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1.  Clinical Monitoring of Chronic Hepatitis C Based on its Natural History and Therapy 
Hepatitis C virus (HCV) infection is a major public health problem and a leading cause of chronic liver disease. Chronic HCV infection often follows a progressive course over years and can result in cirrhosis, hepatocellular carcinoma, and need for liver transplantation. In the United States alone, the estimated prevalence of HCV infection is up to 5.1 million persons. The optimal approach to detecting HCV infection is to screen persons for possible history of risks of exposure to virus and to test those selected individuals with risk factors. Both host and viral factors may be important contributors to the natural history of HCV. Currently, effective pharmacologic therapy are available to induce sustained virologic response (SVR) or virologic “cure,” which results in improved morbidity and mortality. Patient education before treatment is essential and should include a full discussion of potential side effects. It is important to work collaboratively and closely with patients to ensure early recognition of adverse events and to effectively manage them in order to ensure treatment compliance. This paper provides a thorough overview on screening for the diagnosis, clinical management, and treatment indications and contraindications for chronic hepatitis C.
PMCID: PMC4287404  PMID: 25580186
Hepatitis C virus (HCV); chronic hepatitis C (CHC); hepatitis C treatment; cirrhosis; chronic liver disease
2.  A Mouse Model of Timothy Syndrome: a Complex Autistic Disorder Resulting from a Point Mutation in Cav1.2 
Timothy Syndrome (TS) arises from a point mutation in the human voltage-gated L-type Ca2+ channel (Cav1.2). TS is associated with cardiac arrhythmias and sudden cardiac death, as well as congenital heart disease, impaired cognitive function, and autism spectrum disorders. TS results from a de novo gain-of-function mutation which affects the voltage dependent component of Cav1.2 inactivation. We created a knock-in TS mouse. No homozygous TS mice survived, but heterozygous TS2-NEO mice (with the mutation and the neocassette in situ) had a normal outward appearance and survived to reproductive age. Previously, we have demonstrated that these mice exhibit the triad of Autistic traits. In this paper we document other aspects of these mice including Cav1.2 isoform expression levels, normal physical strength, brain anatomy and a marked propensity towards self-injurious scratching. Gross brain anatomy was not markedly different in TS2-NEO mice compared to control littermates, and no missing structures were noted. The lack of obvious changes in brain structure is consistent with theTS2-NEO mice may provide a significant tool in understanding the role of calcium channel inactivation in both cardiac function and brain development.
PMCID: PMC3872133  PMID: 24371506
Autism; channels; calcium; inactivation; brain
3.  Developing a Predictive Gene Classifier for Autism Spectrum Disorders Based upon Differential Gene Expression Profiles of Phenotypic Subgroups 
North American journal of medicine & science  2013;6(3):10.7156/najms.2013.0603107.
Autism spectrum disorders (ASD) are neurodevelopmental disorders which are currently diagnosed solely on the basis of abnormal stereotyped behavior as well as observable deficits in communication and social functioning. Although a variety of candidate genes have been identified on the basis of genetic analyses and up to 20% of ASD cases can be collectively associated with a genetic abnormality, no single gene or genetic variant is applicable to more than 1–2 percent of the general ASD population. In this report, we apply class prediction algorithms to gene expression profiles of lymphoblastoid cell lines (LCL) from several phenotypic subgroups of idiopathic autism defined by cluster analyses of behavioral severity scores on the Autism Diagnostic Interview-Revised diagnostic instrument for ASD. We further demonstrate that individuals from these ASD subgroups can be distinguished from nonautistic controls on the basis of limited sets of differentially expressed genes with a predicted classification accuracy of up to 94% and sensitivities and specificities of ~90% or better, based on support vector machine analyses with leave-one-out validation. Validation of a subset of the “classifier” genes by high-throughput quantitative nuclease protection assays with a new set of LCL samples derived from individuals in one of the phenotypic subgroups and from a new set of controls resulted in an overall class prediction accuracy of ~82%, with ~90% sensitivity and 75% specificity. Although additional validation with a larger cohort is needed, and effective clinical translation must include confirmation of the differentially expressed genes in primary cells from cases earlier in development, we suggest that such panels of genes, based on expression analyses of phenotypically more homogeneous subgroups of individuals with ASD, may be useful biomarkers for diagnosis of subtypes of idiopathic autism.
PMCID: PMC3867975  PMID: 24363828
Autism; subphenotypes; gene expression; class prediction; blood biomarkers
4.  Speech and Language Impairments in Autism: Insights from Behavior and Neuroimaging 
A failure to develop language is one of the earliest signs of autism. The ability to identify the neural signature of this deficit in very young children has become increasingly important, given that the presence of speech before five years of age is the strongest predictor for better outcomes in autism. This review consolidates what is known about verbal and preverbal precursors of language development as a framework for examining behavioral and brain anomalies related to speech and language in autism spectrum disorders. Relating the disruptions in the speech network to the social deficits observed will provide promising targets for behavioral and pharmacological interventions in ASD.
PMCID: PMC3862077  PMID: 24349628
autism; speech; language; neuroimaging; children
5.  Stability and Reproducibility of the Measurement of Plasma Nitrate in Large Epidemiologic Studies 
Inorganic nitrate has emerged as a therapeutic agent for cardiovascular disease; however, nitrate can also metabolize to carcinogenic nitrosamines under pathologic conditions. Few large epidemiologic studies have examined circulating levels of nitrate in relation to cardiovascular disease and cancer. Data on the validity of nitrate measurement in blood samples collected in typical epidemiologic settings are needed before nitrate can be evaluated as an exposure in large epidemiologic studies.
We measured plasma levels of nitrate in three pilot studies to evaluate its laboratory variability, stability with delayed processing, and reproducibility over time among women from the Nurses’ Health Study and healthy female volunteers.
Laboratory variability of nitrate levels was fairly low, with a coefficient variation (CV) of 7%. Plasma nitrate levels in samples stored as whole blood on ice for up to 48 hrs before processing were very stable; the overall intra-class correlation (ICC) from 0 to 48 hours was 0.89 (95%CI, 0.70–0.97). The within-person reproducibility over a one-year period was modest, with an ICC of 0.49 (95% CI, 0.33- 0.94).
Our results indicate that measurement of nitrate in plasma is reliable and stable in blood samples with delayed processing up to 48 hours. Within-person reproducibility was modest but data from this study can be used for measurement error correction in subsequent analyses. The measurement of nitrate cannot be widely used in epidemiologic research without the documentation of its stability and reproducibility.
PMCID: PMC3826455  PMID: 24244804
nitrate; stability; reproducibility; epidemiologic blood collection
6.  Challenges and Needs of Chinese and Korean American Breast Cancer Survivors: In-Depth Interviews 
Breast cancer incidence and the number of breast cancer survivors have been rapidly increasing among Chinese and Korean women in the United States. However, few data are available regarding quality of life in Asian American breast cancer survivors. This qualitative study aims to describe Asian American women’s perceptions of quality of life and their breast cancer experiences. In-depth interviews with four Chinese and five Korean American breast cancer survivors and three oncologists were conducted in Chinese, Korean, or English. Interviews were recorded and transcripts were translated into English. Qualitative analyses were performed by two independent coders and then discussed and agreed upon by the research team. The respondents reported that the breast cancer experience had affected various domains of quality of life, but women reported having limited resources with which to cope effectively. Depression, anxiety, and stress were commonly reported, but women rarely discussed these issues with family and friends or sought professional help. As immigrants, women’s loneliness and a lack of social support and culturally relevant resources seemed to be major barriers to maintaining good quality of life. Women also expressed interest in learning more about alternative therapies and relaxation skills. These findings can be used to help inform the development of a culturally appropriate intervention for Asian American breast cancer survivors. Future programs may provide information in women’s native languages to teach skills to cope with stress and anxiety, increase women’s self-efficacy within the context of their cultural background, and enhance social support among women from the same ethnic group.
PMCID: PMC3766352  PMID: 24019995
breast cancer; quality of life; survivorship; Asian American; Chinese American; Korean American
7.  Plasma Amyloid-β Peptides and Homocysteine in Depression in the Homebound Elderly 
Both plasma amyloid-β peptide 40 (Aβ40) and homocysteine (tHcy) are linked to vascular disease, which is related to depression in the elderly. We sought to study whether the relationship between tHcy and plasma Aβ40 differs in those with and without depression.
Study Design and Methods
In a cross-sectional study of 1058 homebound elders, vascular depression was defined as a score ≥ 16 on the Center for Epidemiological Studies Depression scale (CES-D) along with self-reported cardiovascular disease (CVD). Plasma Aβ40 and Aβ42, and serum tHcy and creatinine were measured.
Elders with high tHcy had higher concentrations of plasma Aβ40 (median: 147.5 vs. 123.1 pg/ml, P < 0.0001) and Aβ42 (median: 20.2 vs. 16.6 pg/ml, P < 0.0001) than those with low tHcy. In elders with depression, the relationship between logarithm of plasma Aβ40 (LogAβ40), but not LogAβ42, and tHcy was significant (β = +0.010, SE = 0.004, P = 0.007); in contrast, this relationship was not observed in those without depression. Subjects with vascular depression had the highest concentration of tHcy (mean ± SD: 12.8 ± 4.6 vs. 11.7 ± 4.5 vs. 11.9 + 5.5, P = 0.008) compared to those without CVD and those without depression. Depressed subjects without CVD had the lowest concentration of plasma Aβ42 (median: 15.5 vs. 19.1 vs. 18.7, P = 0.01) compared to those with CVD and those without depression.
Vascular depression, which is associated with tHcy and Aβ40 in blood, appears to be different from depression that is associated with low plasma Aβ42. This suggests that reducing tHcy and Aβ40 may be an adjunct treatment for vascular depression.
PMCID: PMC3678954  PMID: 23766866
Aβ; Homocysteine; Depression
8.  Factors Associated with Colorectal Cancer Screening Among Cambodians, Vietnamese, Koreans and Chinese Living in the United States 
The purpose of this community-based participatory study was to identify factors associated with colorectal cancer (CRC) screening compliance and non-compliance among Cambodians, Vietnamese, Koreans and Chinese men and women 50 years and older living in the United States. A cross-sectional design was used in the study. The completed sample included 815 Asian Americans which included Cambodians (N=215), Vietnamese (N=195), Koreans (N=94) and Chinese (N=311). A 95-item questionnaire was developed and pilot tested for content validity and reliability. An in-person data collection approach was utilized and participants were given choice in responding in English or their native language. Of the 815 participants, 79.1% (N=645) reported never-screened, 7.9% (N=64), non-compliance, and 13.0% (N=106) compliance. Education was significantly associated with never-screened for CRC for Vietnamese and Chinese; employment status for Cambodians and Koreans; lack of health insurance for Cambodians, Korean and Chinese; English fluency and years lived in the U.S. for Vietnamese, Koreans, and Chinese. Less acculturated Asian Americans were more likely to be never screened, but differentially across ethnic subgroups. Barriers to screening included lack of knowledge, language, transportation, and time. Increased culturally-targeted public awareness and education programs are needed to improve CRC screening and compliance among high risk Asian American ethnic subgroups.
PMCID: PMC3521597  PMID: 23243486
sigmoidoscopy or colonoscopy; fecal occult blood test; Vietnamese; Korean; Chinese; Cambodian; correlates of colorectal cancer screening
9.  Pathology Imaging Informatics for Clinical Practice and Investigative and Translational Research 
Pathologists routinely interpret gross and microscopic specimens to render diagnoses and to engage in a broad spectrum of investigative research. Multiple studies have demonstrated that imaging technologies have progressed to a level at which properly digitized specimens provide sufficient quality comparable to the traditional glass slides examinations. Continued advancements in this area will have a profound impact on the manner in which pathology is conducted from this point on. Several leading institutions have already undertaken ambitious projects directed toward digitally imaging, archiving, and sharing pathology specimens. As a result of these advances, the use of informatics in diagnostic and investigative pathology applications is expanding rapidly. In addition, the advent of novel technologies such as multispectral imaging makes it possible to visualize and analyze imaged specimens using multiple wavelengths simultaneously. As these powerful technologies become increasingly accepted and adopted, the opportunities for gaining new insight into the underlying mechanisms of diseases as well as the potential for discriminating among subtypes of pathologies are growing accordingly.
PMCID: PMC3407842  PMID: 22855694
pathology imaging informatics; digital pathology; whole slide images; telepathology; computer assisted diagnosis; multispectral imaging
10.  Do Apparent Overlaps between Schizophrenia and Autistic Spectrum Disorders Reflect Superficial Similarities or Etiological Commonalities? 
Study Background
Schizophrenia and autism are both neurodevelopmental disorders that were once considered to be the same disorder expressed in different developmental periods. Although they were separated diagnostically about 40 years ago, they share several clinical and possibly, etiological features. This paper reviews overlaps in four domains of function to consider the issue of whether these similarities are sporadic and likely to represent superficial similarities, or whether the disorders are more likely to share some features in common.
Representative areas of function were reviewed and compared for aspects of cognition (nonverbal reasoning, memory and language), social function (orienting/joint attention, eye contact and theory of mind), brain function (structural differences) and genetics. To facilitate comparisons with schizophrenia, a focus on high functioning autism/Asperger’s disorder was utilized, particularly in the sections on cognition and social function.
Significant similarities (and differences) characterized comparisons in each domain.
Disturbed function in similar clinical (in cognition and social function), neurobiological (brain volumes) and genetic (e.g., involvement of the same genes or chromosomal locations) domains in autism and schizophrenia supports the hypothesis that while they are distinct disorders, they are not entirely unique. Additional studies of similarities and differences between them may thus shed light on common etiological mechanisms and hopefully, facilitate the development of novel treatment targets.
PMCID: PMC3342590  PMID: 22563520
Autistic spectrum disorder; cognition; social cognition; schizophrenia spectrum disorder
11.  Molecular and Pathophysiological Features of Angiotensinogen: A Mini Review 
The renin-angiotensin system is an essential regulatory system for blood pressure and fluid homeostasis. Angiotensinogen is the only known precursor of all the peptides generated in this system. While many of the basic understandings of angiotensinogen have come from research efforts to define its role in blood pressure regulation, novel pathophysiological functions of angiotensinogen have been discovered in the last two decades including kidney developmental abnormalities, atherosclerosis, and obesity. Despite the impressive advance in the understanding of angiotensinogen gene structure and protein functions, some fundamental questions remain unanswered. In this short review, we provide contemporary insights into the molecular characteristics of angiotensinogen and its pathophysiological features. In light of the recent progress, we emphasize some newly recognized functional features of angiotensinogen other than its regulation on blood pressure.
PMCID: PMC3291105  PMID: 22389749
angiotensinogen; gene; protein; atherosclerosis; obesity
12.  WRN protein and Werner syndrome 
Werner syndrome is an autosomal recessive disorder associated with premature aging and cancer predisposition. Cells from Werner syndrome patients show increased genomic instability and are hypersensitive to DNA damage agents. Werner syndrome is caused by mutations of the WRN gene. WRN protein is a member of RecQ DNA helicase family. It not only contains a conserved 3'-5' helicase domain as other members of the RecQ family but also contains a unique 3'-5' exonuclease domain. WRN recognizes specific DNA structures as substrates which are intermediates of DNA metabolism. WRN interacts with many other proteins, which function in telomere maintenance, DNA replication, and DNA repair through different pathways.
PMCID: PMC3237395  PMID: 22180828
13.  The role of SIRT1 in tumorigenesis 
NAD-dependent Class III histone deacetylase SIRT1 is a multiple functional protein and has been demonstrated critically involved in stress response, cellular metabolism and aging through deacetylating variety of substrates including p53, forkhead transcription factors, PGC-1α, NF-κB, Ku70 and histones. Increasing evidences indicate that SIRT1 plays a complex role in tumorigenesis with functions in both tumor promoting and tumor suppressing. This review provides an overview of current knowledge of SIRT1 and its controversies regarding the functions of SIRT1 in tumorigenesis.
PMCID: PMC3237400  PMID: 22180829
SIRT1; deacetylase; cancer
14.  Fasting Triglyceride Concentrations are Associated with Early Mortality Following Antiretroviral Therapy in Zambia 
In developing countries, 8 to 71% of patients initiating highly active antiretroviral therapy (HAART) die within the first year of treatment. Apart from baseline CD4 count, viral load, hemoglobin, BMI and stage of the disease, there may be other variables that contribute to AIDS-related mortality. We investigated the potential role of nutrition, lipids and insulin resistance-related phenotypes in predicting early mortality.
We recruited 210 HAART-naïve HIV/AIDS patients in Lusaka, Zambia. Dietary intake, anthropometric measurements, fasting serum insulin, glucose, and lipid profiles were assessed at baseline. Mortality was assessed after 90 days of follow-up. We used logistic regression models to identify variables associated with mortality.
The mean±SD for age, BMI and CD4 count at baseline were 34±7.4 y, 20±3 kg/m2 and 138±52 cells/μL, respectively. Sixteen patients (7.6%) died during follow-up. Triglyceride concentrations were associated with increased mortality [odds ratio (OR) for 1 mmol/L increase in triglyceride concentration=2.51; 95% CI: 1.34-4.71]. This association remained significant (OR=3.24; 95% CI: 1.51-6.95) after adjusting for age, gender, smoking, alcohol use, total cholesterol, BMI, CD4 count and n3 fatty acid intake. Apart from higher n3 fat intake which was inversely associated with mortality (survivors: 1.81±0.99% total energy/day vs. non-survivors 1.28±0.66% energy/day, P=0.04), there were no other macronutrients associated with mortality.
Triglyceride concentrations at the time of initiating HAART are independently associated with increased risk for early mortality. If this association is confirmed in larger studies, assessment of triglycerides could become part of routine care of HIV patients initiating HAART in developing countries.
PMCID: PMC3207243  PMID: 22059107
Triglycerides; lipids; mortality; HIV; HAART; Africa; Zambia
15.  Overcoming Barriers to Cervical Cancer Screening Among Asian American Women 
Significant disparities in cervical cancer incidence and mortality exist among ethnic minority women, and in particular, among Asian American women. These disparities have been attributed primarily to differences in screening rates across ethnic/racial groups. Asian American women have one of the lowest rates of screening compared to other ethnic/racial groups. Yet Asian Americans, who comprise one of the fastest growing populations in the United States, have received the least attention in cancer control research. Studies suggest that various factors, including lack of knowledge, psychosocial and cultural beliefs, and access barriers, are associated with cervical cancer screening behaviors among Asian American women. Indeed, the few interventions that have been developed for Asian American women demonstrate that targeting these factors can yield significant increases in screening rates. It is important to note, however, that the effectiveness of educational interventions is often attenuated if access barriers are not adequately addressed. Hence, interventions that include key essential components, such as the use of community individuals as lay health workers, culturally-tailored and linguistically-appropriate educational materials, and navigation assistance to overcome access barriers, are more likely to be successful in enhancing screening rates. As the benefits of community-based cervical cancer prevention programs become more apparent, it will be essential to identify effective approaches for disseminating such programs more broadly. In conclusion, community-based cervical cancer screening programs have demonstrated promise in addressing existing cervical cancer disparities by increasing awareness and knowledge and promoting recommended screening behaviors. These findings will be instrumental in guiding future community-based programs to reduce cervical cancer health disparities among Asian American women.
PMCID: PMC3115728  PMID: 21687826
cervical cancer; screening; Asian Americans; disparities; cancer prevention; community-based; psychosocial beliefs; access barriers
16.  Tumor Cell Selective Cytotoxicity and Apoptosis Induction by an Herbal Preparation from Brucea javanica 
The plant Brucea javanica has shown impressive efficacy for treating various diseases including cancer. However, the mechanism by which B. javanica acts is poorly understood. We have established tissue culture assays to study the effects of B. javanica on cervical and several other cancer cells. Our results demonstrated that the aqueous extract from B. javanica is selectively toxic to cancer cells. Induction of apoptosis by B. javanica appears to be a possible mechanism by which it kills cancer cells. Interestingly, a significant increase of p53 protein level was observed in these apoptotic cells. Our studies indicated that both p53-dependent and p53-independent activities contributed to herb-induced cell death. These results imply that further studies with B. javanica may lead to the development of novel anti-cancer drugs.
PMCID: PMC3108096  PMID: 21654932
Brucea javanica; Cancer therapy; Cytotoxicity; Apoptosis; p53
17.  Genomic Instability Induced By Human Papillomavirus Oncogenes 
Cervical cancer is one of the leading causes of cancer death in women worldwide. Human papillomavirus (HPV) infection is necessary but not sufficient for the development of cervical cancer. Genomic instability caused by HPV allows cells to acquire additional mutations required for malignant transformation. Genomic instability in the form of polyploidy has been implicated in a causal role in cervical carcinogenesis. Polyploidy not only occurs as an early event during cervical carcinogenesis but also predisposes cervical cells to aneuploidy, an important hallmark of human cancers. Cell cycle progression is regulated at several checkpoints whose defects contribute to genomic instability.
The high-risk HPVs encode two oncogenes, E6 and E7, which are essential for cellular transformation in HPV-positive cells. The ability of high-risk HPV E6 and E7 protein to promote the degradation of p53 and pRb, respectively, has been suggested as a mechanism by which HPV oncogenes induce cellular transformation. E6 and E7 abrogate cell cycle checkpoints and induce genomic instability that leads to malignant conversion.
Although the prophylactic HPV vaccine has recently become available, it will not be effective for immunosuppressed individuals or those who are already infected. Therefore, understanding the molecular basis for HPV-associated cancers is still clinically relevant. Studies on genomic instability will shed light on mechanisms by which HPV induces cancer and hold promise for the identification of targets for drug development.
PMCID: PMC3106442  PMID: 21643539
genomic instability; human papillomavirus (HPV); oncogene; cell cycle checkpint

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