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2.
Stem Cell Res ; 50: 102127, 2020 12 15.
Article in English | MEDLINE | ID: mdl-33360098

ABSTRACT

Niemann-Pick disease Type C (NPC) is a rare progressive neurodegenerative disorder with an incidence of 1:120,000 caused by mutations in the NPC1 or NPC2 gene leading to a massive cholesterol accumulation. Here, we describe the generation of induced pluripotent stem cells (iPSCs) of an affected female adult individual carrying the NPC1 mutation p.Val1023Serfs*15/p.Gly992Arg and an iPSC line from an unrelated healthy female adult control individual. Human iPSCs were derived from fibroblasts using retroviruses carrying the four reprogramming factors OCT4, SOX2, KLF4 and C-MYC. These lines provide a valuable resource for studying the pathophysiology of NPC and for pharmacological intervention.

4.
Value Health ; 21(6): 742-747, 2018 06.
Article in English | MEDLINE | ID: mdl-29909880

ABSTRACT

The US Food and Drug Administration and the Critical Path Institute's Patient-Reported Outcome (PRO) Consortium convened a cosponsored workshop on the use of PRO measures to inform the assessment of safety and tolerability in cancer clinical trials. A broad array of international stakeholders involved in oncology drug development and PRO measurement science provided perspectives on the role of PRO measures to provide complementary clinical data on the symptomatic side effects of anticancer agents. Speakers and panelists explored the utility of information derived from existing and emerging PRO measures, focusing on the PRO version of the National Cancer Institute's Common Terminology Criteria for Adverse Events. Panelists and speakers discussed potential ways to improve the collection, analysis, and presentation of PRO data describing symptomatic adverse events to support drug development and better inform regulatory and treatment decisions. Workshop participants concluded the day with a discussion of possible approaches to the patient-reported assessment of an investigational drug's overall side effect burden as a potential clinical trial end point. The Food and Drug Administration reiterated its commitment to collaborate with international drug development stakeholders to identify rigorous methods to incorporate the patient perspective into the development of cancer therapeutics.


Subject(s)
Neoplasms/therapy , United States Food and Drug Administration , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Critical Pathways , Drug-Related Side Effects and Adverse Reactions , Humans , Medical Oncology , Neoplasms/drug therapy , Patient Reported Outcome Measures , Surveys and Questionnaires , Treatment Outcome , United States
5.
JAMA ; 319(5): 483-494, 2018 02 06.
Article in English | MEDLINE | ID: mdl-29411037

ABSTRACT

Importance: Patient-reported outcome (PRO) data from clinical trials can provide valuable evidence to inform shared decision making, labeling claims, clinical guidelines, and health policy; however, the PRO content of clinical trial protocols is often suboptimal. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was published in 2013 and aims to improve the completeness of trial protocols by providing evidence-based recommendations for the minimum set of items to be addressed, but it does not provide PRO-specific guidance. Objective: To develop international, consensus-based, PRO-specific protocol guidance (the SPIRIT-PRO Extension). Design, Setting, and Participants: The SPIRIT-PRO Extension was developed following the Enhancing Quality and Transparency of Health Research (EQUATOR) Network's methodological framework for guideline development. This included (1) a systematic review of existing PRO-specific protocol guidance to generate a list of potential PRO-specific protocol items (published in 2014); (2) refinements to the list and removal of duplicate items by the International Society for Quality of Life Research (ISOQOL) Protocol Checklist Taskforce; (3) an international stakeholder survey of clinical trial research personnel, PRO methodologists, health economists, psychometricians, patient advocates, funders, industry representatives, journal editors, policy makers, ethicists, and researchers responsible for evidence synthesis (distributed by 38 international partner organizations in October 2016); (4) an international Delphi exercise (n = 137 invited; October 2016 to February 2017); and (5) consensus meeting (n = 30 invited; May 2017). Prior to voting, consensus meeting participants were informed of the results of the Delphi exercise and given data from structured reviews evaluating the PRO protocol content of 3 defined samples of trial protocols. Results: The systematic review identified 162 PRO-specific protocol recommendations from 54 sources. The ISOQOL Taskforce (n = 21) reduced this to 56 items, which were considered by 138 international stakeholder survey participants and 99 Delphi panelists. The final wording of the SPIRIT-PRO Extension was agreed on at a consensus meeting (n = 29 participants) and reviewed by external group of experts during a consultation period. Eleven extensions and 5 elaborations to the SPIRIT 2013 checklist were recommended for inclusion in clinical trial protocols in which PROs are a primary or key secondary outcome. Extension items focused on PRO-specific issues relating to the trial rationale, objectives, eligibility criteria, concepts used to evaluate the intervention, time points for assessment, PRO instrument selection and measurement properties, data collection plan, translation to other languages, proxy completion, strategies to minimize missing data, and whether PRO data will be monitored during the study to inform clinical care. Conclusions and Relevance: The SPIRIT-PRO guidelines provide recommendations for items that should be addressed and included in clinical trial protocols in which PROs are a primary or key secondary outcome. Improved design of clinical trials including PROs could help ensure high-quality data that may inform patient-centered care.


Subject(s)
Clinical Protocols/standards , Clinical Trials as Topic/standards , Guidelines as Topic , Patient Reported Outcome Measures , Decision Making , Humans
6.
Clin Cancer Res ; 24(8): 1780-1784, 2018 04 15.
Article in English | MEDLINE | ID: mdl-29237718

ABSTRACT

Cancer therapeutics frequently lead to symptomatic adverse events (AE) that can affect treatment tolerability. The NCI has developed the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to assess symptomatic AEs by direct patient self-report. Although longitudinal assessment of patient-reported symptomatic AEs holds promise to better inform treatment tolerability, using patient-reported outcome (PRO) measures to assess symptomatic AEs has raised several regulatory and good clinical practice issues among those who conduct cancer clinical trials. These include concerns regarding trial monitoring, clinical review of PRO results by investigators and delegated clinical staff, whether PRO data on symptomatic AEs require investigational new drug (IND) safety reporting, and how the trial conduct and resultant PRO data will be assessed during clinical investigator site inspections. This article addresses current thinking regarding these issues in cancer clinical trials from the FDA, the NCI, and the Office for Human Research Protections. PRO measures, such as PRO-CTCAE, that assess symptomatic AEs in cancer trials are considered similar to other PRO assessments of symptoms, function, and health-related quality of life and can generate complementary data that may inform tolerability. Clarity on operational concerns related to incorporating PRO measures to inform tolerability is critical to continue the advancement of rigorous PRO assessment in cancer clinical trials. Clin Cancer Res; 24(8); 1780-4. ©2017 AACRSee related commentary by Nipp and Temel, p. 1777.


Subject(s)
Antineoplastic Agents/therapeutic use , Clinical Trials as Topic , Neoplasms/drug therapy , Patient Reported Outcome Measures , Antineoplastic Agents/pharmacology , Clinical Trials as Topic/methods , Clinical Trials as Topic/standards , Disclosure , Drug Utilization Review , Drug-Related Side Effects and Adverse Reactions , Drugs, Investigational/pharmacology , Drugs, Investigational/therapeutic use , Humans , Research Design , Research Personnel
7.
Clin Cancer Res ; 22(7): 1553-8, 2016 Apr 01.
Article in English | MEDLINE | ID: mdl-26758559

ABSTRACT

Cancer clinical trials have relied on overall survival and measures of tumor growth or reduction to assess the efficacy of a drug. However, benefits are often accompanied by significant symptomatic toxicities. The degree to which a therapy improves disease symptoms and introduces symptomatic toxicity affects how patients function in their daily lives. These concepts are important contributors to health-related quality of life (HRQOL). In this article, we discuss patient-reported outcome (PRO) assessment in cancer trials and challenges relying solely on static multi-item HRQOL instruments. We propose focusing on three separate measures of well-defined concepts: symptomatic adverse events, physical function, and disease-related symptoms, which are key contributors to the effect of a therapy on HRQOL. Separate measures of these three concepts may facilitate the incorporation of emerging contemporary instruments that can tailor the PRO assessment strategy to different trial contexts. Irrespective of the PRO measures used, continued improvement in trial design and conduct is crucial to decrease missing data and optimize the quality of PRO information. International stakeholder collaboration and continued research into optimal practices for PRO and other clinical outcome assessments are necessary to advance a common framework for generating and reporting rigorous patient-centered data from cancer clinical trials.


Subject(s)
Clinical Trials as Topic , Neoplasms , Patient Reported Outcome Measures , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Humans , Neoplasms/diagnosis , Neoplasms/mortality , Neoplasms/therapy , Patient Outcome Assessment , Quality of Life
9.
Article in English | MEDLINE | ID: mdl-24285980

ABSTRACT

PURPOSE: European Mistletoe (Viscum album L.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM. DESIGN: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events related to platelets and granulocytes only [corrected]; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery. RESULTS: DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1300 mg/m(2) [corrected] and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high. CONCLUSION: GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone.

11.
Cancer Epidemiol Biomarkers Prev ; 18(9): 2391-6, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19690180

ABSTRACT

BACKGROUND: Polycyclic aromatic hydrocarbon (PAH) exposure is a risk factor for esophageal squamous cell carcinoma, and PAHs are ligands of the aryl hydrocarbon receptor (AhR). This study measured the expression of AhR and related genes in frozen esophageal cell samples from patients exposed to different levels of indoor air pollution, who did or did not have high-grade squamous dysplasia and who did or did not have a family history of upper gastrointestinal tract (UGI) cancer. METHODS: 147 samples were evaluated, including 23 (16%) from patients with high-grade dysplasia and 48 (33%) from patients without dysplasia who heated their homes with coal, without a chimney (a "high" indoor air pollution group), and 27 (18%) from patients with high-grade dysplasia and 49 (33%) from patients without dysplasia who did not heat their homes at all (a "low" indoor air pollution group). Sixty-four (44%) had a family history of UGI cancer. RNA was extracted and quantitative PCR analysis was done. RESULTS: AhR gene expression was detectable in 85 (58%) of the samples and was >9-fold higher in those with a family history of UGI cancer [median expression (interquartile range), -1,964 (-18,000, -610) versus -18,000 (-18,000, -1036); P = 0.02, Wilcoxon rank-sum test]. Heating status, dysplasia category, age, gender, and smoking were not associated with AhR expression (linear regression; all P values >or= 0.1). CONCLUSION: AhR expression was higher in patients with a family history of UGI cancer. Such individuals may be more susceptible to the deleterious effects of PAH exposure, including PAH-induced cancer.


Subject(s)
Carcinoma, Squamous Cell/chemically induced , Carcinoma, Squamous Cell/metabolism , Esophageal Neoplasms/chemically induced , Esophageal Neoplasms/metabolism , Polycyclic Aromatic Hydrocarbons/poisoning , Receptors, Aryl Hydrocarbon/biosynthesis , Aged , Air Pollution, Indoor/adverse effects , Biomarkers, Tumor/biosynthesis , Biomarkers, Tumor/genetics , Carcinoma, Squamous Cell/genetics , Cross-Sectional Studies , Esophageal Neoplasms/genetics , Female , Gene Expression , Humans , Male , Middle Aged , Receptors, Aryl Hydrocarbon/genetics , Risk Factors
12.
J Natl Cancer Inst ; 101(7): 507-18, 2009 Apr 01.
Article in English | MEDLINE | ID: mdl-19318634

ABSTRACT

BACKGROUND: The General Population Nutrition Intervention Trial was a randomized primary esophageal and gastric cancer prevention trial conducted from 1985 to 1991, in which 29,584 adult participants in Linxian, China, were given daily vitamin and mineral supplements. Treatment with "factor D," a combination of 50 microg selenium, 30 mg vitamin E, and 15 mg beta-carotene, led to decreased mortality from all causes, cancer overall, and gastric cancer. Here, we present 10-year follow-up after the end of active intervention. METHODS: Participants were assessed by periodic data collection, monthly visits by village health workers, and quarterly review of the Linxian Cancer Registry. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the cumulative effects of four vitamin and mineral supplementation regimens were calculated using adjusted proportional hazards models. RESULTS: Through May 31, 2001, 276 participants were lost to follow-up; 9727 died, including 3242 from cancer (1515 from esophageal cancer and 1199 from gastric cancer). Participants who received factor D had lower overall mortality (HR = 0.95, 95% CI = 0.91 to 0.99; P = .009; reduction in cumulative mortality from 33.62% to 32.19%) and gastric cancer mortality (HR = 0.89, 95% CI = 0.79 to 1.00; P = .043; reduction in cumulative gastric cancer mortality from 4.28% to 3.84%) than subjects who did not receive factor D. Reductions were mostly attributable to benefits to subjects younger than 55 years. Esophageal cancer deaths between those who did and did not receive factor D were not different overall; however, decreased 17% among participants younger than 55 (HR = 0.83, 95% CI = 0.71 to 0.98; P = .025) but increased 14% among those aged 55 years or older (HR = 1.14, 95% CI = 1.00 to 1.30; P = .047) [corrected]. Vitamin A and zinc supplementation was associated with increased total and stroke mortality; vitamin C and molybdenum supplementation, with decreased stroke mortality. CONCLUSION: The beneficial effects of selenium, vitamin E, and beta-carotene on mortality were still evident up to 10 years after the cessation of supplementation and were consistently greater in younger participants. Late effects of other supplementation regimens were also observed.


Subject(s)
Dietary Supplements , Micronutrients/administration & dosage , Neoplasms/mortality , Neoplasms/prevention & control , Selenium/administration & dosage , Vitamins/administration & dosage , alpha-Tocopherol/administration & dosage , beta Carotene/administration & dosage , Adult , Age Factors , Aged , Aged, 80 and over , Antioxidants/administration & dosage , Ascorbic Acid/administration & dosage , China/epidemiology , Confounding Factors, Epidemiologic , Diterpenes , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Male , Malnutrition/complications , Middle Aged , Molybdenum/administration & dosage , Niacin/administration & dosage , Odds Ratio , Retinyl Esters , Riboflavin/administration & dosage , Risk Factors , Vitamin A/administration & dosage , Vitamin A/analogs & derivatives , Zinc Oxide/administration & dosage
13.
Cancer Epidemiol Biomarkers Prev ; 17(6): 1424-35, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18559558

ABSTRACT

Molecular events associated with the initiation and progression of esophageal squamous cell carcinoma (ESCC) remain poorly understood but likely hold the key to effective early detection approaches for this almost invariably fatal cancer. CDC25B and LAMC2 are two promising early detection candidates emerging from new molecular studies of ESCC. To further elucidate the role of these two genes in esophageal carcinogenesis, we did a series of studies to (a) confirm RNA overexpression, (b) establish the prevalence of protein overexpression, (c) relate protein overexpression to survival, and (d) explore their potential as early detection biomarkers. Results of these studies indicated that CDC25B mRNA was overexpressed (>/=2-fold overexpression in tumor compared with normal) in 64% of the 73 ESCC cases evaluated, whereas LAMC2 mRNA was overexpressed in 89% of cases. CDC25B protein expression was categorized as positive in 59% (144 of 243) of ESCC cases on a tumor tissue microarray, and nonnegative LAMC2 patterns of protein expression were observed in 82% (225 of 275) of cases. Multivariate-adjusted proportional hazard regression models showed no association between CDC25B protein expression score and risk of death [hazard ratio (HR) for each unit increase in expression score, 1.00; P = 0.90]; however, several of the LAMC2 protein expression patterns strongly predicted survival. Using the cytoplasmic pattern as the reference (the pattern with the lowest mortality), cases with a diffuse pattern had a 254% increased risk of death (HR, 3.52; P = 0.007), cases with no LAMC2 expression had a 169% increased risk of death (HR, 2.69; P = 0.009), and cases with a peripheral pattern had a 130% greater risk of death (HR, 2.30; P = 0.02). CDC25B protein expression scores in subjects with esophageal biopsies diagnosed as normal (n = 35), dysplastic (n = 23), or ESCC (n = 32) increased significantly with morphologic progression. For LAMC2, all normal and dysplastic patients had a continuous pattern of protein expression, whereas all ESCCs showed alternative, noncontinuous patterns. This series of studies showed that both CDC25B and LAMC2 overexpress RNA and protein in a significant majority of ESCC cases. The strong relation of LAMC2 pattern of protein expression to survival suggests a role in prognosis, whereas the association of CDC25B with morphologic progression indicates a potential role as an early detection marker.


Subject(s)
Carcinoma, Squamous Cell/genetics , Esophageal Neoplasms/genetics , Laminin/genetics , Precancerous Conditions/genetics , RNA, Messenger/metabolism , cdc25 Phosphatases/genetics , China/epidemiology , Female , Gene Expression Profiling , Humans , Immunoenzyme Techniques , Linear Models , Male , Middle Aged , Proportional Hazards Models , Protein Array Analysis , Reverse Transcriptase Polymerase Chain Reaction
14.
Arch Intern Med ; 166(16): 1775-82, 2006 Sep 18.
Article in English | MEDLINE | ID: mdl-16983058

ABSTRACT

BACKGROUND: Insomnia and other disorders that result in trouble sleeping are common in the United States and are often associated with chronic health conditions. Some individuals with insomnia or trouble sleeping use complementary and alternative medicine (CAM) therapies to treat their condition, but the prevalence of such use and the most common types of CAM therapies selected are not known. METHODS: Prevalence of insomnia or trouble sleeping and of CAM use for treating such conditions was examined using the 2002 National Health Interview Survey. Logistic regression was used to examine associations between insomnia or trouble sleeping, comorbid conditions, and use of CAM treatments. RESULTS: The 12-month prevalence rate of insomnia or trouble sleeping was 17.4%. There was a strong positive association between adults who reported having insomnia or trouble sleeping and adults who reported 4 of 5 common conditions: obesity (adjusted odds ratio [OR], 1.15; 99% confidence interval [CI], 1.01-1.31), hypertension (OR, 1.32; 99% CI, 1.16-1.51), congestive heart failure (OR, 2.24; 99% CI, 1.60-3.14), and anxiety or depression (OR, 5.64; 99% CI, 5.07-6.29). Of those with insomnia or trouble sleeping, 4.5% used some form of CAM therapy to treat their condition. CONCLUSIONS: According to the National Health Interview Survey analysis, over 1.6 million civilian, noninstitutionalized adult US citizens use CAM to treat insomnia or trouble sleeping. The details of this analysis will serve as a guide for future research on CAM therapies for sleep disorders.


Subject(s)
Complementary Therapies/statistics & numerical data , Sleep Initiation and Maintenance Disorders/prevention & control , Adolescent , Adult , Age Distribution , Aged , Aged, 80 and over , Anxiety/epidemiology , Attitude to Health , Depression/epidemiology , Educational Status , Female , Health Surveys , Heart Failure/epidemiology , Humans , Hypertension/epidemiology , Male , Middle Aged , Obesity/epidemiology , Racial Groups , Sex Distribution , Sleep Initiation and Maintenance Disorders/epidemiology , United States/epidemiology
15.
Integr Cancer Ther ; 5(3): 192-201, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16880423

ABSTRACT

Tai chi chuan (TCC) has been used as a mind-body practice in Asian culture for centuries to improve wellness and reduce stress and has recently received attention by researchers as an exercise intervention. A review of the English literature on research in TCC published from 1989 to 2006 identified 20 prospective, randomized, controlled clinical trials in a number of populations, including elderly participants (7 studies), patients with cardiovascular complications (3 studies), patients with chronic disease (6 studies), and patients who might gain psychological benefit from TCC practice (2 studies). However, only the studies of TCC in the elderly and 2 studies of TCC for cardiovascular disease had adequate designs and size to allow conclusions about the efficacy of TCC. Most (11 studies) were small and provided limited information on the benefit of TCC in the settings tested. There is growing awareness that cancer survivors represent a population with multiple needs related to physical deconditioning, cardiovascular disease risk, and psychological stress. TCC as an intervention may provide benefit to cancer survivors in these multiple areas of need based on its characteristics of combining aspects of meditation and aerobic exercise. However, little research has been conducted to date to determine the benefit of TCC in this population. We propose a model to study the unique characteristics of TCC compared to physical exercise that may highlight characteristic features of this mind-body intervention in cancer survivors.


Subject(s)
Neoplasms/therapy , Tai Ji , Exercise , Humans , Randomized Controlled Trials as Topic , Research Design , Treatment Outcome
16.
J Clin Endocrinol Metab ; 91(11): 4313-8, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16912126

ABSTRACT

CONTEXT: Chronic pain has been associated with elevated cortisol, reduced LH and testosterone (T), and/or augmented circulating or excreted catecholamines. Most endocrine studies have been conducted in patients in whom the potentially confounding effects of depression, inflammatory disease, or coexistent medication use have not been controlled. OBJECTIVE: The objective of the study was to test the hypothesis that chronic pain activates ACTH-cortisol and suppresses LH-T. DESIGN AND SETTING: This was a case control study conducted at a clinical research center. PARTICIPANTS: Participants included 16 opioid-naive men with chronic osteoarthritis pain, aged 35-65 yr with body mass index 20-30 kg/m2, and 12 healthy, opioid- and pain-free men of similar ages and body mass indexes. METHODS: We compared circulating concentrations of ACTH, cortisol, LH, and T derived from every 20-min blood sampling (2000-0800 h), and 24-h urinary excretion of cortisol, epinephrine, norepinephrine, and dopamine. RESULTS: There were no significant differences in mean or integrated concentrations of ACTH, cortisol, LH, or T, or in the corresponding approximate entropy scores in osteoarthritis patients, compared with control subjects. The 0800-h serum LH concentrations were elevated in patients vs. controls (6.42 +/- 1.65 vs. 3.99 +/- 1.54 IU/liter, mean +/- sd, P = 0.02), whereas there were no significant group differences in total or free T, SHBG, cortisol binding globulin, dehydroepiandrosterone sulfate, or urinary cortisol and catecholamines. CONCLUSIONS: These data suggest that neuroendocrine function is not significantly altered in otherwise healthy men with chronic musculoskeletal pain and that prior reports of such hormonal abnormalities may have resulted from the confounding effects of coexistent illness or medication use.


Subject(s)
Neurosecretory Systems/physiology , Osteoarthritis/complications , Pain/complications , Adrenocorticotropic Hormone/blood , Adult , Aged , Blood Specimen Collection/methods , Case-Control Studies , Chronic Disease , Dopamine/urine , Epinephrine/urine , Humans , Hydrocortisone/blood , Hydrocortisone/urine , Luteinizing Hormone/blood , Male , Middle Aged , Norepinephrine/urine , Testosterone/blood
17.
Cancer Res ; 66(13): 6851-60, 2006 Jul 01.
Article in English | MEDLINE | ID: mdl-16818663

ABSTRACT

A randomized, double-blinded, placebo-controlled 2 x 2 factorial chemoprevention trial was conducted in Linxian, China to assess the effects of selenomethionine and celecoxib on the natural history of esophageal squamous dysplasia. Results from this study indicated that asymptomatic adults with mild dysplasia were more likely to show an improvement when treated with selenomethionine compared with placebo (P = 0.02). Prompted by this finding, we examined the molecular profiles associated with regression and progression of dysplastic lesions in normal mucosa from 29 individuals, a subset of the Linxian cohort, using the Affymetrix U133A chip. Twenty differentially expressed genes were associated with regression and 129 were associated with progression when we compared the change in gene expression over time. Genes associated with immune response (n = 15), cell cycle (n = 15), metabolism (n = 15), calcium transport or calcium ion activity (n = 10), regulation of transcription (n = 9), signal transduction (n = 7), cytoskeleton and microtubules (n = 5), nucleotide processing and biosynthesis (n = 4), G-coupled signaling (n = 4), and apoptosis (n = 3) were present in the list of 149 genes. Using the Expression Analysis Systematic Explorer pathway analysis program, only the immune response pathway was significantly overrepresented among these 149 genes. Individuals whose lesions regressed seemed to have higher expression of genes associated with immune stimulation, such as antigen presentation, survival of T cells, and T-cell activation (HLA-DRA, HLA-DPA1, HLA-DBQ1, CD58, and FCER1A). In contrast, individuals whose lesions progressed had higher expression of genes involved in immune suppression and inflammation (CNR2, NFATC4, NFRKB, MBP, INHBB, CMKLR1, CRP, ORMS, SERPINA7, and SERPINA1). These data suggest that local and systemic immune responses may influence the natural history of esophageal squamous dysplasia.


Subject(s)
Carcinoma, Squamous Cell/genetics , Esophageal Neoplasms/genetics , Esophagus/physiology , Precancerous Conditions/genetics , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/prevention & control , Celecoxib , China , Disease Progression , Double-Blind Method , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/pathology , Esophageal Neoplasms/prevention & control , Esophagus/metabolism , Esophagus/pathology , Female , Gene Expression , Humans , Male , Middle Aged , Mucous Membrane/metabolism , Mucous Membrane/pathology , Mucous Membrane/physiology , Oligonucleotide Array Sequence Analysis , Precancerous Conditions/drug therapy , Precancerous Conditions/metabolism , Pyrazoles/therapeutic use , Risk Factors , Selenomethionine/therapeutic use , Sulfonamides/therapeutic use
18.
Cancer Epidemiol Biomarkers Prev ; 15(5): 1046-7, 2006 May.
Article in English | MEDLINE | ID: mdl-16702392

ABSTRACT

Selenium is a promising cancer chemoprevention agent. A recent randomized controlled chemoprevention trial found that selenomethionine (SeMet) supplementation for 10 months favorably effected a change in esophageal dysplasia grade among participants who started the trial with mild dysplasia. To further explore the role of SeMet in this trial, we compared gene expression profiles by treatment group using Affymetrix HU 133A chips in before/after supplementation paired normal esophageal biopsies from a subset of 29 trial participants, 16 who received SeMet, and 13 who received placebo. Using P < 0.001 as a cutoff, 11 differentially expressed genes were found in the SeMet supplementation group but these genes did not include either known selenoprotein genes or genes previously shown to be modulated by selenium treatment. Because the number of differentially expressed genes (n = 11) was less than expected by chance (n = 18), we concluded that SeMet supplementation had no measurable effect on gene expression in the normal squamous esophagus of these subjects with dysplasia.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Esophageal Neoplasms/drug therapy , Gene Expression , Selenomethionine/therapeutic use , Adult , Aged , China , Esophagus/drug effects , Esophagus/pathology , Female , Humans , Male , Middle Aged , Mucous Membrane/drug effects , Mucous Membrane/pathology , Placebos
19.
J Clin Epidemiol ; 58(11): 1115-24, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16223654

ABSTRACT

BACKGROUND AND OBJECTIVES: Longitudinal studies of health over time may be misleading if some people die. Self-rated health (excellent to poor) and the SF-36 profile scores have been transformed to incorporate death. We applied the same approaches to incorporate death into activities of daily living difficulties (ADLs), IADLs, mini-mental state examination, depressive symptoms, blocks walked per week, bed days, the timed walk, body mass index and blood pressure. STUDY DESIGN AND SETTING: The Cardiovascular Health Study of 5,888 older adults, was followed up to 9 years. Mean age was 73 at baseline, and 658 had an incident stroke during follow-up. METHODS: We recoded each variable as the probability of being healthy 1 year in the future (PHF), conditional on the current value of the variable. This was done for 11 health variables, using three definitions of healthy, and two estimation models. Deaths were set to zero, and mean PHF was plotted in the 3 years before and after an incident stroke. RESULTS: Analyses without the deaths were too optimistic. The effect of stroke was greatest on hospitalization, self-rated health, and IADLs. Alternative transformation approaches had slightly different results. CONCLUSION: These methods provide an additional approach for handling death in longitudinal studies.


Subject(s)
Death , Health Status Indicators , Longitudinal Studies , Activities of Daily Living , Humans , Proportional Hazards Models
20.
Genes Chromosomes Cancer ; 44(4): 423-8, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16114033

ABSTRACT

This study characterizes the frequency of exon 3 CTNNB1 mutations and compares the expression of CTNNB1 transcript variants and downstream targets MYC and WAF1 (p21) across the neoplastic progression of esophageal squamous cell carcinomas (ESCCs). Mutational analysis was performed on 56 tumors and corresponding germline DNA, using primers to exon 3 of CTNNB1 and SSCP DNA sequencing gels. Quantitative Real Time RT-PCR was performed on 45 foci representing the histological spectrum from normal to invasive cancer, using specific primer sets for alternative splice variants that differ by the presence (16A) or absence (16B) of a 159-bp noncoding segment of exon 16 of CTNNB1, in conjunction with downstream targets MYC and WAF1. Two unique mutations were identified, S37F in the SxxxS repeat region, and a germline polymorphism, T59A. Thus, mutation of CTNNB1 exon 3 is a rare event in this population. RT-PCR analysis successfully confirmed the presence of both beta-catenin splice variants in histologically normal and preneoplastic squamous epithelium, and invasive tumors of the esophagus, and identified a significant reduction in the 16A/16B ratio (P = 0.014) and an accompanying significant increase in the MYC/WAF1 expression ratio (P = 0.001) with progression from normal mucosa to dysplasia. This represents the first identification of two CTNNB1 transcripts in histologically "normal" esophageal squamous cells, squamous dysplasia, and invasive ESCC. These results show an increase in the minor mRNA (16B) isoform and changes in the expression of downstream markers consistent with increased transcription during the histological progression from normal to squamous dysplasia.


Subject(s)
Alternative Splicing , Esophageal Neoplasms/genetics , Genetic Variation , beta Catenin/genetics , Base Pairing , Base Sequence , Carcinoma, Squamous Cell/pathology , DNA Mutational Analysis , Disease Progression , Esophageal Neoplasms/pathology , Exons , Gene Expression , Genetic Markers , Humans , Mutation , Polymorphism, Single-Stranded Conformational , Precancerous Conditions , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transcription, Genetic , beta Catenin/metabolism
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