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The aim of this study was to explore the gene expression pattern produced by the cancer-associated BRCA1 5083del19 founder mutation by using a microarray analysis. Such a mutation, identified in a subset of familial breast cancer patients, involves a deletion at the 3′ end of the BRCA1 messenger leading, in the mature protein, to the ablation of the BRCT tandem domain. Experimental Design: We generated HeLa cells stably expressing both exogenous wild-type (HeLa/wtBRCA1), used as a control, and 5083del19 BRCA1 (HeLa/5083del19BRCA1) alleles; gene chips were then used to investigate any changes in the transcription profile induced by the 5083del19 BRCA1 mutant compared with controls. Results: Among the genes showing perturbation of their expression, periostin was found to be up-regulated in HeLa/5083del19BRCA1 cells to an extent of 72-fold versus HeLa/pcDNA3.1/empty and 76-fold versus HeLa/wtBRCA1 cells. This finding was validated both in vitro in breast cancer cell lines harboring mutations of BRCA1 and in vivo by immunohistochemistry of breast cancer specimens bearing the 5083del19 BRCA1 mutation as well as by Western blot analysis of sera obtained from patients and healthy carriers of the same mutation. Conclusions: Our results suggest that periostin overexpression, whose product is released from cells in the extracellular fluids, might be a potential marker for early cancer detection in a specific subset of hereditary breast carcinomas triggered by cancer-associated BRCA1 mutations that affect the BRCT tandem domain.
Gradient Model Versus Mosaic Model of the Sinoatrial Node
Authors: H. Zhang, A. V. Holden, M. R. Boyett
Journal: Circulation (2001)

Background —A radical reinterpretation (mosaic model) of the makeup of the sinoatrial (SA) node has been proposed to explain the characteristic regional differences in electrical activity between the periphery and center of the SA node. According to the mosaic model, the differences result from a change in the mix of atrial cells and uniform SA node cells from periphery to center, whereas according to the alternative gradient model, there are no atrial cells within the functional SA node, and the differences result from a change in the intrinsic properties of SA node cells from periphery to center. Methods and Results —A mosaic model of peripheral and central tissue has been constructed computationally by use of a coupled ordinary differential equation network (CODE) in a 2D lattice (20×20), with each node of the lattice designated randomly as an atrial cell or SA node cell (in correct proportions for periphery and center). The mosaic model fails to predict the characteristic differences in action potential rate and shape between the periphery and center, whereas the existing gradient model can do so. Conclusions —The mosaic model of the SA node is untenable, and the SA node is adequately described by the gradient model.
Inhibition of Norepinephrine Uptake in Patients With Major Depression Treated With Paroxetine
Authors: Michelle L. Gilmor, Michael J. Owens, Charles B. Nemeroff
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: The study examined whether paroxetine inhibits the human norepinephrine transporter in addition to the human serotonin (5-HT) transporter in patients with major depressive disorder. METHOD: In an open-label, parallel-group, forced-titration study, 52 outpatients with DSM-IV major depressive disorder and a baseline Montgomery Åsberg Depression Rating Scale score ≥20 were randomly assigned to treatment with paroxetine (to 60 mg/day) or desipramine (to 30 mg/day) in a 3-to-1 ratio, respectively. Norepinephrine and 5-HT transporter function were assayed by using human transporter transfected cells in the presence of serum collected at baseline and the end of each treatment week. Data from 36 patients were analyzed. RESULTS: Paroxetine decreased norepinephrine uptake to 73% of control (27% inhibition) at an average serum concentration of 100 ng/ml and 57% of control (43% inhibition) at 200 ng/ml. Uptake of 5-HT was decreased to less than 15% (greater than 85% inhibition) of control at these paroxetine concentrations. Desipramine decreased norepinephrine uptake to near maximal 15% of control (85% inhibition) at 100 ng/ml. Uptake of 5-HT was decreased to 82% of control (18% inhibition) at 100 ng/ml and 49% of control (51% inhibition) at 500 ng/ml. CONCLUSIONS: Paroxetine, currently classified as a selective 5-HT reuptake inhibitor, can act as a 5-HT/norepinephrine uptake inhibitor in vivo. The clinical significance of this action on norepinephrine uptake is currently unknown, but this action may contribute to the broad therapeutic efficacy of paroxetine in the treatment of depression, panic disorder, social anxiety disorder, posttraumatic stress disorder, and generalized anxiety disorder.
Primary biliary cirrhosis, cutaneous capillaritis, and IgM-associated membranous glomerulonephritis.
Authors: G S Rai, A N Hamlyn, M G Dahl, A R Morley, R Wilkinson
Journal: BMJ (1977)

been a total of 19 cases in seven families reported, our patients bringing the total to 21 cases in eight families.The familial incidence of hypernephromas may be fortuitous, but if a genetic factor is present the question of screening other members of the family arises.Brinton2 and Steinberg et al3 reported hypernephroma in two generations and it would therefore seem reasonable to carry out regular five-year investigations in the other siblings and the children of our two brothers.