Publications by authors named "Victoria Brown"

87 Publications

Factors associated with optimized tacrolimus dosing in hematopoietic stem cell transplantation.

J Oncol Pharm Pract 2016 Apr 22;22(2):275-83. Epub 2015 Mar 22.

Department of Pharmacy, The Johns Hopkins Hospital, Baltimore, USA.

Objective: The primary objective was to analyze the initial tacrolimus concentrations achieved in allogeneic hematopoietic stem cell transplantation patients using the institutional dosing strategy of 1 mg IV daily initiated on day +5. The secondary objectives were to ascertain the tacrolimus dose, days of therapy, and dose changes necessary to achieve a therapeutic concentration, and to identify patient-specific factors that influence therapeutic dose. The relationships between the number of pre-therapeutic days and incidence of graft-versus-host disease and graft failure were delineated.

Methods: A retrospective chart review included adult allogeneic hematopoietic stem cell patients who received tacrolimus for graft-versus-host disease prophylaxis in 2012. Descriptive statistics, linear and logistic regression, and graphical analyses were utilized.

Results: Ninety-nine patients met the inclusion criteria. The first concentration was subtherapeutic (<10 ng/ml) in 97 patients (98%). The median number of days of tacrolimus needed to achieve a therapeutic trough was 10 with a median of two dose changes. The median therapeutic dose was 1.6 mg IV daily. Approximately 75% of patients became therapeutic on ≤ 2 mg IV tacrolimus daily. No relationship was found between therapeutic dose and any patient-specific factor tested, including weight. No relationship was found between the number of days of therapy required to achieve a therapeutic trough and incidence of graft-versus-host disease or graft failure.

Conclusion: An initial flat tacrolimus dose of 1 mg IV daily is a suboptimal approach to achieve therapeutic levels at this institution. A dose of 1.6 mg or 2 mg IV daily is a reasonable alternative to the current institutional practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1078155215577809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696901PMC
April 2016

Experiences, perceptions and preferences of mothers towards childhood immunization reminder/recall in Ibadan, Nigeria: a cross-sectional study.

Pan Afr Med J 2015 13;20:243. Epub 2015 Mar 13.

Primary Health Care and Health Management Centre (PriHEMAC), Ibadan, Nigeria.

Introduction: Immunization reminder/recall system is proven as one of the effective ways of improving immunization rates. Prior to the development and implementation of an immunization reminder/recall system intervention, we explored the experiences, preferences and perceptions towards childhood immunization reminder/recall among 614 mothers of infants in Ibadan, Nigeria.

Methods: A cross-sectional health facility-based survey utilizing a semi-structured questionnaire was conducted in four Primary Health Care centers. Descriptive statistics were computed using SPSS. Logistic models were used to investigate the relationships with specific outcomes.

Results: Only 3.9% had ever heard of immunization reminder/recall and 1.5% had ever received one. However, 97.9% were willing to record their cellphone numbers in the clinics for immunization reminder/recall and 95.1% were willing to receive. Their preferred communication modes were cell phone calls (57.6%) or text messages/SMS (35.6%). Only 2.2% preferred home-visits and 0.4%, e-mails. About 4% were not willing to receive any form of immunization reminder/recall. Mothers with post-secondary education were more likely to prefer SMS than other mothers (OR 2.3, 95% CI 1.7-3.3, p.

Conclusion: This study provided critical baseline data for designing a reminder/recall intervention for routine childhood immunization in the study communities. The findings may serve as a guide for public health professionals in designing reminder/recall strategies to improve childhood immunization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11604/pamj.2015.20.243.6019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919677PMC
December 2016

Quantitative ChIP-Seq normalization reveals global modulation of the epigenome.

Cell Rep 2014 Nov 30;9(3):1163-70. Epub 2014 Oct 30.

Syros Pharmaceuticals, 480 Arsenal Street, Watertown, MA 02472, USA. Electronic address:

Epigenomic profiling by chromatin immunoprecipitation coupled with massively parallel DNA sequencing (ChIP-seq) is a prevailing methodology used to investigate chromatin-based regulation in biological systems such as human disease, but the lack of an empirical methodology to enable normalization among experiments has limited the precision and usefulness of this technique. Here, we describe a method called ChIP with reference exogenous genome (ChIP-Rx) that allows one to perform genome-wide quantitative comparisons of histone modification status across cell populations using defined quantities of a reference epigenome. ChIP-Rx enables the discovery and quantification of dynamic epigenomic profiles across mammalian cells that would otherwise remain hidden using traditional normalization methods. We demonstrate the utility of this method for measuring epigenomic changes following chemical perturbations and show how reference normalization of ChIP-seq experiments enables the discovery of disease-relevant changes in histone modification occupancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2014.10.018DOI Listing
November 2014

Matrix-enhanced surface-assisted laser desorption/ionization mass spectrometry (ME-SALDI-MS) for mass spectrometry imaging of small molecules.

Methods Mol Biol 2015 ;1203:175-84

Department of Chemistry, North Carolina State University, 2620 Yarbrough Drive, CB 8204, Raleigh, NC, 27695, USA.

Surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS), a parallel technique to matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), utilizes inorganic particles or porous surfaces to aid in the desorption/ionization of low-molecular-weight (MW) analytes. As a matrix-free and "soft" LDI approach, SALDI offers the benefit of reduced background noise in the low MW range, allowing for easier detection of biologically significant small MW species. Despite the inherent advantages of SALDI-MS, it has not reached comparable sensitivity levels to MALDI-MS. In relation to mass spectrometry imaging (MSI), intense efforts have been made in order to improve sensitivity and versatility of SALDI-MSI. We describe herein a detailed protocol that utilizes a hybrid LDI method, matrix-enhanced SALDI-MS (ME-SALDI MS), to detect and image low MW species in an imaging mode.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-4939-1357-2_17DOI Listing
June 2015

Nanostructure-initiator mass spectrometry (NIMS) for molecular mapping of animal tissues.

Methods Mol Biol 2015 ;1203:151-7

Department of Chemistry, North Carolina State University, 2620 Yarbrough Drive, CB 8204, Raleigh, NC, 27695, USA.

Nanostructure-initiator mass spectrometry (NIMS) is an established method for sensitive detection of small molecules in complex samples. It is based on the optimal combination of a porous Si substrate and a carefully selected polymer coating to allow certain analytes of interest to be concentrated on the substrate for effective ionization with minimal background interference from conventional organic matrices. The previous chapter has detailed the history and current state of the art of the technique in small-molecule profiling and imaging applications. We describe here a simple step-by-step protocol for substrate fabrication and sample preparation that provides a starting point for the technique to be adapted and optimized for 2-D biological imaging applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-4939-1357-2_15DOI Listing
June 2015

Current status and future prospects of mass spectrometry imaging of small molecules.

Methods Mol Biol 2015 ;1203:1-7

Department of Chemistry, North Carolina State University, 2620 Yarbrough Drive, CB 8204, Raleigh, NC, 27695, USA.

In the field of small-molecule studies, vast efforts have been put forth in order to comprehensively characterize and quantify metabolites formed from complex mechanistic pathways within biochemical and biological organisms. Many technologies and methodologies have been developed to aid understanding of the inherent complexities within biological metabolomes. Specifically, mass spectroscopy imaging (MSI) has emerged as a foundational technique in gaining insight into the molecular entities within cells, tissues, and whole-body samples. In this chapter we provide a brief overview of major technical components involved in MSI, including topics such as sample preparation, analyte ionization, ion detection, and data analysis. Emerging applications are briefly summarized as well, but details will be presented in the following chapters.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-4939-1357-2_1DOI Listing
June 2015

Expression of KOC, S100P, mesothelin and MUC1 in pancreatico-biliary adenocarcinomas: development and utility of a potential diagnostic immunohistochemistry panel.

BMC Clin Pathol 2014 23;14:35. Epub 2014 Jul 23.

Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden G61 1QH, UK ; Department of Pathology, Southern General Hospital, Greater Glasgow & Clyde NHS, Glasgow G51 4TF, UK.

Background: Pancreatico-biliary adenocarcinomas (PBA) have a poor prognosis. Diagnosis is usually achieved by imaging and/or endoscopy with confirmatory cytology. Cytological interpretation can be difficult especially in the setting of chronic pancreatitis/cholangitis. Immunohistochemistry (IHC) biomarkers could act as an adjunct to cytology to improve the diagnosis. Thus, we performed a meta-analysis and selected KOC, S100P, mesothelin and MUC1 for further validation in PBA resection specimens.

Methods: Tissue microarrays containing tumour and normal cores in a ratio of 3:2, from 99 surgically resected PBA patients, were used for IHC. IHC was performed on an automated platform using antibodies against KOC, S100P, mesothelin and MUC1. Tissue cores were scored for staining intensity and proportion of tissue stained using a Histoscore method (range, 0-300). Sensitivity and specificity for individual biomarkers, as well as biomarker panels, were determined with different cut-offs for positivity and compared by summary receiver operating characteristic (ROC) curve.

Results: The expression of all four biomarkers was high in PBA versus normal ducts, with a mean Histoscore of 150 vs. 0.4 for KOC, 165 vs. 0.3 for S100P, 115 vs. 0.5 for mesothelin and 200 vs. 14 for MUC1 (p < .0001 for all comparisons). Five cut-offs were carefully chosen for sensitivity/specificity analysis. Four of these cut-offs, namely 5%, 10% or 20% positive cells and Histoscore 20 were identified using ROC curve analysis and the fifth cut-off was moderate-strong staining intensity. Using 20% positive cells as a cut-off achieved higher sensitivity/specificity values: KOC 84%/100%; S100P 83%/100%; mesothelin 88%/92%; and MUC1 89%/63%. Analysis of a panel of KOC, S100P and mesothelin achieved 100% sensitivity and 99% specificity if at least 2 biomarkers were positive for 10% cut-off; and 100% sensitivity and specificity for 20% cut-off.

Conclusion: A biomarker panel of KOC, S100P and mesothelin with at least 2 biomarkers positive was found to be an optimum panel with both 10% and 20% cut-offs in resection specimens from patients with PBA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1472-6890-14-35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112611PMC
July 2014

CCGs. The rules of research rewritten.

Health Serv J 2013 Nov;Suppl:24-6

View Article and Find Full Text PDF

Download full-text PDF

Source
November 2013

Multiple myeloma maintenance therapy: a review of the pharmacologic treatment.

J Oncol Pharm Pract 2015 Feb 6;21(1):36-51. Epub 2014 Jan 6.

McKesson Specialty Health, The Woodlands, TX, USA.

Over the last decade, numerous drug therapies have emerged for the treatment of multiple myeloma including immunomodulating agents namely thalidomide, lenalidomide, and pomalidomide and proteasome inhibitors namely bortezomib and carfilzomib. These agents have transformed the treatment of multiple myeloma and the role of high-dose chemotherapy followed by stem cell transplantation in the treatment of the disease. There are now studies that evaluate the use of drug therapy as maintenance following autologous stem cell transplantation; these studies have shown improvements in surrogate endpoints such as progression-free survival. Studies that have evaluated thalidomide or lenalidomide maintenance therapy have demonstrated an overall survival (OS) benefit in individuals with multiple myeloma who received high-dose chemotherapy followed by stem cell transplantation. A meta-analysis of thalidomide maintenance therapy did show a possible late survival benefit. The use of dexamethasone, thalidomide, lenalidomide, or combination bortezomib with thalidomide in patients who did not undergo transplantation demonstrated progression-free survival benefit; although there was no OS advantage for these agents in this population. There are a number of important considerations when selecting a drug therapy strategy for maintenance therapy which includes practical considerations such as route of administration and frequency of administration. Additionally, patient-specific elements such as potential toxicities, end-organ function, quality of life, cytogenetics, and previous treatment should be considered. Additional studies are needed to elicit the timing for initiation and duration of maintenance therapy, determine the role of cytogenetics, further characterize possible resistance patterns, and determine the combinations necessary to achieve an optimal increase in OS. Until more data are available, the risks and benefits should be evaluated on a patient-specific basis when deciding to initiate maintenance therapy or observation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1078155213514468DOI Listing
February 2015

Prequit fMRI responses to pleasant cues and cigarette-related cues predict smoking cessation outcome.

Nicotine Tob Res 2014 Jun 27;16(6):697-708. Epub 2013 Dec 27.

University of Texas MD Anderson Cancer Center, Houston, TX;

Introduction: The reasons that some smokers find it harder to quit than others are unclear. Understanding how individual differences predict smoking cessation outcomes may allow the development of more successful personalized treatments for nicotine dependence. Theoretical models suggest that drug users might be characterized by increased sensitivity to drug cues and by reduced sensitivity to nondrug-related natural rewards. We hypothesized that baseline differences in brain sensitivity to natural rewards and cigarette-related cues would predict the outcome of a smoking cessation attempt.

Methods: Using functional magnetic resonance imaging, we recorded prequit brain responses to neutral, emotional (pleasant and unpleasant), and cigarette-related cues from 55 smokers interested in quitting. We then assessed smoking abstinence, mood, and nicotine withdrawal symptoms during the course of a smoking cessation attempt.

Results: Using cluster analysis, we identified 2 groups of smokers who differed in their baseline responses to pleasant cues and cigarette-related cues in the posterior visual association areas, the dorsal striatum, and the medial and dorsolateral prefrontal cortex. Smokers who showed lower prequit levels of brain reactivity to pleasant stimuli than to cigarette-related cues were less likely to be abstinent 6 months after their quit attempt, and they had higher levels of negative affect during the course of the quit attempt.

Conclusions: Smokers with blunted brain responses to pleasant stimuli, relative to cigarette-related stimuli, had more difficulty quitting smoking. For these individuals, the lack of alternative forms of reinforcement when nicotine deprived might be an important factor underlying relapse. Normalizing these pathological neuroadaptations may help them achieve abstinence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ntr/ntt214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015090PMC
June 2014

Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-null tumors.

Cell 2013 Nov;155(4):844-57

Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.

Here, we show that a subset of breast cancers express high levels of the type 2 phosphatidylinositol-5-phosphate 4-kinases α and/or β (PI5P4Kα and β) and provide evidence that these kinases are essential for growth in the absence of p53. Knocking down PI5P4Kα and β in a breast cancer cell line bearing an amplification of the gene encoding PI5P4K β and deficient for p53 impaired growth on plastic and in xenografts. This growth phenotype was accompanied by enhanced levels of reactive oxygen species (ROS) leading to senescence. Mice with homozygous deletion of both TP53 and PIP4K2B were not viable, indicating a synthetic lethality for loss of these two genes. Importantly however, PIP4K2A(-/-), PIP4K2B(+/-), and TP53(-/-) mice were viable and had a dramatic reduction in tumor formation compared to TP53(-/-) littermates. These results indicate that inhibitors of PI5P4Ks could be effective in preventing or treating cancers with mutations in TP53.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2013.09.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070383PMC
November 2013

Sulfate metabolites provide an intracellular pool for resveratrol generation and induce autophagy with senescence.

Sci Transl Med 2013 Oct;5(205):205ra133

Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE2 7LX, UK.

The phytochemical resveratrol has been shown to exert numerous health benefits in preclinical studies, but its rapid metabolism and resulting poor bioavailability may limit translation of these effects to humans. Resveratrol metabolites might contribute to in vivo activity through regeneration of the parent compound. We present quantitation of sulfate and glucuronide conjugates of resveratrol in human plasma and tissue after repeated ingestion of resveratrol by volunteers and cancer patients, respectively. Subsequent pharmacokinetic characterization of a mixture of resveratrol-3-O-sulfate and resveratrol-4'-O-sulfate in mice showed that these metabolites are absorbed orally but have low bioavailabilities of ~14 and 3%, respectively. Sulfate hydrolysis in vivo liberated free resveratrol, which accounted for ~2% of the total resveratrol species present in mouse plasma. Monosulfate metabolites were also converted to the parent in human colorectal cells. The extent of cellular uptake was dependent on specific membrane transporters and dictated antiproliferative activity. Sulfate metabolites induced autophagy and senescence in human cancer cells; these effects were abrogated by inclusion of a sulfatase inhibitor, which reduced intracellular resveratrol. Together, our findings suggest that resveratrol is delivered to target tissues in a stable sulfate-conjugated form and that the parent compound is gradually regenerated in selected cells and may give rise to the beneficial effects in vivo. At doses considered to be safe in humans, resveratrol generated via this route may be of greater importance than the unmetabolized form.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.3005870DOI Listing
October 2013

The role of aberrant VHL/HIF pathway elements in predicting clinical outcome to pazopanib therapy in patients with metastatic clear-cell renal cell carcinoma.

Clin Cancer Res 2013 Sep 23;19(18):5218-26. Epub 2013 Jul 23.

Authors' Affiliations: Dana-Farber Cancer Institute; Brigham and Women's Hospital; Harvard Medical School, Boston, Massachusetts; GlaxoSmithKline, Collegeville, Pennsylvania; Memorial Sloan-Kettering Cancer Center, New York, New York; and Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, Texas.

Purpose: Inactivation of von Hippel-Lindau (VHL) gene in clear-cell renal cell carcinoma (RCC) leads to increased levels of hypoxia-inducible factors (HIF) and overexpression of HIF target genes, such as VEGF and others. VEGF-targeted agents are standard in advanced clear-cell RCC but biomarkers of activity are lacking.

Experimental Design: We analyzed tumor tissue samples from metastatic clear-cell RCC patients who received pazopanib as part of clinical trial VEG102616. We evaluated several components of the VHL/HIF pathway: VHL gene inactivation (mutation and/or methylation), HIF-1α and HIF-2α immunohistochemistry staining, and HIF-1α transcriptional signature. We evaluated the association of these biomarkers with best overall response rate (ORR) and progression-free survival (PFS) to pazopanib, a standard first-line VEGF-targeted agent.

Results: The VEG102616 trial enrolled 225 patients, from whom 78 samples were available for tumor DNA extraction. Of these, 70 patients had VHL mutation or methylation. VHL gene status did not correlate with ORR or PFS. Similarly, HIF-1α (65 samples) and HIF-2α (66 samples) protein levels (high vs. low) did not correlate with ORR or PFS to pazopanib. The HIF-1α transcriptional signature (46 samples) was enriched in tumors expressing high HIF-1α levels. However, the HIF-1α gene expression signature was not associated with clinical outcome to pazopanib.

Conclusions: In patients with advanced clear-cell RCC, several potential biomarkers along the VHL/HIF-1α/HIF-2α axis were not found to be predictive for pazopanib activity. Additional efforts must continue to identify biomarkers associated with clinical outcome to VEGF-targeted agents in metastatic RCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-13-0491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522695PMC
September 2013

Designing insurance to promote use of childhood obesity prevention services.

J Obes 2013 9;2013:379513. Epub 2013 Apr 9.

Rollins School of Public Health of Emory University, Atlanta, GA 30322, USA.

Childhood obesity is a recognized public health crisis. This paper reviews the lessons learned from a voluntary initiative to expand insurance coverage for childhood obesity prevention and treatment services in the United States. In-depth telephone interviews were conducted with key informants from 16 participating health plans and employers in 2010-11. Key informants reported difficulty ensuring that both providers and families were aware of the available services. Participating health plans and employers are beginning new tactics including removing enrollment requirements, piloting enhanced outreach to selected physician practices, and educating providers on effective care coordination and use of obesity-specific billing codes through professional organizations. The voluntary initiative successfully increased private health insurance coverage for obesity services, but the interviews described variability in implementation with both best practices and barriers identified. Increasing utilization of obesity-related health services in the long term will require both family- and provider-focused interventions in partnership with improved health insurance coverage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2013/379513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3649320PMC
December 2013

The late positive potential (LPP) in response to varying types of emotional and cigarette stimuli in smokers: a content comparison.

Int J Psychophysiol 2013 Jul 2;89(1):18-25. Epub 2013 May 2.

Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77230-1439, USA.

Identifying neural mechanisms associated with addiction has substantially improved the overall understanding of addictive processes. Indeed, research suggests that drug-associated cues may take advantage of neural mechanisms originally intended for emotional processing of stimuli relevant to survival. In this study, we investigated cortical responses to several categories of emotional cues (erotic, romance, pleasant objects, mutilation, sadness, and unpleasant objects) as well as two types of smoking-related cues (people smoking and cigarette-related objects). We recorded ERPs from 180 smokers prior to their participation in a smoking cessation clinical trial and assessed emotional salience by measuring the amplitude of the late positive potential (LPP; 400 to 600 ms after picture onset). As expected, emotional and cigarette-related pictures prompted a significantly larger LPP than neutral pictures. The amplitude of the LPP increased as a function of picture arousal level, with high-arousing erotic and mutilation pictures showing the largest response in contrast to low-arousing pleasant and unpleasant objects, which showed the smallest response (other than neutral). Compared to females, male participants showed larger LPPs for high-arousing erotic and mutilation pictures. However, unlike emotional pictures, no difference was noted for the LPP between cigarette stimuli containing people versus those containing only objects, suggesting that in contrast to emotional objects, cigarette-related objects are highly relevant for smokers. We also compared the smokers to a small (N=40), convenience sample of never-smokers. We found that never-smokers had significantly smaller LPPs in response to erotic and cigarette stimuli containing only objects compared to smokers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpsycho.2013.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771859PMC
July 2013

Effects of varenicline and bupropion sustained-release use plus intensive smoking cessation counseling on prolonged abstinence from smoking and on depression, negative affect, and other symptoms of nicotine withdrawal.

JAMA Psychiatry 2013 May;70(5):522-33

Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77230-1439, USA.

Importance: Given the actions of varenicline tartrate and bupropion hydrochloride sustained-release (SR) on neurobiological targets related to affect and reward, it is thought that the modulation of nicotine withdrawal symptoms may contribute to their effectiveness.

Objective: To assess the relative efficacy of varenicline and bupropion SR plus intensive counseling on smoking cessation and emotional functioning.

Design And Setting: Placebo-controlled randomized clinical trial at a university medical center.

Participants: In total, 294 community volunteers who wanted to quit smoking.

Interventions: Twelve weeks of varenicline, bupropion SR, or placebo plus intensive smoking cessation counseling (10 sessions, for a total of approximately 240 minutes of counseling).

Main Outcome Measures: Prolonged abstinence from smoking and weekly measures of depression, negative affect, and other symptoms of nicotine withdrawal.

Results: Significant differences were found in abstinence at the end of treatment and through the 3-month postquit follow-up visit, favoring both active medications compared with placebo. At the 6-month postquit follow-up visit, only the varenicline vs placebo comparison remained significant. Varenicline use was also associated with a generalized suppression of depression and reduced smoking reward compared with the other treatments, while both active medications improved concentration, reduced craving, and decreased negative affect and sadness compared with placebo, while having little effect (increase or decrease) on anxiety and anger. No differences were noted in self-reported rates of neuropsychiatric adverse events.

Conclusions And Relevance: In a community sample, varenicline exerts a robust and favorable effect on smoking cessation relative to placebo and may have a favorable (suppressive) effect on symptoms of depression and other affective measures, with no clear unfavorable effect on neuropsychiatric adverse events.

Trial Registration: clinicaltrials.gov Identifier: NCT00507728.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamapsychiatry.2013.678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128024PMC
May 2013

Identification of CDCP1 as a hypoxia-inducible factor 2α (HIF-2α) target gene that is associated with survival in clear cell renal cell carcinoma patients.

Proc Natl Acad Sci U S A 2013 Feb 1;110(9):3483-8. Epub 2013 Feb 1.

Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.

CUB domain-containing protein 1 (CDCP1) is a transmembrane protein that is highly expressed in stem cells and frequently overexpressed and tyrosine-phosphorylated in cancer. CDCP1 promotes cancer cell metastasis. However, the mechanisms that regulate CDCP1 are not well-defined. Here we show that hypoxia induces CDCP1 expression and tyrosine phosphorylation in hypoxia-inducible factor (HIF)-2α-, but not HIF-1α-, dependent fashion. shRNA knockdown of CDCP1 impairs cancer cell migration under hypoxic conditions, whereas overexpression of HIF-2α promotes the growth of tumor xenografts in association with enhanced CDCP1 expression and tyrosine phosphorylation. Immunohistochemistry analysis of tissue microarray samples from tumors of patients with clear cell renal cell carcinoma shows that increased CDCP1 expression correlates with decreased overall survival. Together, these data support a critical role for CDCP1 as a unique HIF-2α target gene involved in the regulation of cancer metastasis, and suggest that CDCP1 is a biomarker and potential therapeutic target for metastatic cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1222435110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587206PMC
February 2013

Professional accountability: implications for primary healthcare nursing practice.

JONAS Healthc Law Ethics Regul 2012 Oct-Dec;14(4):109-14

Department of Nursing, University of Ibadan, Oyo, Nigeria.

The hallmark of professionalism is accountability, and this is necessary to consolidate the professional status of nursing. This article presents a review of the concept of professional accountability within the theoretical orientation of the role theory. It assumes that the nurse is performing roles that must be duly accounted for. It discusses the various areas of professional accountability with particular reference to primary healthcare nursing practice. It concludes that primary healthcare nurses are involved directly with the public on a daily basis, hence the need to be cognizant of their public position, level of responsibility, and professional accountability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JHL.0b013e318276308fDOI Listing
December 2013

Alpha oscillations in response to affective and cigarette-related stimuli in smokers.

Nicotine Tob Res 2013 May 11;15(5):917-24. Epub 2012 Oct 11.

Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.

Introduction: The presence of cigarette-related cues has been associated with smoking relapse. These cues are believed to activate brain mechanisms underlying emotion, attention, and memory. Electroencephalography (EEG) alpha desynchronization (i.e., reduction in alpha power) has been suggested to index the engagement of these mechanisms. Analyzing EEG alpha desynchronization in response to affective and smoking cues might improve our understanding of how smokers process these cues, and the potential impact of this processing on relapse.

Methods: Before the start of a medication-assisted cessation attempt, we recorded EEG from 179 smokers during the presentation of neutral, pleasant, unpleasant, and cigarette-related pictures. Wavelet analysis was used to extract EEG alpha oscillations (8-12 Hz) in response to these pictures. Alpha oscillations were analyzed as a function of picture valence and arousal dimensions.

Results: Emotional and cigarette-related stimuli induced a higher level of alpha desynchronization (i.e., less power in the alpha frequency band) than neutral stimuli. In addition, the level of alpha desynchronization induced by cigarette-related stimuli was similar to that induced by highly arousing stimuli (i.e., erotica and mutilations).

Conclusions: These results suggest that, for smokers, cigarette-related cues are motivationally significant stimuli that may engage emotional, attentional, and memory-related neural mechanisms at a level comparable to that seen in response to highly arousing stimuli. This finding suggests that activation of emotional, attentional, and memory-related brain mechanisms may be an important contributor to cue-induced smoking relapse.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ntr/nts209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3621581PMC
May 2013

Identification of luminal breast cancers that establish a tumor-supportive macroenvironment defined by proangiogenic platelets and bone marrow-derived cells.

Cancer Discov 2012 Dec 15;2(12):1150-65. Epub 2012 Aug 15.

Hematology Division, Brigham & Women's Hospital, Cambridge, Massachusetts 02115, USA.

Unlabelled: Breast cancer recurrence rates vary following treatment, suggesting that tumor cells disseminate early from primary sites but remain indolent indefinitely before progressing to symptomatic disease. The reasons why some indolent disseminated tumors erupt into overt disease are unknown. We discovered a novel process by which certain luminal breast cancer (LBC) cells and patient tumor specimens (LBC "instigators") establish a systemic macroenvironment that supports outgrowth of otherwise-indolent disseminated tumors ("responders"). Instigating LBCs secrete cytokines that are absorbed by platelets, which are recruited to responding tumor sites where they aid vessel formation. Instigator-activated bone marrow cells enrich responding tumor cell expression of CD24, an adhesion molecule for platelets, and provide a source of VEGF receptor 2(+) tumor vessel cells. This cascade results in growth of responder adenocarcinomas and is abolished when platelet activation is inhibited by aspirin. These findings highlight the macroenvironment as an important component of disease progression that can be exploited therapeutically.

Significance: Currently, processes that mediate progression of otherwise indolent tumors are not well understood, making it difficult to accurately predict which cancer patients are likely to relapse. Our findings highlight the macroenvironment as an important component of disease progression that can be exploited to more accurately identify patients who would benefit from adjuvant therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-12-0216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517696PMC
December 2012

BRAF mutations in metanephric adenoma of the kidney.

Eur Urol 2012 Nov 9;62(5):917-22. Epub 2012 Jun 9.

Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Background: Metanephric adenoma (MA) of the kidney is a rare, indolent tumor that may be difficult to differentiate from other small renal masses (SRMs). Genetic alterations associated with MA remain largely unknown.

Objective: We aimed at defining genetic events in MA of the kidney and determining their influence in the management of this disease.

Design, Setting, And Participants: Multiplexed mass spectrometric genotyping was performed on 29 MA cases after tumor DNA extraction. We also conducted a mutational screen in an additional 129 renal neoplasms. Immunohistochemistry was performed on the MA cases to assess molecular markers of signaling pathway activation. Patients' baseline characteristics, as well as follow-up data, were captured.

Outcome Measurements And Statistical Analysis: We used descriptive statistics for baseline clinical characteristics and incidence of mutations. The Wilcoxon rank-sum test was used to correlate patient characteristics with mutational status.

Results And Limitations: We identified the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E mutation in 26 of 29 MA cases. These results were validated in all cases using the commercially available BRAF Pyro Kit (QIAGEN). In contrast, BRAF mutations were rare in the other 129 non-MA renal neoplasms that were screened. We detected a BRAF mutation (V600E) in only one papillary renal cell carcinoma case. In all MA tumors, we documented expression of phosphorylated mitogen-activated protein kinase and phosphorylated extracellular signal-regulated kinase, accompanied by immunoreactivity for p16 (INK4a). All patients were treated with a partial or radical nephrectomy, and after a median follow-up of 26.5 mo, there were no local or distant recurrences. Limitations include the retrospective nature of this study.

Conclusions: BRAF V600E mutations are present in approximately 90% of all MA cases, serving as a potential valuable diagnostic tool in the differential diagnosis of SRMs undergoing a percutaneous biopsy. The presence of BRAF V600E and mitogen-activated protein kinase activation in a largely benign tumor supports the necessity for secondary events (e.g., p16 loss) in BRAF-driven oncogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eururo.2012.05.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516083PMC
November 2012

Differential cigarette-related startle cue reactivity among light, moderate, and heavy smokers.

Addict Behav 2012 Aug 15;37(8):885-9. Epub 2012 Feb 15.

Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, USA.

In this study, we examined the relationship between the level of daily cigarette consumption and the startle response to affective and cigarette-related cues among treatment-seeking smokers. Before receiving any behavioral or pharmacological treatment, 136 smokers attended a baseline laboratory session, during which we recorded their reflexive eyeblink responses to acoustic startle probes while they were viewing pleasant, unpleasant, neutral, and cigarette-related pictures. We found that 1) cigarette-related and pleasant pictures similarly reduced the startle magnitude compared to neutral pictures; 2) the magnitude of startle modulation rendered by pleasant or unpleasant pictures did not differ among light, moderate, and heavy smokers; and 3) startle attenuation by cigarette-related pictures was greater in heavy smokers than in light smokers. These results suggest that similar to pleasant stimuli, cigarette-related cues are motivationally salient for smokers, and that this salience increases with nicotine dependence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.addbeh.2012.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358408PMC
August 2012

A pressure cooking-based DNA extraction from archival formalin-fixed, paraffin-embedded tissue.

Anal Biochem 2012 Jun 23;425(2):128-34. Epub 2012 Mar 23.

Tissue Array Research Program, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

As emerging novel DNA-based methodologies are adopted, nucleic acid-based assays depend critically on the quality and quantity of extracted DNA. Formalin-fixed, paraffin embedded (FFPE) tissue samples provide an invaluable resource for subsequent molecular studies of clinical phenotypes, but high-quality DNA extraction from archival FFPE tissue specimens remains complex and time-consuming. To address this challenge, we have developed a reliable rapid DNA extraction method for FFPE tissue specimens. It is based on deparaffinization at high temperature coupled with relieving crosslink in a pressure cooker. The DNA yield by this rapid method resulted in an average 1.8-fold increase in comparison with the commercial kit and OD 260/280 ratios between 1.87 and 1.95. The DNA obtained by the rapid method was suitable for methylation analyses in colon cancer patients. These data suggest that this new DNA extraction method coupled with methylation-specific polymerase chain reaction can be used for epigenetic studies with the advantages of rapidity and high quality and may contribute to the development of biomarkers in clinical studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ab.2012.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358925PMC
June 2012

Resumption of valued activities in the first year post liver transplant.

Occup Ther Health Care 2012 Jan;26(1):48-63

1Department of Occupational Therapy, Indiana University, Indianapolis, Indiana, USA.

ABSTRACT Current practice in education of transplant recipients includes general guidelines about return to involvement in life activities emphasizing medical precautions during wound healing and avoidance of activities that present risk of infection or rejection. This approach assumes patients gradually resume pre-transplant involvement in life activities: an assumption that has not been tested. Using the Canadian Occupational Performance Measure, this cross-sectional descriptive pilot study (n = 20) explored differences in the performance of activities of daily living, instrumental activities of daily living, leisure, and productivity at three time periods within the first year. Results showed basic daily tasks are stable by the third month but some instrumental tasks declined by the end of the first year post transplant. Results indicated that there were significant differences in the Short Form-36 mental component score of the group performing "worse than expected" suggesting that preparation of recipients is needed to enable them to set realistic expectations. Results indicate the need for a longitudinal study of the resumption patterns of life activities for realistic expectations of recovery and guidelines for the treatment team.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/07380577.2011.643856DOI Listing
January 2012

Neural substrates of smoking cue reactivity: a meta-analysis of fMRI studies.

Neuroimage 2012 Mar 21;60(1):252-62. Epub 2011 Dec 21.

Department of Behavioral Science – Unit 1330, The University of Texas MD Anderson Cancer Center, P. O. Box 301439, Houston, TX 77030, USA.

Reactivity to smoking-related cues may be an important factor that precipitates relapse in smokers who are trying to quit. The neurobiology of smoking cue reactivity has been investigated in several fMRI studies. We combined the results of these studies using activation likelihood estimation, a meta-analytic technique for fMRI data. Results of the meta-analysis indicated that smoking cues reliably evoke larger fMRI responses than neutral cues in the extended visual system, precuneus, posterior cingulate gyrus, anterior cingulate gyrus, dorsal and medial prefrontal cortex, insula, and dorsal striatum. Subtraction meta-analyses revealed that parts of the extended visual system and dorsal prefrontal cortex are more reliably responsive to smoking cues in deprived smokers than in non-deprived smokers, and that short-duration cues presented in event-related designs produce larger responses in the extended visual system than long-duration cues presented in blocked designs. The areas that were found to be responsive to smoking cues agree with theories of the neurobiology of cue reactivity, with two exceptions. First, there was a reliable cue reactivity effect in the precuneus, which is not typically considered a brain region important to addiction. Second, we found no significant effect in the nucleus accumbens, an area that plays a critical role in addiction, but this effect may have been due to technical difficulties associated with measuring fMRI data in that region. The results of this meta-analysis suggest that the extended visual system should receive more attention in future studies of smoking cue reactivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroimage.2011.12.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288122PMC
March 2012

High dose intermittent sorafenib shows improved efficacy over conventional continuous dose in renal cell carcinoma.

J Transl Med 2011 Dec 21;9:220. Epub 2011 Dec 21.

Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Background: Renal cell carcinoma (RCC) responds to agents that inhibit vascular endothelial growth factor (VEGF) pathway. Sorafenib, a multikinase inhibitor of VEGF receptor, is effective at producing tumor responses and delaying median progression free survival in patients with cytokine refractory RCC. However, resistance to therapy develops at a median of 5 months. In an effort to increase efficacy, we studied the effects of increased sorafenib dose and intermittent scheduling in a murine RCC xenograft model.

Methods: Mice bearing xenografts derived from the 786-O RCC cell line were treated with sorafenib according to multiple doses and schedules: 1) Conventional dose (CD) continuous therapy; 2) high dose (HD) intermittent therapy, 3) CD intermittent therapy and 4) HD continuous therapy. Tumor diameter was measured daily. Microvessel density was assessed after 3 days to determine the early effects of therapy, and tumor perfusion was assessed serially by arterial spin labeled (ASL) MRI at day 0, 3, 7 and 10.

Results: Tumors that were treated with HD sorafenib exhibited slowed tumor growth as compared to CD using either schedule. HD intermittent therapy was superior to CD continous therapy, even though the total dose of sorafenib was essentially equivalent, and not significantly different than HD continuous therapy. The tumors exposed to HD sorafenib had lower microvessel density than the untreated or the CD groups. ASL MRI showed that tumor perfusion was reduced to a greater extent with the HD sorafenib at day 3 and at all time points thereafter relative to CD therapy. Further the intermittent schedule appeared to maintain RCC sensitivity to sorafenib as determined by changes in tumor perfusion.

Conclusions: A modification of the sorafenib dosing schedule involving higher dose intermittent treatment appeared to improve its efficacy in this xenograft model relative to conventional dosing. MRI perfusion imaging and histologic analysis suggest that this benefit is related to enhanced and protracted antiangiogenic activity. Thus, better understanding of dosing and schedule issues may lead to improved therapeutic effectiveness of VEGF directed therapy in RCC and possibly other tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1479-5876-9-220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258225PMC
December 2011

Do brain responses to emotional images and cigarette cues differ? An fMRI study in smokers.

Eur J Neurosci 2011 Dec 20;34(12):2054-63. Epub 2011 Nov 20.

Department of Behavioral Science-Unit 1330, The University of Texas MD Anderson Cancer Center, PO Box 30149, Houston, TX 77230, USA.

Chronic smoking is thought to cause changes in brain reward systems that result in overvaluation of cigarette-related stimuli and undervaluation of natural rewards. We tested the hypotheses that, in smokers, brain circuits involved in emotional processing: (i) would be more active during exposure to cigarette-related than neutral pictures; and (ii) would be less active to pleasant compared with cigarette-related pictures, suggesting a devaluation of intrinsically pleasant stimuli. We obtained whole-brain blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging data from 35 smokers during the presentation of pleasant (erotica and romance), unpleasant (mutilations and sad), neutral, and cigarette-related pictures. Whole-brain analyses showed significantly larger BOLD responses during presentation of cigarette-related pictures relative to neutral ones within the secondary visual areas, the cingulate gyrus, the frontal gyrus, the dorsal striatum, and the left insula. BOLD responses to erotic pictures exceeded responses to cigarette-related pictures in all clusters except the insula. Within the left insula we observed larger BOLD responses to cigarette-related pictures than to all other picture categories. By including intrinsically pleasant and unpleasant pictures in addition to neutral ones, we were able to conclude that the presentation of cigarette-related pictures activates brain areas supporting emotional processes, but we did not find evidence of overall reduced activation of the brain reward systems in the presence of intrinsically pleasant stimuli.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1460-9568.2011.07915.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237919PMC
December 2011

Beyond cue reactivity: blunted brain responses to pleasant stimuli predict long-term smoking abstinence.

Addict Biol 2012 Nov 4;17(6):991-1000. Epub 2011 Oct 4.

Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Identifying addicts with higher risk of relapse would provide the opportunity to implement individualized interventions and increase cessation success rates. Unfortunately, the ability to predict the long-term success of drug cessation treatments continues to elude researchers. We tested whether brain responses to emotional and cigarette-related pictures were predictive of the ability to abstain from smoking. Smokers interested in quitting (n=180) participated in a smoking cessation clinical trial. Before the initiation of any treatment, we recorded event-related potentials (ERPs) evoked by emotional (both pleasant and unpleasant), neutral, and cigarette-related images. Cluster analysis was used to assign smokers to two groups based on the amplitude of the late positive potential (LPP) to the experimental stimuli. While both groups showed enhanced responses to cigarette-related cues, one group (n=81) also showed blunted brain responses to intrinsically pleasant stimuli. Smokers in the latter group were significantly less likely to be abstinent at 10, 12 and 24 weeks after their quit date. In conclusion, using ERPs, a direct measure of brain activity, we found that smokers with blunted brain responses to intrinsically pleasant stimuli had lower rates of long-term smoking abstinence. This response offers a new biomarker for identifying smokers at higher risk of relapse and for testing the efficacy of new interventions aimed at normalizing brain reward systems' responses to intrinsically pleasant stimuli.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1369-1600.2011.00372.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3252422PMC
November 2012
-->