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1.  Household air pollution and lung cancer in China: a review of studies in Xuanwei 
Chinese Journal of Cancer  2014;33(10):471-475.
Over half of the world's population is exposed to household air pollution from the burning of solid fuels at home. Household air pollution from solid fuel use is a leading risk factor for global disease and remains a major public health problem, especially in low- and mid-income countries. This is a particularly serious problem in China, where many people in rural areas still use coal for household heating and cooking. This review focuses on several decades of research carried out in Xuanwei County, Yunnan Province, where household coal use is a major source of household air pollution and where studies have linked household air pollution exposure to high rates of lung cancer. We conducted a series of case-control and cohort studies in Xuanwei to characterize the lung cancer risk in this population and the factors associated with it. We found lung cancer risk to vary substantially between different coal types, with a higher risk associated with smoky (i.e., bituminous) coal use compared to smokeless (i.e., anthracite) coal use. The installation of a chimney in homes resulted in a substantial reduction in lung cancer incidence and mortality. Overall, our research underscores the need among existing coal users to improve ventilation, use the least toxic fuel, and eventually move toward the use of cleaner fuels, such as gas and electricity.
PMCID: PMC4198749  PMID: 25223911
Coal; household air pollution; lung cancer
2.  History of lung disease and risk of lung cancer in a population with high household fuel combustion exposures in rural China 
Lung cancer (Amsterdam, Netherlands)  2013;81(3):10.1016/j.lungcan.2013.06.019.
History of chronic lung diseases and household coal use for heating and cooking are established risk factors of lung cancer; however, few studies have been able to explore these risk factors simultaneously. Xuanwei, China, has some of the highest rates of lung cancer in China and most residents experience substantial in-home coal smoke exposures. Using a population-based case-control study of 498 lung cancer cases and 498 age-matched controls, we evaluated the risk of lung cancer in relation to coal smoke exposure and history of chronic lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, tuberculosis (TB), chronic bronchitis, and emphysema. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logistic regression adjusting for potential confounders. We observed an increased risk of lung cancer with history of any chronic lung disease among males (OR=14.2; 95%CI =4.3 to 46.9), females (OR=2.6; 95%CI =1.1 to 6.3), smokers (OR=12.7; 95%CI =3.5 to 45.8), and nonsmokers (OR=2.6; 95%CI =1.1 to 6.4). Specifically, TB (OR=83.7; 95%CI =11.0 to 634.7), COPD (OR=3.2; 95%CI =1.7 to 6.0), and emphysema and chronic bronchitis (OR=3.3; 95%CI =1.7 to 6.4) were associated with increased risks. These findings suggest that history of chronic lung diseases may also increase risk of lung cancer in populations with indoor coal smoke exposures.
PMCID: PMC3845667  PMID: 23891511
Chronic lung disease; lung cancer; never smoking; Xuanwei; China
3.  Factors Affecting Perceived Stigma in Leprosy Affected Persons in Western Nepal 
There are various factors which construct the perception of stigma in both leprosy affected persons and unaffected persons. The main purpose of this study was to determine the level of perceived stigma and the risk factors contributing to it among leprosy affected person attending the Green Pastures Hospital, Pokhara municipality of western Nepal.
A cross-sectional study was conducted among 135 people affected by leprosy at Green Pastures Hospital and Rehabilitation Centre. Persons above the age of 18 were interviewed using a set of questionnaire form and Explanatory Model Interview Catalogue (EMIC). In addition, two sets of focused group discussions each containing 10 participants from the ward were conducted with the objectives of answering the frequently affected EMIC items.
Among 135 leprosy affected persons, the median score of perceived stigma was 10 while it ranged from 0–34. Higher perceived stigma score was found in illiterate persons (p = 0.008), participants whose incomes were self-described as inadequate (p = 0.014) and who had changed their occupation due to leprosy (p = 0.018). Patients who lacked information on leprosy (p = 0.025), knowledge about the causes (p = 0.02) and transmission of leprosy (p = 0.046) and those who had perception that leprosy is a severe disease (p<0.001) and is difficult to treat (p<0.001) had higher perceived stigma score. Participants with disfigurement or deformities (p = 0.014), ulcers (p = 0.022) and odorous ulcers (p = 0.043) had higher perceived stigma score.
The factors associated with higher stigma were illiteracy, perceived economical inadequacy, change of occupation due to leprosy, lack of knowledge about leprosy, perception of leprosy as a severe disease and difficult to treat. Similarly, visible deformities and ulcers were associated with higher stigma. There is an urgent need of stigma reduction strategies focused on health education and health awareness programs in addition to the necessary rehabilitation support.
Author Summary
A total of 135 leprosy affected persons were interviewed with a questionnaire containing EMIC questions designed to assess the level of perceived stigma and the questionnaire containing variables for socio-demographic characteristics, knowledge about leprosy and the clinical presentations of the participants. Clinical presentation as disability was graded according to WHO guidelines, where grade 0 means no disability found, grade I means loss of sensation has been noted in the hand or foot while grade II means visible damage or disability. Total EMIC score was analyzed between sub-variables to see the factors associated with the higher level of perceived stigma score. Additionally, among the total participants, we included 20 of them who were admitted at hospital for various reasons. Two sets of focus group discussions were conducted with additional questions to derive the reasons behind frequently affected EMIC stigma domains. The factors associated with higher perceived stigma score were illiteracy (those who could not read and write), perceived economical inadequacy, lack of knowledge on leprosy, the perceptions as difficult to treat and severe disease and presence of visible deformities and ulcers. Considering our findings pertaining to higher perceived stigma, there is an urgent need of stigma reduction strategies which should focus on health education about leprosy that can change the perceived stigma in leprosy.
PMCID: PMC4046961  PMID: 24901307
4.  Development of a Question Prompt List as a Communication Intervention to Reduce Racial Disparities in Cancer Treatment 
Racial disparities have been found in the use of chemotherapy as cancer treatment. These disparities may be, in part, due to well-documented differences in the quality of communication during clinical interactions with oncologists and Black versus White patients. In this study using a Community-Based Participatory Research (CBPR) approach, academic researchers, community members, and oncologists formed a partnership to develop a communication intervention to address racial disparities in cancer care. Partners developed a Question Prompt List (QPL), a simple tool that can be used to improve communication, and thus treatment, during clinical interactions in which oncologists and Black patients discuss chemotherapy. Partners endorsed the use of a QPL, provided specific suggestions for content and format, conducted and analyzed qualitative interviews with Black patients receiving chemotherapy, and approved the final version. The feasibility and effectiveness of the QPL that resulted from this research process are currently under evaluation in a separate study.
PMCID: PMC3665702  PMID: 23440665
5.  The Impact of AD Drug Treatments on Event-Related Potentials as Markers of Disease Conversion 
Current Alzheimer research  2013;10(7):732-741.
This paper investigates how commonly prescribed pharmacologic treatments for Alzheimer’s disease (AD) affect Event-Related Potential (ERP) biomarkers as tools for predicting AD conversion in individuals with Mild Cognitive Impairment (MCI). We gathered baseline ERP data from two MCI groups (those taking AD medications and those not) and later determined which subjects developed AD (Convert->AD) and which subjects remained cognitively stable (Stable). We utilized a previously developed and validated multivariate system of ERP components to measure medication effects among these four subgroups. Discriminant analysis produced classification scores for each individual as a measure of similarity to each clinical group (Convert->AD, Stable), and we found a large significant main Group effect but no main AD Medications effect and no Group by Medications interaction. This suggested AD medications have negligible influence on this set of ERP components as weighted markers of disease progression. These results provide practical information to those using ERP measures as a biomarker to identify and track AD in individuals in a clinical or research setting.
PMCID: PMC4021490  PMID: 23905997
Alzheimer’s disease (AD); AD Drug Treatments; Biomarker; Discriminant Analysis; EEG; Event-Related Potentials (ERP); Mild Cognitive Impairment (MCI); Neurophysiology; Prediction; Principal Components Analysis (PCA)
6.  Ovary Transcriptome Profiling via Artificial Intelligence Reveals a Transcriptomic Fingerprint Predicting Egg Quality in Striped Bass, Morone saxatilis 
PLoS ONE  2014;9(5):e96818.
Inherited gene transcripts deposited in oocytes direct early embryonic development in all vertebrates, but transcript profiles indicative of embryo developmental competence have not previously been identified. We employed artificial intelligence to model profiles of maternal ovary gene expression and their relationship to egg quality, evaluated as production of viable mid-blastula stage embryos, in the striped bass (Morone saxatilis), a farmed species with serious egg quality problems. In models developed using artificial neural networks (ANNs) and supervised machine learning, collective changes in the expression of a limited suite of genes (233) representing <2% of the queried ovary transcriptome explained >90% of the eventual variance in embryo survival. Egg quality related to minor changes in gene expression (<0.2-fold), with most individual transcripts making a small contribution (<1%) to the overall prediction of egg quality. These findings indicate that the predictive power of the transcriptome as regards egg quality resides not in levels of individual genes, but rather in the collective, coordinated expression of a suite of transcripts constituting a transcriptomic “fingerprint”. Correlation analyses of the corresponding candidate genes indicated that dysfunction of the ubiquitin-26S proteasome, COP9 signalosome, and subsequent control of the cell cycle engenders embryonic developmental incompetence. The affected gene networks are centrally involved in regulation of early development in all vertebrates, including humans. By assessing collective levels of the relevant ovarian transcripts via ANNs we were able, for the first time in any vertebrate, to accurately predict the subsequent embryo developmental potential of eggs from individual females. Our results show that the transcriptomic fingerprint evidencing developmental dysfunction is highly predictive of, and therefore likely to regulate, egg quality, a biologically complex trait crucial to reproductive fitness.
PMCID: PMC4018430  PMID: 24820964
7.  Phase II Trial of Sorafenib in Patients with Advanced Anaplastic Carcinoma of the Thyroid 
Thyroid  2013;23(5):600-604.
Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy with a median survival of 3–5 months. The BRAF oncogene is mutated to its active form in up to 24% of ATC cases. Sorafenib is a tyrosine kinase inhibitor that acts on the RAF-1 serine/threonine kinase. In preclinical mouse models, sorafenib inhibits the growth of ATC xenografts and improves survival. No study of sorafenib in ATC has been conducted. We conducted a multi-institutional phase II trial of sorafenib in patients with ATC who had failed up to two previous therapies.
The primary endpoint of the trial was the Response Evaluation Criteria In Solid Tumors (RECIST)–defined imaging response rate. Twenty patients with ATC were treated with sorafenib 400 mg twice daily.
Two of the 20 patients had a partial response (10%) and an additional 5 of 20 (25%) had stable disease. The duration of response in the two responders was 10 and 27 months, respectively. For the patients with stable disease, the median duration was 4 months (range 3–11 months). The overall median progression-free survival was 1.9 months with a median and a 1-year survival of 3.9 months and 20%, respectively. Toxicity was manageable and as previously described for sorafenib, including hypertension and skin rash.
Sorafenib has activity in ATC, but at a low frequency and similar to our previous experience with fosbretabulin. One patient with a response had previously progressed on fosbretabulin. Toxicities were both predictable and manageable.
PMCID: PMC3643255  PMID: 23113752
8.  Ambient particulate matter and lung function growth in Chinese children 
Epidemiology (Cambridge, Mass.)  2012;23(3):464-472.
Exposure to particulate matter (PM) has been associated with deficits in lung function growth among children in Western countries. However, few studies have explored this association in developing countries, where PM levels are often substantially higher.
Children (n=3273) aged 6–12 years were recruited from eight schools in four cities. The lung function parameters of forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were measured using computerized spirometers twice a year for up to three years (1993–1996). Dichotomous samplers placed in each schoolyard were used to measure PM2.5 and PM10 (PM with diameter ≤ 2.5 and ≤ 10, respectively). Multivariable generalized estimating equations were used to examine the association between the quarterly average PM levels and lung function growth over the period of follow-up.
Annual average PM2.5 and PM10 levels in the four cities ranged from 57 to 158 μg/m3 and 95 to 268 μg/m3, respectively. In multivariable models, an increase of 10 μg/m3 of PM2.5 was associated with decreases of 2.7 ml FEV1 (95% confidence interval= −3.5 to −2.0), 3.5 ml FVC (−4.3 to −2.7), 1.4 ml/year FEV1 growth (−1.8 to −0.9), and 1.5 ml/year FVC growth (−2.0 to −1.0). Similar results were seen with PM10 exposure.
Exposure to ambient particulate matter was associated with decreased growth in lung function among Chinese children.
PMCID: PMC3985859  PMID: 22407138
9.  Effects of an injury and illness prevention program on occupational safety behaviors among rice farmers in Nakhon Nayok Province, Thailand 
The objective of this study was to determine the effects of an Injury and Illness Prevention (IIP) program intervention on occupational safety behavior among rice farmers in Nakhon Nayok Province, Thailand. This was a quasi-experimental study in an intervention group and a control group. It was carried out in two rice farming communities, in which most people are rice farmers with similar socio-demographic characteristics. Multistage sampling was employed, selecting one person per rice farming household. The intervention group was 62 randomly selected rice farmers living in a rural area; another 55 rice farmers served as the control group. A structured face-to-face interview questionnaire was administered to participants to evaluate their safety behaviors in four areas: equipment use, pesticide use, ergonomics, and working conditions. The 2-week intervention program consisted of four elements: 1) health education, 2) safety inspection, 3) safety communication, and 4) health surveillance. Data were collected at baseline and 4 months after the intervention (follow-up). We used a general linear model repeated-measures analysis of variance to assess the mean difference between baseline and follow-up occupational safety behavior points between the intervention and control groups. Pesticide safety behaviors significantly increased in the intervention group compared with the control group. Ergonomics and working conditions points also increased in the intervention group, but not significantly so. The equipment use score decreased in the intervention group. It is necessary to identify and develop further measures to improve occupational safety behaviors. Some methods, such as effective risk communication, could be added to increase risk perception.
PMCID: PMC3953033  PMID: 24634590
occupational safety behaviors; rice farmers; safety program; injury and illness prevention program
10.  Modeling the sustainability of community health networks: novel approaches for analyzing collaborative organization partnerships across time 
Sustainability is important if community health organizations are to be effective in collaborating to achieve long term health goals. We present a multi-method set of longitudinal analyses examining structural markers applied to a group of organizations brought together to reduce cancer disparities among older African American adults. At the overall network level, sustainability was seen in the growth of outgoing connections and multiplexity. Results of hierarchical clustering analyses identified distinct patterns of collaborative activation over time at the relationship level. Growth modeling indicated the effects of continuing network membership and participation in collaborative events on several structural markers of sustainability. Results of these analyses provide longitudinal indicators for how collaborations among partner organizations impacted their likelihood of continuing in the community network program. The strategy presented here introduces novel methods to assist with planning and evaluation of future community based public health endeavors.
PMCID: PMC3958587  PMID: 24653776
Community; Networks; Partnerships; Sustainability; Hierarchical cluster analysis; Growth modeling
11.  Effects of an intervention to reduce insecticide exposure on insecticide-related knowledge and attitude: a quasi-experimental study in Shogun orange farmers in Krabi Province, Thailand 
An intervention to reduce insecticide exposure in Shogun orange farmers was implemented in Krabi Province, Thailand. Intervention effects on insecticide-related knowledge and attitude were evaluated in a quasi-experimental study in two farms about 20 kilometers (km) apart. The intervention was conducted at one farm; the other served as control. The study included 42 and 50 farmers at the intervention and control farms, respectively. The intervention included several components, including didactic instruction, practical demonstrations, use of a fluorescent tracer, and continuing guidance on insecticide use via a small, specially trained group within the overall intervention group. To the best of our knowledge, this was the first such intervention in Thailand. Knowledge and attitude were measured at baseline (pre-intervention), and at 2 and 5 months after the intervention (follow-up 1 and follow-up 2, respectively). Intervention effects were assessed with linear mixed models, specified to enable testing of effects at each follow-up time. The intervention was associated with substantial and statistically significant improvements in both knowledge score and attitude score (P < 0.001 for each score at each follow-up time). Intervention-related improvements in knowledge score and attitude score were equivalent to about 27% and 14% of baseline mean knowledge and attitude scores, respectively. Intervention-related benefits were similar at both follow-up times. Findings were similar before and after adjustment for covariates. These findings increase confidence that well-designed interventions can reduce farmers’ insecticide exposure in Thailand and elsewhere. In future research, it would be desirable to address long-term intervention effects on farmers’ health and quality of life.
PMCID: PMC3785400  PMID: 24082797
insecticides; pesticides; intervention; farmers; knowledge; attitude
12.  Abca1 Deficiency Affects Alzheimer's Disease-Like Phenotype in Human ApoE4 But Not in ApoE3-Targeted Replacement Mice 
The Journal of Neuroscience  2012;32(38):13125-13136.
ATP-binding cassette transporter A1 (ABCA1) transporter regulates cholesterol efflux and is an essential mediator of high-density lipoprotein (HDL) formation. In amyloid precursor protein (APP) transgenic mice, Abca1 deficiency increased amyloid deposition in the brain paralleled by decreased levels of Apolipoprotein E (ApoE). The APOEε4 allele is the major genetic risk factor of sporadic Alzheimer's disease (AD). Here, we reveal the effect of Abca1 deficiency on phenotype in mice expressing human ApoE3 or ApoE4. We used APP/E3 and APP/E4 mice generated by crossing APP/PS1ΔE9 transgenic mice to human APOE3- and APOE4-targeted replacement mice and examined Abca1 gene dose effect on amyloid deposition and cognition. The results from two behavior tests demonstrate that lack of one copy of Abca1 significantly exacerbates memory deficits in APP/E4/Abca1−/+ but not in APP/E3/Abca1−/+ mice. The data for amyloid plaques and insoluble amyloid-β (Aβ) also show that Abca1 hemizygosity increases Aβ deposition only in APP/E4/Abca1−/+ but not in APP/E3/Abca1−/+ mice. Our in vivo microdialysis assays indicate that Abca1 deficiency significantly decreases Aβ clearance in ApoE4-expressing mice, while the effect of Abca1 on Aβ clearance in ApoE3-expressing mice was insignificant. In addition, we demonstrate that plasma HDL and Aβ42 levels in APP/E4/Abca1−/+ mice are significantly decreased, and there is a negative correlation between plasma HDL and amyloid plaques in brain, suggesting that plasma lipoproteins may be involved in Aβ clearance. Overall, our results prove that the presence of functional Abca1 significantly influences the phenotype of APP mice expressing human ApoE4 and further substantiate therapeutic approaches in AD based on ABCA1–APOE regulatory axis.
PMCID: PMC3646580  PMID: 22993429
13.  C145 as a short-latency electrophysiological index of cognitive compensation in Alzheimer's disease 
Brain plasticity and cognitive compensation in the elderly are of increasing interest, and Alzheimer's disease (AD) offers an opportunity to elucidate how the brain may overcome damage. We provide neurophysiological evidence of a short-latency ERP component (C145) linked to stimulus relevancy that may reflect cognitive compensation in early-stage Alzheimer's disease (AD). Thirty-six subjects with early-stage, mild AD and 36 like-aged normal elderly (Controls) had their EEG recorded while performing our Number-Letter task, a cognitive/perceptual paradigm that manipulates stimulus relevancies. ERP components, including C145, were extracted from ERPs using Principal Components Analysis. C145 amplitudes and spatial distributions were compared among Controls, AD subjects with high performance on the Number-Letter task, and AD subjects with low performance. Compared to AD subjects, Control subjects showed enhanced C145 processing of visual stimuli in the occipital region where differential processing of relevant stimuli occurred. AD high performers recruited central brain areas in processing task relevancy. Controls and AD low performers did not show a significant task relevancy effect in these areas. We conclude that short-latency ERP components can detect electrophysiological differences in early-stage AD that reflect altered cognition. Differences in C145 amplitudes between AD and normal elderly groups regarding brain locations and types of task effects suggest compensatory mechanisms can occur in the AD brain to overcome loss of normal functionality, and this early compensation may have a profound effect on the cognitive efficiency of AD individuals.
PMCID: PMC3576817  PMID: 22886016
Event-Related Potentials (ERP); Electrophysiology; Alzheimer's disease (AD); EEG; Principal Components Analysis (PCA); Short-latency ERP component; Compensatory mechanisms; Brain plasticity; C145
14.  Arsenic Exposure to Killifish During Embryogenesis Alters Muscle Development 
Toxicological Sciences  2011;125(2):522-531.
Epidemiological studies have correlated arsenic exposure in drinking water with adverse developmental outcomes such as stillbirths, spontaneous abortions, neonatal mortality, low birth weight, delays in the use of musculature, and altered locomotor activity. Killifish (Fundulus heteroclitus) were used as a model to help to determine the mechanisms by which arsenic could impact development. Killifish embryos were exposed to three different sodium arsenite concentrations and were collected at 32 h post-fertilization (hpf), 42 hpf, 168 hpf, or < 24 h post-hatch. A killifish oligo microarray was developed and used to examine gene expression changes between control and 25-ppm arsenic-exposed hatchlings. With artificial neural network analysis of the transcriptomic data, accurate prediction of each group (control vs. arsenic-exposed embryos) was obtained using a small subset of only 332 genes. The genes differentially expressed include those involved in cell cycle, development, ubiquitination, and the musculature. Several of the genes involved in cell cycle regulation and muscle formation, such as fetuin B, cyclin D–binding protein 1, and CapZ, were differentially expressed in the embryos in a time- and dose-dependent manner. Examining muscle structure in the hatchlings showed that arsenic exposure during embryogenesis significantly reduces the average muscle fiber size, which is coupled with a significant 2.1- and 1.6-fold upregulation of skeletal myosin light and heavy chains, respectively. These findings collectively indicate that arsenic exposure during embryogenesis can initiate molecular changes that appear to lead to aberrant muscle formation.
PMCID: PMC3262854  PMID: 22058191
arsenic; Fundulus; muscle; embryonic; CapZ; development; microarray
15.  Coal mining is associated with lung cancer risk in Xuanwei, China 
Xuanwei, China, experiences some of the highest rates of lung cancer in China. While lung cancer risk has been linked to the household use of bituminous coal, no study has comprehensively evaluated the risk of lung cancer associated with the mining of this coal in Xuanwei. In Xuanwei, coal is typically extracted from underground mines, without ventilation, and transported to the surface using carts powered by manpower or electricity.
We evaluated the risk of lung cancer and working as a coal miner, in the absence of diesel exhaust exposure, in a population-based case-control study of 260 male lung cancer cases and 260 age-matched male controls with information on occupational histories. Odds ratios (ORs) and 95% confidence intervals (CIs) for working as a coal miner and years of working as a coal miner were calculated by conditional logistic regression, adjusting for potential confounders, such as smoking and household coal use.
We observed an increased risk of lung cancer among coal miners (OR=2.7; 95%CI =1.3–5.6) compared to non-coal miners. Further, a dose-response relationship was observed for the risk of lung cancer and the number of years working as a coal miner (ptrend=0.02), with those working as miners for more than 10 years experiencing an almost 4-fold increased risk (OR=3.8; 95%CI=1.4–10.3) compared to non-coal miners.
These findings suggest that coal mining in Xuanwei may be a risk factor for lung cancer.
PMCID: PMC3308012  PMID: 21987405
Coal mining; lung cancer; occupation; Xuanwei; China
16.  Women Have Farther to Fall: Gender Differences Between Normal Elderly and Alzheimer’s Disease in Verbal Memory Engender Better Detection of AD in Women 
We analyzed verbal episodic memory learning and recall using the Logical Memory (LM) subtest of the Wechsler Memory Scale-III in order to determine how gender differences in AD compare to those seen in normal elderly and whether or not these differences impact assessment of AD. We administered the LM to both an AD and a Control group, each comprised of 21 men and 21 women, and found a large drop in performance from normal elders to AD. Of interest was a gender interaction whereby the women’s scores dropped 1.6 times more than the men’s did. Control women on average outperformed Control men on every aspect of the test, including immediate recall, delayed recall, and learning. Conversely, AD women tended to perform worse than AD men. Additionally, the LM achieved perfect diagnostic accuracy in discriminant analysis of AD vs. Control women, a statistically significantly higher result than for men. The results indicate the LM is a more powerful and reliable tool in detecting AD in women than in men.
PMCID: PMC3387297  PMID: 21486518
Gender differences; Alzheimer’s disease (AD); normal elderly; Logical Memory; Wechsler Memory Scale (WMS); verbal episodic memory; learning; sex; diagnosis
17.  Brain ERP components predict which individuals progress to Alzheimer’s disease and which do not 
Neurobiology of aging  2009;32(10):1742-1755.
Predicting which individuals will progress to Alzheimer’s disease (AD) is important in both clinical and research settings. We used brain Event-Related Potentials (ERPs) obtained in a perceptual/cognitive paradigm with various processing demands to predict which individual Mild Cognitive Impairment (MCI) subjects will develop AD versus which will not. ERP components, including P3, memory “storage” component, and other earlier and later components, were identified and measured by Principal Components Analysis. When measured for particular task conditions, a weighted set of eight ERP component_conditions performed well in discriminant analysis at predicting later AD progression with good accuracy, sensitivity, and specificity. The predictions for most individuals (79%) had high posterior probabilities and were accurate (88%). This method, supported by a cross-validation where the prediction accuracy was 70–78%, features the posterior probability for each individual as a method of determining the likelihood of progression to AD. Empirically obtained prediction accuracies rose to 94% when the computed posterior probabilities for individuals were 0.90 or higher (which was found for 40% of our MCI sample).
PMCID: PMC2902777  PMID: 20005599
Event-Related Potentials (ERP); Biomarker; Neurophysiology; Mild Cognitive Impairment (MCI); Alzheimer’s disease (AD); Diagnosis; Prediction; EEG; Principal Components Analysis (PCA); Discriminant Analysis; Posterior Probability; Early Detection
18.  Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with Toll-like receptor stimulation to induce immunity to self antigens in cancer patients 
The use of tumor-derived proteins as cancer vaccines is complicated by tolerance to these self antigens. Tolerance may be broken by immunization with activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting cells (APC); however, targeting tumor antigen directly to APC in vivo would be a less complicated strategy. We wished to test whether targeted delivery of an otherwise poorly immunogenic, soluble antigen to APC through their mannose receptors (MR) would induce clinically relevant immunity.
Experimental Design
Two phase I studies were performed with CDX-1307, a vaccine composed of human chorionic gonadotropin beta chain (hCG-β) fused to a MR-specific monoclonal antibody, administered either locally (intradermally) or systemically (intravenously) in patients with advanced epithelial malignancies. An initial dose-escalation of single agent CDX-1307 was followed by additional cohorts of CDX-1307 combined with GM-CSF and the Toll-like receptor (TLR)-3 agonist poly-ICLC and TLR7/8 agonist resiquimod to activate the APC.
CDX-1307 induced consistent humoral and T cell responses to hCG-β when co-administered with TLR agonists. Greater immune responses and clinical benefit, including the longest duration of stable disease, were observed with immunization combined with local TLR agonists. Immune responses were induced equally efficiently in patients with elevated and non-elevated levels of serum hCG-β. Antibodies within the serum of vaccinated participants had tumor suppressive function in vitro. Toxicity consisted chiefly of mild injection site reactions.
APC targeting and activation induce adaptive immunity against poorly immunogenic self antigens which has implications for enhancing the efficacy of cancer immunotherapy.
PMCID: PMC3139834  PMID: 21632857
TLR agonist; cancer vaccine; hCG-β; T cell; B cell
19.  Antiandrogen Withdrawal in Castrate-refractory Prostate Cancer 
Cancer  2008;112(11):2393-2400.
Antiandrogen withdrawal is a potential therapeutic maneuver for patients with progressive prostate cancer. This study was designed to examine antiandrogen withdrawal effects within the context of a large multi-institutional prospective trial.
Eligibility criteria included progressive prostate adenocarcinoma despite combined androgen blockade. Eligible patients received prior initial treatment with an antiandrogen plus orchiectomy or luteinizing hormone-releasing hormone (LHRH) agonist. Patients were stratified according to type of antiandrogen, type of progression (prostate-specific antigen [PSA] or radiographic), presence or absence of metastatic disease, and prior LHRH agonist versus surgical castration.
A total of 210 eligible and evaluable patients had a median follow-up of 5.0 years; 64% of patients previously received flutamide, 32% bicalutamide, and 3% nilutamide. Of the 210 patients, 21% of patients had confirmed PSA decreases of ≥50% (95% CI, 16% to 27%). No radiographic responses were recorded. Median progression-free survival (PFS) was 3 months (95% CI, 2 months to 4 months); however, 19% had 12-month or greater progression-free intervals. Median overall survival (OS) after antiandrogen withdrawal was 22 months (20 and 40 months for those with and without radiographic evidence of metastatic disease, respectively). Multivariate analyses indicated that longer duration of antiandrogen use, lower PSA at baseline, and PSA-only progression at study entry were associated with both longer PFS and OS. Longer antiandrogen use was the only significant predictor of PSA response.
These data indicate a relatively modest rate of PSA response in patients who were undergoing antiandrogen withdrawal; however, PFS can be relatively prolonged (≥1 year) in approximately 19% of patients.
PMCID: PMC3359896  PMID: 18383517
antiandrogen withdrawal; prostate cancer; PSA; prognosis; survival; secondary hormonal therapy; hormone-refractory prostate cancer
20.  An ovary transcriptome for all maturational stages of the striped bass (Morone saxatilis), a highly advanced perciform fish 
BMC Research Notes  2012;5:111.
The striped bass and its relatives (genus Morone) are important fisheries and aquaculture species native to estuaries and rivers of the Atlantic coast and Gulf of Mexico in North America. To open avenues of gene expression research on reproduction and breeding of striped bass, we generated a collection of expressed sequence tags (ESTs) from a complementary DNA (cDNA) library representative of their ovarian transcriptome.
Sequences of a total of 230,151 ESTs (51,259,448 bp) were acquired by Roche 454 pyrosequencing of cDNA pooled from ovarian tissues obtained at all stages of oocyte growth, at ovulation (eggs), and during preovulatory atresia. Quality filtering of ESTs allowed assembly of 11,208 high-quality contigs ≥ 100 bp, including 2,984 contigs 500 bp or longer (average length 895 bp). Blastx comparisons revealed 5,482 gene orthologues (E-value < 10-3), of which 4,120 (36.7% of total contigs) were annotated with Gene Ontology terms (E-value < 10-6). There were 5,726 remaining unknown unique sequences (51.1% of total contigs). All of the high-quality EST sequences are available in the National Center for Biotechnology Information (NCBI) Short Read Archive (GenBank: SRX007394). Informative contigs were considered to be abundant if they were assembled from groups of ESTs comprising ≥ 0.15% of the total short read sequences (≥ 345 reads/contig). Approximately 52.5% of these abundant contigs were predicted to have predominant ovary expression through digital differential display in silico comparisons to zebrafish (Danio rerio) UniGene orthologues. Over 1,300 Gene Ontology terms from Biological Process classes of Reproduction, Reproductive process, and Developmental process were assigned to this collection of annotated contigs.
This first large reference sequence database available for the ecologically and economically important temperate basses (genus Morone) provides a foundation for gene expression studies in these species. The predicted predominance of ovary gene expression and assignment of directly relevant Gene Ontology classes suggests a powerful utility of this dataset for analysis of ovarian gene expression related to fundamental questions of oogenesis. Additionally, a high definition Agilent 60-mer oligo ovary 'UniClone' microarray with 8 × 15,000 probe format has been designed based on this striped bass transcriptome (eArray Group: Striper Group, Design ID: 029004).
PMCID: PMC3305648  PMID: 22353237
21.  Two Immunoglobulin Tandem Proteins with a Linking β-Strand Reveal Unexpected Differences in Cooperativity and Folding Pathways 
Journal of Molecular Biology  2012;416(1-5):137-147.
The study of the folding of single domains, in the context of their multidomain environment, is important because more than 70% of eukaryotic proteins are composed of multiple domains. The structures of the tandem immunoglobulin (Ig) domain pairs A164–A165 and A168–A169, from the A-band of the giant muscle protein titin, reveal that they form tightly associated domain arrangements, connected by a continuous β-strand. We investigate the thermodynamic and kinetic properties of these tandem domain pairs. While A164–A165 apparently behaves as a single cooperative unit at equilibrium, unfolding without the accumulation of a large population of intermediates, domains in A168–A169 behave independently. Although A169 appears to be stabilized in the tandem protein, we show that this is due to nonspecific stabilization by extension. We elucidate the folding and unfolding pathways of both tandem pairs and show that cooperativity in A164–A165 is a manifestation of the relative refolding and unfolding rate constants of each individual domain. We infer that the differences between the two tandem pairs result from a different pattern of interactions at the domain/domain interface.
Graphical Abstract
► We investigate the stability and folding of titin Ig domains in a multidomain environment. ► Tandem A-band domains in A164–A165 and A168–A169 are linked by a continuous β-strand. ► At equilibrium, A164–A165 exhibits cooperativity, but A168–A169 domains do not interact. ► Modeling using kinetic data shows that an intermediate accumulates in A164–A165. ► Biophysical studies show that these homologous proteins exhibit very different properties.
PMCID: PMC3277889  PMID: 22197372
multidomain; Beta sheet; titin A-band; tandem repeat; protein folding; FNIII, fibronectin type III
22.  Predicting Conversion from Mild Cognitive Impairment to Alzheimer’s Disease Using Neuropsychological Tests and Multivariate Methods 
Behavioral markers measured through neuropsychological testing in Mild Cognitive Impairment (MCI) were analyzed and combined in multivariate ways to predict conversion to Alzheimer’s disease (AD) in a longitudinal study of 43 MCI patients. The test measures taken at a baseline evaluation were first reduced to underlying components (Principal Components Analysis, PCA) and then the component scores were used in discriminant analysis to classify MCI individuals as likely to convert or not. When empirically weighted and combined, episodic memory, speeded executive functioning, recognition memory (false and true positives), visuospatial memory processing speed, and visuospatial episodic memory were together strong predictors of conversion to AD. These multivariate combinations of the test measures achieved through the PCA were good, statistically significant predictors of MCI conversion to AD (84% accuracy, 86% sensitivity, and 83% specificity). Importantly, the posterior probabilities of group membership that accompanied the binary prediction for each participant indicated the confidence of the prediction. Most of the subjects (81%) were in the highly confident probability bins (0.70 – 1.00), where the obtained prediction accuracy was more than 90%. The strength and reliability of this multivariate prediction method were tested by cross-validation and randomized resampling.
PMCID: PMC3048956  PMID: 20711906
Neuropsychological tests; predict; multivariate; Alzheimer’s disease (AD); Mild Cognitive Impairment (MCI); discriminant analysis; Principal Components Analysis (PCA); posterior probability
23.  Diagnosis of Alzheimer’s Disease Using Neuropsychological Testing Improved by Multivariate Analyses 
Neuropsychological assessment aids in the diagnosis of Alzheimer’s disease (AD) by objectively establishing cognitive impairment from standardized tests. We present new criteria for diagnosis that use weighted combined scores from multiple tests. Our method employs two multivariate analyses: Principal Components Analysis (PCA) and discriminant analysis. PCA (N = 216 subjects) created more interpretable cognitive dimensions by resolving 49 test measures in our neuropsychological battery to 13 component scores for each subject. The component scores were used to build discriminant functions that classified each participant as either an early-stage AD (N = 55) or normal elderly (N = 78). Our discriminant function performed with high accuracy, sensitivity, and specificity (nearly all >90%) in the development, a cross-validation, and a new subjects validation. When contrasted to two different traditional empirical methods for diagnosis (using cutscores and defining AD as falling below 5% on two or more test domains), our results suggested that the multivariate method was superior in classification (approximately 20% more accurate).
PMCID: PMC2896992  PMID: 20358452
Discriminant analysis; neuropsychological tests; diagnosis; Alzheimer’s disease (AD); Principal Components Analysis (PCA); multivariate analyses; NINCDS-ADRDA criteria; posterior probability
24.  Consortium for Oral Health-Related Informatics: Improving Dental Research, Education, and Treatment 
Journal of dental education  2010;74(10):1051-1065.
Advances in informatics, particularly the implementation of electronic health records (EHR), in dentistry have facilitated the exchange of information. The majority of dental schools in North America use the same EHR system, providing an unprecedented opportunity to integrate these data into a repository that can be used for oral health education and research. In 2007, fourteen dental schools formed the Consortium for Oral Health-Related Informatics (COHRI). Since its inception, COHRI has established structural and operational processes, governance and bylaws, and a number of work groups organized in two divisions: one focused on research (data standardization, integration, and analysis), and one focused on education (performance evaluations, virtual standardized patients, and objective structured clinical examinations). To date, COHRI (which now includes twenty dental schools) has been successful in developing a data repository, pilot-testing data integration, and sharing EHR enhancements among the group. This consortium has collaborated on standardizing medical and dental histories, developing diagnostic terminology, and promoting the utilization of informatics in dental education. The consortium is in the process of assembling the largest oral health database ever created. This will be an invaluable resource for research and provide a foundation for evidence-based dentistry for years to come.
PMCID: PMC3114442  PMID: 20930236
dentistry; dental education; informatics; education; research; evidence-based dentistry
25.  Phase II Trial of Depsipeptide (NSC-630176) in Previously Treated Colorectal Cancer Patients with Advanced Disease: A Southwest Oncology Group Study (S0336) 
Investigational new drugs  2008;27(5):469-475.
Patients with metastatic colorectal cancer who progress on standard chemotherapy have limited treatment options. New and effective drugs are needed for these patients. Depsipeptide is a histone deacetylase inhibitor that can alter chromatin structure and gene transcription leading to multiple changes in cellular protein production. This may result in cell cycle arrest and tumor growth inhibition. Depsipeptide has shown anti-proliferative activity in vitro against multiple mouse and human tumor cell lines and in vivo in human tumor xenograft models.
Patients and Methods
Patients were required to have pathologically verified, measurable, metastatic or locally advanced colorectal cancer that was surgically unresectable. They must have failed either one or two prior chemotherapy regimens, had performance status of 0–1, adequate bone marrow, renal and hepatic function, and no significant cardiac disease. Patients were treated with depsipeptide at a dose of 13 mg/m2 as a 4 hour iv infusion on days 1, 8, and 15 of a 28 day cycle. The study had a two stage design. The primary objective of the study was to determine the confirmed response probability in this group of patients treated with depsipeptide.
Twenty-eight patients were registered to the study, two of whom were ineligible. One eligible patient refused all treatment and was not analyzed. For the 25 remaining patients, performance status was 0 in 16 patients and 1 in 9 patients. Ten patients had received one prior chemotherapy regimen and fifteen 2 prior regimens. Out of the 25 eligible and analyzable patients accrued in the first stage of the protocol, no objective responses were observed and the study was permanently closed. Four patients had stable disease as the best response. Twenty-five patients were assessed for toxicity. No grade 4 or greater toxicities were seen. Fourteen of the 25 patients experienced grade 3 toxicities the most common of which were fatigue or anorexia.
Depsipeptide at this dose and schedule is ineffective in the treatment of patients with metastatic colorectal cancer after prior chemotherapy. Future trials might evaluate combinations of depsipeptide with chemotherapeutic or other agents.
PMCID: PMC3024913  PMID: 18941712

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