tbuckley/cabot-search huggingface dataset:
O6-Methylguanine DNA methyltransferase protein expression in tumor cells predicts outcome of temozolomide therapy in glioblastoma patients
Authors: S. Spiegl-Kreinecker, C. Pirker, M. Filipits, D. Lotsch, J. Buchroithner, J. Pichler, R. Silye, S. Weis, M. Micksche, J. Fischer, W. Berger
Journal: Neuro-Oncology (2009)

O(6)-Methylguanine DNA methyltransferase (MGMT) is implicated as a major predictive factor for treatment response to alkylating agents including temozolomide (TMZ) of glioblastoma multiforme (GBM) patients. However, whether the MGMT status in GBM patients should be detected at the level of promoter methylation or protein expression is still a matter of debate. Here, we compared promoter methylation (by methylation-specific polymerase chain reaction) and protein expression (by Western blot) in tumor cell explants with respect to prediction of TMZ response and survival of GBM patients (n = 71). Methylated MGMT gene promoter sequences were detected in 47 of 71 (66%) cases, whereas 37 of 71 (52%) samples were scored positive for MGMT protein expression. Although overall promoter methylation correlated significantly with protein expression (chi(2) test, P < .001), a small subgroup of samples did not follow this association. In the multivariate Cox regression model, a significant interaction between MGMT protein expression, but not promoter methylation, and TMZ therapy was observed (test for interaction, P = .015). In patients treated with TMZ (n = 42), MGMT protein expression predicted a significantly shorter overall survival (OS; hazard ratio [HR] for death 5.53, 95% confidence interval [CI] 1.76-17.37; P = .003), whereas in patients without TMZ therapy (n = 29), no differences in OS were observed (HR for death 1.00, 95% CI 0.45-2.20; P = .99). These data suggest that lack of MGMT protein expression is superior to promoter methylation as a predictive marker for TMZ response in GBM patients.
hZIP1 zinc uptake transporter down regulation and zinc depletion in prostate cancer
Authors: Renty B Franklin, Pei Feng, B Milon, Mohamed M Desouki, Keshav K Singh, André Kajdacsy-Balla, Omar Bagasra, Leslie C Costello
Journal: Molecular Cancer (2005)

Abstract Background The genetic and molecular mechanisms responsible for and associated with the development and progression of prostate malignancy are largely unidentified. The peripheral zone is the major region of the human prostate gland where malignancy develops. The normal peripheral zone glandular epithelium has the unique function of accumulating high levels of zinc. In contrast, the ability to accumulate zinc is lost in the malignant cells. The lost ability of the neoplastic epithelial cells to accumulate zinc is a consistent factor in their development of malignancy. Recent studies identified ZIP1 (SLC39A1) as an important zinc transporter involved in zinc accumulation in prostate cells. Therefore, we investigated the possibility that down-regulation of hZIP1 gene expression might be involved in the inability of malignant prostate cells to accumulate zinc. To address this issue, the expression of hZIP1 and the depletion of zinc in malignant versus non-malignant prostate glands of prostate cancer tissue sections were analyzed. hZIP1 expression was also determined in malignant prostate cell lines. Results hZIP1 gene expression, ZIP1 transporter protein, and cellular zinc were prominent in normal peripheral zone glandular epithelium and in benign hyperplastic glands (also zinc accumulating glands). In contrast, hZIP1 gene expression and transporter protein were markedly down-regulated and zinc was depleted in adenocarcinomatous glands and in prostate intra-epithelial neoplastic foci (PIN). These changes occur early in malignancy and are sustained during its progression in the peripheral zone. h ZIP1 is also expressed in the malignant cell lines LNCaP, PC-3, DU-145; and in the nonmalignant cell lines HPr-1 and BPH-1. Conclusion The studies clearly establish that hZIP1 gene expression is down regulated and zinc is depleted in adenocarcinomatous glands. The fact that all the malignant cell lines express hZIP1 indicates that the down-regulation in adenocarcinomatous glands is likely due to in situ gene silencing. These observations, coupled with the numerous and consistent reports of loss of zinc accumulation in malignant cells in prostate cancer, lead to the plausible proposal that down regulation of hZIP1 is a critical early event in the development prostate cancer.
The Extent of Nucleotide Polymorphism is Highly Variable Across a 3-kb Region on Plasmodium falciparum Chromosome 2
Authors: Somchai Jongwutiwes, Chaturong Putaporntip, Robert Friedman, Austin L Hughes
Journal: Molecular Biology and Evolution (2002)

Genomic nucleotide polymorphism in the virulent human malarial parasite Plasmodium falciparum was surveyed by sequencing a 3-kb region of chromosome 2 from 21 isolates, including the MSP4 and MSP5 genes. Extensive sequence polymorphism was observed in the coding regions of these genes and in the region downstream to MSP5, and the average pairwise divergence time of haplotypes in this region was estimated to be at least about 200,000 years. But nucleotide polymorphism was not found in the introns and was much reduced in the intergenic region. Over the entire region, nucleotide diversity was negatively correlated with a nucleotide content skewed toward thymine. Together with the previous evidence of limited nucleotide polymorphism in introns of P. falciparum, these data suggest the existence of a mechanism suppressing single-nucleotide polymorphism in regions of the P. falciparum genome with highly skewed nucleotide content.
Challenges relating to solid tumour brain metastases in clinical trials, part 1: patient population, response, and progression. A report from the RANO group
Authors: Nancy U Lin, Eudocia Q Lee, Hidefumi Aoyama, Igor J Barani, Brigitta G Baumert, Paul D Brown, D Ross Camidge, Susan M Chang, Janet Dancey, Laurie E Gaspar, Gordon J Harris, F Stephen Hodi, Steven N Kalkanis, Kathleen R Lamborn, Mark E Linskey, David R Macdonald, Kim Margolin, Minesh P Mehta, David Schiff, Riccardo Soffietti, John H Suh, Martin J van den Bent, Michael A Vogelbaum, Jeffrey S Wefel, Patrick Y Wen
Journal: The Lancet Oncology (2013)
Regulatory Mechanisms that Determine the Development and Function of Plasma Cells
Authors: Kathryn L. Calame, Kuo-I Lin, Chainarong Tunyaplin
Journal: Annual Review of Immunology (2003)

Plasma cells are terminally differentiated final effectors of the humoral immune response. Plasma cells that result from antigen activation of B-1 and marginal zone B cells provide the first, rapid response to antigen. Plasma cells that develop after a germinal center reaction provide higher-affinity antibody and often survive many months in the bone marrow. Transcription factors Bcl-6 and Pax5, which are required for germinal center B cells, block plasmacytic differentiation and repress Blimp-1 and XBP-1, respectively. When Bcl-6-dependent repression of Blimp-1 is relieved, Blimp-1 ensures that plasmacytic development is irreversible by repressing BCL-6 and PAX5. In plasma cells, Blimp-1, XBP-1, IRF4, and other regulators cause cessation of cell cycle, decrease signaling from the B cell receptor and communication with T cells, inhibit isotype switching and somatic hypermutation, downregulate CXCR5, and induce copious immunoglobulin synthesis and secretion. Thus, commitment to plasmacytic differentiation involves inhibition of activities associated with earlier B cell developmental stages as well as expression of the plasma cell phenotype.
VSOP/Hv1 proton channels sustain calcium entry, neutrophil migration, and superoxide production by limiting cell depolarization and acidification
Authors: Antoun El Chemaly, Yoshifumi Okochi, Mari Sasaki, Serge Arnaudeau, Yasushi Okamura, Nicolas Demaurex
Journal: The Journal of Experimental Medicine (2009)

Neutrophils kill microbes with reactive oxygen species generated by the NADPH oxidase, an enzyme which moves electrons across membranes. Voltage-gated proton channels (voltage-sensing domain only protein [VSOP]/Hv1) are required for high-level superoxide production by phagocytes, but the mechanism of this effect is not established. We show that neutrophils from VSOP/Hv1-/- mice lack proton currents but have normal electron currents, indicating that these cells have a fully functional oxidase that cannot conduct protons. VSOP/Hv1-/- neutrophils had a more acidic cytosol, were more depolarized, and produced less superoxide and hydrogen peroxide than neutrophils from wild-type mice. Hydrogen peroxide production was rescued by providing an artificial conductance with gramicidin. Loss of VSOP/Hv1 also aborted calcium responses to chemoattractants, increased neutrophil spreading, and decreased neutrophil migration. The migration defect was restored by the addition of a calcium ionophore. Our findings indicate that proton channels extrude the acid and compensate the charge generated by the oxidase, thereby sustaining calcium entry signals that control the adhesion and motility of neutrophils. Loss of proton channels thus aborts superoxide production and causes a severe signaling defect in neutrophils.
Endothelin-B receptor activation triggers an endogenous analgesic cascade at sites of peripheral injury
Authors: Alla Khodorova, Betsy Navarro, Laurence Sophie Jouaville, Jo-Ellen Murphy, Frank L Rice, Joseph E Mazurkiewicz, Denise Long-Woodward, Markus Stoffel, Gary R Strichartz, Rus Yukhananov, Gudarz Davar
Journal: Nature Medicine (2003)
Letter by DeGroff Regarding Article, “Direction of Preoperative Ventricular Shunting Affects Ventricular Mechanics After Tetralogy of Fallot Repair”
Authors: Curt G. DeGroff
Journal: Circulation (2009)

I enjoyed the work presented recently in Circulation by Richmond et al 1 entitled "Direction of Preoperative Ventricular Shunting Affects Ventricular Mechanics After Tetralogy of Fallot Repair."However, a major limitation of this work was not discussed in the detail it deserves.The authors use of 2-dimensional echocardiographic "stroke area" of the left ventricle has a number of significant limitations in the assessment of myocardial contractile state, many of which should have been at least mentioned in the article.One simple imaging limitation of this method has particular significance here because of the subjects included in this study (ie, subjects with right and left volume-or pressure-overloaded ventricles).This limitation was described elegantly more than a decade ago by Matsumori et al. 2 Matsumori et al illustrated the effects of right ventricular volume and pressure overloads on assessment of left ventricular volume with the use of 2-dimensional echocardiographic methods.This raises the con-cern that the differences that Richmond et al are seeing between patient groups are simply effects from limitations of the technique itself.
Sedentary lifestyle could be masking serious health problems in children
Authors: A. O'Dowd
Journal: BMJ (2009)

Children who seem healthy and of normal weight could have serious health problems because of the United Kingdom’s increasingly sedentary lifestyle, new research says.

A study published in the Archives of Disease in Childhood also warns that fitness levels of children in the UK are falling twice as fast as those in the rest of the world.

Researchers from the University of Essex’s Centre for Sports and Exercise Science said that increasing weight gain did not explain the “large and worrying” falls in UK children’s cardiorespiratory fitness levels over the past decade.

Global fitness levels of children have dropped by around 4% in the past 10 years, but this UK based …
N-terminal pro-brain-type natriuretic peptide (NT-pro-BNP) and mortality risk in early inflammatory polyarthritis: results from the Norfolk Arthritis Registry (NOAR)
Authors: Hoda Mirjafari, Paul Welsh, Suzanne M M Verstappen, Paddy Wilson, Tarnya Marshall, Helena Edlin, Diane Bunn, Jacqueline Chipping, Mark Lunt, Deborah P M Symmons, Naveed Sattar, Ian N Bruce
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> We measured N-terminal pro-brain natriuretic peptide (NT-pro-BNP), a marker of cardiac dysfunction, in an inception cohort with early inflammatory polyarthritis (IP) and assessed its association with disease phenotype, cardiovascular disease (CVD), all-cause and CVD related mortality. <h3>Methods</h3> Subjects with early IP were recruited to the Norfolk Arthritis Register from January 2000 to December 2008 and followed up to death or until March 2010 including any data from the national death register. The associations of baseline NT-pro-BNP with IP related factors and CVD were assessed by linear regression. Cox proportional hazards models examined the independent association of baseline NT-pro-BNP with all-cause and CVD mortality. <h3>Results</h3> We studied 960 early IP subjects; 163 (17%) had prior CVD. 373 (39%) patients had a baseline NT-pro-BNP levels ≥100 pg/ml. NT-pro-BNP was associated with age, female gender, HAQ score, CRP, current smoking, history of hypertension, prior CVD and the presence of carotid plaque. 92 (10%) IP subjects died including 31 (3%) from CVD. In an age and gender adjusted analysis, having a raised NT-pro-BNP level (≥100 pg/ml) was associated with both all-cause and CVD mortality (adjusted HR (95% CI) 2.36 (1.42 to 3.94) and 3.40 (1.28 to 9.03), respectively). These findings were robust to adjustment for conventional CVD risk factors and prevalent CVD. <h3>Conclusions</h3> In early IP patients, elevated NT-pro-BNP is related to HAQ and CRP and predicts all-cause and CVD mortality independently of conventional CVD risk factors. Further study is required to identify whether NT-pro-BNP may be clinically useful in targeting intensive interventions to IP patients at greatest risk of CVD.
Clinical Aspects of Iron Use in the Anemia of Kidney Disease
Authors: Walter H. Hörl
Journal: Journal of the American Society of Nephrology (2007)

Iron deficiency occurs in the vast majority of patients with chronic kidney disease (CKD). The causes of iron deficiency in these patients are multifactorial. Main factors that contribute to iron deficiency in patients with end-stage renal disease (ESRD) are reduced intake and impaired intestinal
Smoking and the incidence of asthma during adolescence: results of a large cohort study in Germany
Authors: J Genuneit
Journal: Thorax (2006)

<b>Background:</b> The association between smoking and asthma or wheeze has been extensively studied in cross sectional studies, but evidence from large prospective cohort studies on the incidence of asthma during adolescence is scarce. <b>Methods:</b> We report data from a cohort study in two German cities, Dresden and Munich. The study population (n = 2936) was first studied in 1995/6 at age 9–11 years as part of phase II of the International Study of Asthma and Allergies in Childhood (ISAAC II) and followed up in 2002/3. At baseline the parents completed a questionnaire and children underwent clinical examination and blood sampling. At follow up the young adults completed questionnaires on respiratory health, living, and exposure conditions. Incidence risk ratios (IRR) were calculated and adjusted for potential confounders using a modified Poisson regression approach. <b>Results:</b> The adjusted IRR for incident wheeze for active smokers compared with non-smokers was 2.30 (95% confidence interval (CI) 1.88 to 2.82). The adjusted IRR was slightly higher for incident wheeze without a cold (2.76, 95% CI 1.99 to 3.84) and the incidence of diagnosed asthma (2.56, 95% CI 1.55 to 4.21). Analysis of duration and intensity of active smoking indicated dose dependent associations. Stratified analyses showed that the risk of incident wheeze without a cold in atopic smokers increased with decreasing plasma α<sub>1</sub>-antitrypsin levels at baseline (1.64, 95% CI 1.22 to 2.20 per interquartile range). <b>Conclusions:</b> Active smoking is an important risk factor for the incidence of asthma during adolescence. Relatively lower plasma levels of α<sub>1</sub>-antitrypsin, although well above currently accepted thresholds, may increase susceptibility to respiratory disease among atopic smokers.
Very-Low-Calorie Diets
Authors: Karl J. Niedershuh
Journal: JAMA (1990)

To the Editor.—  A recent commentary by Wadden et al1on the irresponsible use of very-low-calorie diets hints at the possibility of yet another epidemic of sudden cardiac death among the obese and desperate. In this light, it should be noted that research has yet to explain adequately the appearance of prolonged QT intervals or malignant ventricular arrhythmias in patients who undergo rapid and substantial weight loss.  Sours et al2found that supplemented fasting deaths could not be explained by such factors as the quality or quantity of medical care, the biologic quality of the protein supplement, or electrolyte balance as determined by potassium intake. More recent research has challenged the assumption that nutritional depletion or lean tissue loss precipitated these deaths.3,4These studies suggest that a portion of the obese population is at increased risk of developing malignant arrhythmias in response to stress, regardless of the
Abstract 4906: mTOR kinase inhibition enhances radiosensitivity in glioblastoma
Authors: Anita T. Tandle, Philip Tofilon, Kevin Camphausen
Journal: Cancer Research (2014)

Abstract Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor and predicts a poor prognosis despite current treatment modalities. Aberrant activation of the phosphatidyl-inositol-3-kinase (PI3K) pathway is observed in nearly 90% of GBMs making the downstream effector, mammalian target of rapamycin (mTOR), a potential drug target. mTOR is a serine/threonine kinase that regulates cell growth, proliferation, survival, protein translation and metabolism by integrating signals received from the PI3 K/Akt signaling pathway. The allosteric mTOR inhibitor rapamycin has failed in the clinic as a treatment for GBM patients. Therefore, in the current study, we examined the potential benefit of MLN0128, a novel potent mTOR ATP competitive inhibitor, as a therapeutic strategy for GBM. We assessed in vitro antiproliferative activity of MLN0128 in a panel of GBM tumor and stem cell lines. MLN0128 significantly inhibited cell proliferation of both GBM tumor and stem cells. It decreased the phosphorylation of mTOR, Akt, S6, 4E-BP1, and NDRG1, inhibiting both mTORC1 and mTORC2 signaling in GBM. Thus, MLN0128 appears to be superior in blocking mTORC1/2 signaling in contrast to rapamycin. It inhibited migration and invasion of GBM cells in a matrigel coated chamber assay. On clonogenic survival assay MLN0128 decreased GBM cell survival and increased radiosensitivity. To investigate the mechanism of radiosensitization, the induction and repair of DNA double-strand breaks were evaluated by γH2AX foci formation. MLN0128 exposure significantly delayed the dispersal of radiation induced γH2AX foci formation in both tumor and stem cells. These results indicate that MLN0128 enhances tumor cell radiosensitivity by inhibiting DNA repair. Next we combined MLN0128 with temozolomide (TMZ), a FDA approved radiosensitizer for GBM therapy. Although, we did not observe any synergy in inhibition, addition of TMZ did not adversely affect MLN0128 inhibitory effects. These findings support the rationale for clinical testing of MLN0128 in patients with GBM to provide insight towards optimizing therapeutic efficacy of mTOR kinase inhibitors with standard care. Note: This abstract was not presented at the meeting. Citation Format: Anita T. Tandle, Philip Tofilon, Kevin Camphausen. mTOR kinase inhibition enhances radiosensitivity in glioblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4906. doi:10.1158/1538-7445.AM2014-4906
Where Does Fetal and Embryonic Cholesterol Originate and What Does It Do?
Authors: Laura A. Woollett
Journal: Annual Review of Nutrition (2008)

The development of a single-celled fertilized egg, through the blastocyst stage of a ball of cells and the embryonic stage when almost all organ systems begin to develop, and finally to the fetal stage where growth and physiological maturation occurs, is a complex and multifaceted process. A change in metabolism during gestation, especially when organogenesis occurs, can lead to abnormal development and congenital defects. Although many studies have described the roles of specific proteins in development, the roles of specific lipids, such as sterols, have not been studied as intensely. Sterol's functions in development range from being a structural component of membranes to regulating the patterning of the forebrain through sonic hedgehog to regulating expression of key proteins involved in metabolic processes. This review focuses on the roles of sterols in embryonic and fetal development and metabolism. Potential sources of cholesterol for the fetus and embryo are also discussed.
How Should We Design Supportive Cancer Care? The Patient's Perspective
Authors: David Casarett, Jessica Fishman, Peter J. O'Dwyer, Frances K. Barg, Mary Naylor, David A. Asch
Journal: Journal of Clinical Oncology (2008)

Purpose Hospice services are designed to meet the needs of patients near the end of life. Although so-called open-access hospice programs and bridge programs are beginning to offer these services to patients who are still receiving treatment, it is not known whether they best meet patients’ needs. Patients and Methods Three hundred adult patients receiving treatment for cancer completed interviews in which each patient's value or ability for supportive care services were calculated from the choices that they made among combinations of those services. Preferences for five traditional hospice services and six alternative supportive care services were measured, and patients were followed up for 6 months or until death. Results Patients’ utilities for alternative services were higher than those for traditional hospice services (0.53 v 0.39; sign-rank test P &lt; .001). Alternative services were also preferred among patients with poor functional status (Eastern Cooperative Oncology Group performance score &gt; 2; n = 54; 0.65 v 0.48; P &lt; .001) and among those who were in the last 6 months of life (0.68 v 0.56; sign-rank test P = .003). Even patients who were willing to forgo cancer treatment (n = 38; 13%) preferred alternative services (3.1 v 1.8; P &lt; .001). Conclusion Patients who are receiving active treatment for cancer, and even those who are willing to stop treatment, express a clear preference for alternative supportive care services over traditional hospice services. Supportive care programs for patients with advanced cancer should reconsider the services that they offer and might seek to include novel services in addition to, or perhaps instead of, traditional hospice services.