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1.  Targeting Protein Kinase CK2 Suppresses Pro-survival Signaling Pathways and Growth of Glioblastoma 
Purpose
Gliomas are the most frequently occurring primary malignancies in the brain, and glioblastoma (GBM) is the most aggressive of these tumors. Protein kinase CK2 is composed of two catalytic subunits (α and/or α’) and two β regulatory subunits. CK2 suppresses apoptosis, promotes neo-angiogenesis, and enhances activation of the JAK/STAT, NF-κB, PI3K/AKT, Hsp90, Wnt and Hedgehog pathways. Aberrant activation of the NF-κB, PI3K/AKT and JAK/STAT-3 pathways is implicated in GBM progression. Since CK2 is involved in their activation, the expression and function of CK2 in GBM was evaluated.
Experimental Design and Results
Analysis of 537 GBMs from The Cancer Genome Atlas Project demonstrates the CSNK2A1 gene, encoding CK2α, has gene dosage gains in GBM (33.7%), and is significantly associated with the classical GBM subtype. Inhibition of CK2 activity by CX-4945, a selective CK2 inhibitor, or CK2 knockdown by siRNA suppresses activation of the JAK/STAT, NF-κB and AKT pathways and downstream gene expression in human GBM xenografts. On a functional level, CX-4945 treatment decreases the adhesion and migration of GBM cells, in part through inhibition of integrin β1 and α4 expression. In vivo, CX-4945 inhibits activation of STAT-3, NF-κB p65 and AKT, and promotes survival of mice with intracranial human GBM xenografts.
Conclusions
CK2 inhibitors may be considered for treatment of patients with GBM.
doi:10.1158/1078-0432.CCR-13-0265
PMCID: PMC3932633  PMID: 24036851
Glioblastoma; JAK/STAT Pathway; NF-κB Pathway; Protein Kinase CK2; Integrins
2.  Functional chromatin features are associated with structural mutations in cancer 
BMC Genomics  2014;15(1):1013.
Background
Structural mutations (SMs) play a major role in cancer development. In some cancers, such as breast and ovarian, DNA double-strand breaks (DSBs) occur more frequently in transcribed regions, while in other cancer types such as prostate, there is a consistent depletion of breakpoints in transcribed regions. Despite such regularity, little is understood about the mechanisms driving these effects. A few works have suggested that protein binding may be relevant, e.g. in studies of androgen receptor binding and active chromatin in specific cell types. We hypothesized that this behavior might be general, i.e. that correlation between protein-DNA binding (and open chromatin) and breakpoint locations is common across divergent cancers.
Results
We investigated this hypothesis by comprehensively analyzing the relationship among 457 ENCODE protein binding ChIP-seq experiments, 125 DnaseI and 24 FAIRE experiments, and 14,600 SMs from 8 diverse cancer datasets covering 147 samples. In most cancers, including breast and ovarian, we found enrichment of protein binding and open chromatin in the vicinity of SM breakpoints at distances up to 200 kb. Furthermore, for all cancer types we observed an enhanced enrichment in regions distant from genes when compared to regions proximal to genes, suggesting that the SM-induction mechanism is independent from the bias of DSBs to occur near transcribed regions. We also observed a stronger effect for sites with more than one protein bound.
Conclusions
Protein binding and open chromatin state are associated with nearby SM breakpoints in many cancer datasets. These observations suggest a consistent mechanism underlying SM locations across different cancers.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-1013) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-1013
PMCID: PMC4253614  PMID: 25417144
Protein binding; Chromatin state; Structural mutations; Cancer
3.  Measurement of Glycosylated Alpha-Fetoprotein Improves Diagnostic Power over the Native Form in Hepatocellular Carcinoma 
PLoS ONE  2014;9(10):e110366.
Serum alpha-fetoprotein (AFP) has long been used as a diagnostic marker for hepatocellular carcinoma (HCC), albeit controversially. Although it remains widely used in clinics, the value of AFP in HCC diagnosis has recently been challenged due to its significant rates of false positive and false negative findings. To improve the efficacy of AFP as HCC diagnostic marker, we developed a method of measuring total and glycosylated AFP by multiple reaction monitoring (MRM)-MS. In this study, we verified the total amount of AFP (nonglycopeptide levels) and the degree of glycosylated AFP (deglycopeptide levels) in 60 normal (41 men and 19 women; mean age 53 years; range 32–74 years), 35 LC (23 men and 12 women; mean age 56 years; range 43–78 years; HBV-related), and 60 HCC subjects (42 men and 18 women; mean age 58 years; range 38–76 years; HBV-related; 30 stage I, 15 stage II, and 10 stage III). By MRM-MS analysis, the nonglycopeptide had 56.7% sensitivity, 68.3% specificity, and an AUC of 0.687 [cutoff value: ≥0.02 (light/heavy ratio)], comparing the normal and HCC group, whereas the deglycopeptide had 93.3% sensitivity, 68.3% specificity, and an AUC of 0.859 [cutoff value: ≥0.02 (light/heavy ratio)]. In comparing the stage I HCC subgroup with the LC group, the nonglycopeptide had a sensitivity of 66.7%, specificity of 80.0%, and an AUC of 0.712 [cutoff value: ≥0.02 (light/heavy ratio)], whereas the deglycopeptide had a sensitivity of 96.7%, specificity of 80.0%, and an AUC of 0.918 [cutoff value: ≥0.02 (light/heavy ratio)]. These data demonstrate that the discriminatory power of the deglycopeptide is greater than that of the nonglycopeptide. We conclude that deglycopeptide can distinguish cancer status between normal subjects and HCC patients better than nonglycopeptide.
doi:10.1371/journal.pone.0110366
PMCID: PMC4195728  PMID: 25310463
4.  Changes in Personal Networks of Women in Residential and Outpatient Substance Abuse Treatment 
Changes in personal network composition, support and structure over 12 months were examined in 377 women from residential (n=119) and intensive outpatient substance abuse treatment (n=258) through face-to-face interviews utilizing computer based data collection. Personal networks of women who entered residential treatment had more substance users, more people with whom they had used alcohol and/or drugs, and fewer people from treatment programs or self- help groups than personal networks of women who entered intensive outpatient treatment. By 12 months post treatment intake, network composition improved for women in residential treatment; however, concrete support was still lower and substance users still more prevalent in their networks. Network composition of women in outpatient treatment remained largely the same over time. Both groups increased cohesiveness within the network over 12 months. Targeting interventions that support positive changes in personal networks may heighten positive long term outcomes for women entering treatment.
doi:10.1016/j.jsat.2013.04.006
PMCID: PMC3742636  PMID: 23755971
Women; Substance Abuse Treatment; Personal Networks; Treatment Modality
5.  Pathways linking childhood maltreatment and adult physical health☆ 
Child abuse & neglect  2012;37(6):361-373.
Objectives
This study examined whether a self-reported history of childhood maltreatment (physical, emotional, and sexual abuse and physical and emotional neglect) is related to poor adult physical health through health risk behaviors (obesity, substance dependence, and smoking), adverse life events, and psychological distress.
Methods
Two hundred and seventy nine (279) women aged 31–54, primarily poor, urban, and African American with a history of substance use during pregnancy, were assessed for perceived physical health status using the Health Status Questionnaire (SF-36) and any reported chronic medical condition. Hierarchical multiple and logistic regression were used to test mediation, as well as to assess relative contributions of multiple mediators on physical health.
Results
More than two-thirds (n = 195, 70%) of the sample reported at least 1 form of childhood maltreatment, with 42% (n = 110) having a lifetime history of substance dependence and 59% (n = 162) having a chronic medical condition. Controlling for age, education, and race, childhood maltreatment was related to increased likelihood of lifetime history of substance dependence (OR = 1.19, 95% CI = 1.01–1.39), more adverse life events (β = .14), and greater psychological distress (β = .21). Psychological distress and adverse life events partially mediated the relationship between childhood maltreatment and perceived physical health, accounting for 42% of the association between childhood maltreatment and perceived physical health. Adverse life events accounted for 25% of the association between childhood maltreatment and chronic medical condition.
Conclusions
Our findings provide additional evidence that the ill health effects associated with childhood maltreatment persist into adulthood. Adverse life events and psychological distress were key mechanisms shaping later physical health consequences associated with childhood maltreatment among relatively young urban women with a history of substance use.
Practice implications
Health care providers should be aware that childhood maltreatment contributes to adult health problems. Interventions aimed at preventing child maltreatment and addressing life stress and psychological distress will improve long-term physical health among abused children, adults with such histories, as well as children who are likely to be affected by maternal history of childhood maltreatment.
doi:10.1016/j.chiabu.2012.09.008
PMCID: PMC3672368  PMID: 23195701
Childhood maltreatment; Physical health (SF-36); Mediators; Adverse life events; Psychological distress
6.  Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression 
The Journal of Clinical Investigation  2014;124(7):2861-2876.
Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones.
doi:10.1172/JCI68836
PMCID: PMC4071411  PMID: 24865424
7.  Tmem64 modulates calcium signaling during RANKL-mediated osteoclast differentiation 
Cell metabolism  2013;17(2):249-260.
SUMMARY
Osteoclast maturation and function primarily depend on receptor activator of NF-κB ligand (RANKL)-mediated induction of nuclear factor of activated T cells c1 (NFATc1), which is further activated via increased intracellular calcium ([Ca2+]i) oscillation. However, the coordination mechanism that mediates Ca2+ oscillation during osteoclastogenesis remains ill defined. Here, we identified transmembrane protein 64 (Tmem64) as a regulator of Ca2+ oscillation during osteoclastogenesis. We found that Tmem64-deficient mice exhibit increased bone mass due in part to impaired osteoclast formation. Using in vitro osteoclast culture systems, we show here that Tmem64 interacts with sarcoplasmic endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) and modulates its activity. Consequently, Tmem64 deficiency significantly diminishes RANKL-induced [Ca2+]i oscillation, which results in reduced Ca2+/calmodulin-dependent protein kinases (CaMK) IV and mitochondrial ROS, both of which contribute to achieving the CREB activity necessary for osteoclast formation. These data demonstrate that Tmem64 is a positive modulator of osteoclast differentiation via SERCA2-dependent Ca2+ signaling.
doi:10.1016/j.cmet.2013.01.002
PMCID: PMC3569742  PMID: 23395171
8.  Modulation of lysine methylation in myocyte enhancer factor 2 during skeletal muscle cell differentiation 
Nucleic Acids Research  2013;42(1):224-234.
Myocyte enhancer factor 2 (MEF2) is a family of transcription factors that regulates many processes, including muscle differentiation. Due to its many target genes, MEF2D requires tight regulation of transcription activity over time and by location. Epigenetic modifiers have been suggested to regulate MEF2-dependent transcription via modifications to histones and MEF2. However, the modulation of MEF2 activity by lysine methylation, an important posttranslational modification that alters the activities of transcription factors, has not been studied. We report the reversible lysine methylation of MEF2D by G9a and LSD1 as a regulatory mechanism of MEF2D activity and skeletal muscle differentiation. G9a methylates lysine-267 of MEF2D and represses its transcriptional activity, but LSD1 counteracts it. This residue is highly conserved between MEF2 members in mammals. During myogenic differentiation of C2C12 mouse skeletal muscle cells, the methylation of MEF2D by G9a decreased, on which MEF2D-dependent myogenic genes were upregulated. We have also identified lysine-267 as a methylation/demethylation site and demonstrate that the lysine methylation state of MEF2D regulates its transcriptional activity and skeletal muscle cell differentiation.
doi:10.1093/nar/gkt873
PMCID: PMC3874188  PMID: 24078251
9.  Feature selection and survival modeling in The Cancer Genome Atlas 
International Journal of Nanomedicine  2013;8(Suppl 1):57-62.
Purpose
Personalized medicine is predicated on the concept of identifying subgroups of a common disease for better treatment. Identifying biomarkers that predict disease subtypes has been a major focus of biomedical science. In the era of genome-wide profiling, there is controversy as to the optimal number of genes as an input of a feature selection algorithm for survival modeling.
Patients and methods
The expression profiles and outcomes of 544 patients were retrieved from The Cancer Genome Atlas. We compared four different survival prediction methods: (1) 1-nearest neighbor (1-NN) survival prediction method; (2) random patient selection method and a Cox-based regression method with nested cross-validation; (3) least absolute shrinkage and selection operator (LASSO) optimization using whole-genome gene expression profiles; or (4) gene expression profiles of cancer pathway genes.
Results
The 1-NN method performed better than the random patient selection method in terms of survival predictions, although it does not include a feature selection step. The Cox-based regression method with LASSO optimization using whole-genome gene expression data demonstrated higher survival prediction power than the 1-NN method, but was outperformed by the same method when using gene expression profiles of cancer pathway genes alone.
Conclusion
The 1-NN survival prediction method may require more patients for better performance, even when omitting censored data. Using preexisting biological knowledge for survival prediction is reasonable as a means to understand the biological system of a cancer, unless the analysis goal is to identify completely unknown genes relevant to cancer biology.
doi:10.2147/IJN.S40733
PMCID: PMC3790279  PMID: 24098079
brain; feature selection; glioblastoma; personalized medicine; survival modeling; TCGA
10.  Prospective Patterns and Correlates of Quality of Life among Women in Substance Abuse Treatment 
Drug and Alcohol Dependence  2012;124(3):242-249.
Background
Quality of life (QOL) is increasingly recognized as central to the broad construct of recovery in substance abuse services. QOL measures can supplement more objective symptom measures, identify specific service needs and document changes in functioning that are associated with substance use patterns. To date however, QOL remains an under investigated area in the addictions field, especially in the United States.
Methods
This study examines patterns and predictors of QOL at 1 and 6 months post treatment intake among 240 women enrolled in substance abuse treatment in Cleveland, Ohio. The World Health Organization Quality of Life (WHOQOL-BREF) measure was used to assess physical, psychological, social and environmental domains. Hierarchical multiple regressions were conducted to identify correlates of QOL at 6 months post treatment intake.
Results
All QOL domains across the follow up time points improved significantly. However, QOL scores across domains remained below those of healthy population norms. Trauma symptoms significantly predicted Physical and Psychological QOL. Among treatment process variables, alcohol use was the sole significant factor associated with QOL and only for Environmental QOL. Recovery support and friends support for abstinence were consistently associated with QOL across all four domains.
Implications
This study suggests the usefulness of the WHOQOL measure as an indicator of functioning in substance abusing populations. Findings underline the importance of helping women deal with trauma symptoms and develop support for recovery. Further research is needed on the longitudinal relationship between QOL and substance use patterns
doi:10.1016/j.drugalcdep.2012.01.010
PMCID: PMC3366154  PMID: 22333265
Substance use; quality of life; women; recovery; social networks
11.  Development of Biomarkers for Screening Hepatocellular Carcinoma Using Global Data Mining and Multiple Reaction Monitoring 
PLoS ONE  2013;8(5):e63468.
Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers and is associated with a poor survival rate. Clinically, the level of alpha-fetoprotein (AFP) has been used as a biomarker for the diagnosis of HCC. The discovery of useful biomarkers for HCC, focused solely on the proteome, has been difficult; thus, wide-ranging global data mining of genomic and proteomic databases from previous reports would be valuable in screening biomarker candidates. Further, multiple reaction monitoring (MRM), based on triple quadrupole mass spectrometry, has been effective with regard to high-throughput verification, complementing antibody-based verification pipelines. In this study, global data mining was performed using 5 types of HCC data to screen for candidate biomarker proteins: cDNA microarray, copy number variation, somatic mutation, epigenetic, and quantitative proteomics data. Next, we applied MRM to verify HCC candidate biomarkers in individual serum samples from 3 groups: a healthy control group, patients who have been diagnosed with HCC (Before HCC treatment group), and HCC patients who underwent locoregional therapy (After HCC treatment group). After determining the relative quantities of the candidate proteins by MRM, we compared their expression levels between the 3 groups, identifying 4 potential biomarkers: the actin-binding protein anillin (ANLN), filamin-B (FLNB), complementary C4-A (C4A), and AFP. The combination of 2 markers (ANLN, FLNB) improved the discrimination of the before HCC treatment group from the healthy control group compared with AFP. We conclude that the combination of global data mining and MRM verification enhances the screening and verification of potential HCC biomarkers. This efficacious integrative strategy is applicable to the development of markers for cancer and other diseases.
doi:10.1371/journal.pone.0063468
PMCID: PMC3661589  PMID: 23717429
12.  Intra-osseous injection of donor mesenchymal stem cell (MSC) into the bone marrow in living donor kidney transplantation; a pilot study 
Background
Mesenchymal stem cells (MSCs) are multi-potent non-hematopoietic progenitor cells possessing an immune-regulatory function, with suppression of proliferation of activated lymphocytes. In this study, adult living donor kidney transplantation (LDKT) recipients were given MSCs derived from the donor bone marrow to evaluate the safety and the feasibility of immunological changes related to the intra-osseous injection of MSC into the bone marrow.
Methods
MSCs were derived from negative HLA cross-match donors. Donor bone marrow was harvested 5 weeks prior to KT. At the time of transplantation, 1 x 106 cell/kg of donor MSC was directly injected into the bone marrow of the recipient’s right iliac bone. Patients’ clinical outcomes, presence of mixed chimerism by short tandem repeat polymerase chain reaction, analysis of plasma FoxP3 mRNA and cytokine level, and mixed lymphocyte reaction (MLR) were performed.
Results
Seven patients enrolled in this study and received donor MSC injections simultaneously with LDKT. The median age of recipients was 36 years (32 ~ 48). The number of HLA mismatches was 3 or less in 5 and more than 3 in 2. No local complications or adverse events such as hypersensitivity occurred during or after the injection of donor MSC. There was no graft failure, but the biopsy-proven acute rejections were observed in 3 recipients during the follow-up period controlled well with steroid pulse therapy (SPT). The last serum creatinine was a median of 1.23 mg/dL (0.83 ~ 2.07). Mixed chimerism was not detected in the peripheral blood of the recipients at 1 and 8 week of post-transplantation. Donor-specific lymphocyte or T cell proliferation and Treg priming responses were observed in some patients. Plasma level of IL-10, a known mediator of MSC-induced immune suppression, increased in the patients with Treg induction.
Conclusion
Donor MSC injection into the iliac bone at the time of KT was feasible and safe. A possible correlation was observed between the induction of inhibitory immune responses and the clinical outcome in the MSC-kidney transplanted patients. Further research will be performed to evaluate the efficacy of MSC injection for the induction of mixed chimerism and subsequent immune tolerance in KT.
doi:10.1186/1479-5876-11-96
PMCID: PMC3630056  PMID: 23578110
Donor MSC; Intra-osseous injection; Living Donor Kidney Transplantation (LDKT); Immune response
13.  Comparison of Endoscopic Variceal Ligation and Endoscopic Variceal Obliteration in Patients with GOV1 Bleeding 
Chonnam Medical Journal  2013;49(1):14-19.
The aim of this study was to compare the efficacy, rebleeding rates, survival, and complications of endoscopic variceal ligation (EVL) with those of endoscopic variceal obliteration (EVO) in patients with acute type 1 gastroesophageal variceal (GOV1) bleeding. Data were collected retrospectively at a single center. A total of 84 patients were selected (20 patients underwent EVL; 64 patients underwent EVO) from February 2004 to September 2011. Their clinical characteristics, laboratory results, vital signs, Child-Pugh score, Model for End-stage Liver Disease (MELD) score, and overall mortality were evaluated. There were no significant differences in baseline characteristics between the two groups. The success rate in initial control of active bleeding was not significantly different between the EVL and EVO groups (18/20 EVL, or 90.0%, compared with 62/64 EVO, or 96.9%; p=0.239). The early rebleeding rate was also not significantly different between the groups (3/18 EVL, or 16.7% compared with 17/62 EVO, or 27.4%; p=0.422). The late rebleeding rate of the EVL group was lower than that of the EVO group (3/18 EVL, or 16.7%, compared with 26/59 EVO, or 44.1%; p=0.042). The time-to-rebleeding was 594 days for the EVL group and 326 days for the EVO group (p=0.054). In the multivariate analysis, portal vein thrombosis (PVT) was a significant risk factor for early rebleeding. Hepatocellular carcinoma (HCC) and previous history of bleeding were significant risk factors for very late rebleeding. In conclusion, EVL is better than EVO in reducing late rebleeding in acute GOV1 bleeding. HCC, PVT, and previous bleeding history were significant risk factors for rebleeding.
doi:10.4068/cmj.2013.49.1.14
PMCID: PMC3651981  PMID: 23678472
Esophageal and gastric varices; Hemostasis; Endoscopy; Risk factors
14.  Mediating Links Between Maternal Childhood Trauma and Preadolescent Behavioral Adjustment 
Journal of interpersonal violence  2012;28(4):831-851.
Structural equation modeling was used to simultaneously examine maternal psychological distress and social support as mediators linking maternal childhood trauma (MCT) to both maternal and child-reported behavior at 9 years of age in 231 birth mother-child dyads, who were primarily poor, urban, and African American. One half of the mothers (n = 116) reported a history of childhood abuse and neglect. Although MCT was associated with both increased maternal psychological distress and limited social support at 6 years, the pathway to child behavior ratings at 9 years was informant dependent. MCT influenced maternal ratings of her child’s behavior, with some effects mediated through psychological distress. MCT indirectly influenced children’s self-perception of behavior through maternal experience of social support. Maternal ratings and child self-ratings of child behavior problems were moderately correlated. No significant gender interaction was found. Findings suggest a need for understanding trauma histories in the lives of mothers who seek assistance for parenting and child behavior problems, especially in urban low income communities. Interventions targeting both increasing maternal social support and reducing psychological distress may promote competency and resiliency among children for whom MCT poses a risk to optimal development.
doi:10.1177/0886260512455868
PMCID: PMC3587847  PMID: 22935951
Maternal childhood abuse & neglect; child behavioral problems; maternal psychological distress; maternal social support; cross-informant
15.  Anaphylactic Transfusion Reaction in a Patient with Anhaptoglobinemia: The First Case in Korea 
Annals of Laboratory Medicine  2012;32(4):304-306.
Anaphylactic transfusion reactions are rare complications of blood transfusions. Anhaptoglobinemia, a condition that has high incidence in Asia, can cause allergic transfusion reactions or anaphylaxis in severe cases. A 50-yr-old Korean woman was diagnosed with relapsed acute promyelocytic leukemia. She developed thrombocytopenia during chemotherapy and an anaphylactic transfusion reaction on the 4th and 5th platelet transfusions immediately after the transfusion of the platelet concentrates was initiated. Blood analysis showed no detectable serum haptoglobin. We examined her genetic phenotype and detected anhaptoglobinemia, which occurs because of an allelic deletion in the Hp gene cluster. The presence of an antibody against haptoglobin was detected by performing ELISA. To prevent anaphylactic reactions, apheresis platelets were transfused after washing. Consequently, anaphylactic transfusion reactions did not develop. Here, we report the first case of anhaptoglobinemia causing anaphylactic transfusion reaction in Korea.
doi:10.3343/alm.2012.32.4.304
PMCID: PMC3384814  PMID: 22779074
Platelet transfusion; Anaphylaxis; Haptoglobin
16.  Substance Abuse Treatment Stage and Personal Networks of Women in Substance Abuse Treatment 
This study examines the relationship among 4 treatment stages (i.e., engagement, persuasion, active treatment, relapse prevention) and the composition, social support, and structural characteristics of personal networks. The study sample includes 242 women diagnosed with substance dependence who were interviewed within their first month of intensive outpatient treatment. Using EgoNet software, the women reported on their 25 alter personal networks and the characteristics of each alter. With one exception, few differences were found in the network compositions at different stages of substance abuse treatment. The exception was the network composition of women in the active treatment stage, which included more network members from treatment programs or 12-Step meetings. Although neither the type nor amount of social support differed across treatment stages, reciprocity differed between women in active treatment and those in the engagement stage. Networks of women in active treatment were less connected, as indicated by a higher number of components, whereas networks of women in the persuasion stage had a higher degree of centralization, as indicated by networks dominated by people with the most ties. Overall, we find social network structural variables to relate to the stage of treatment, whereas network composition, type of social support, and sociodemographic variables (with a few exceptions) do not relate to treatment stage. Results suggest that social context, particularly how social contacts are arranged around clients, should be incorporated into treatment programs, regardless of demographic background.
PMCID: PMC3358724  PMID: 22639705
women; substance dependence; social networks; treatment stage
17.  Body Mass Index and Nonresponse to Antiviral Treatment in Korean Patients with Genotype 2 and 3 Chronic Hepatitis C 
Chonnam Medical Journal  2012;48(1):21-26.
Pegylated-interferon plus ribavirin is the standard treatment for chronic hepatitis C. Sustained virological response (SVR) rates of up to 80% are reported in genotype 2 and 3 chronic hepatitis C cases. Obesity, a modifiable risk factor, may have a deleterious effect on antiviral treatment. We performed this study to examine the efficacy and safety of pegylated-interferon and ribavirin therapy in Korean patients with genotype 2 and 3 chronic hepatitis C and to investigate the risk factors for nonresponse to antiviral treatment. A total of 121 patients were treated with peginterferon alpha-2a 180 mcg/week plus ribavirin 800 mg/day for 24 weeks. The end-of-treatment virologic response (ETVR), the SVR, the end-of-treatment biochemical response (ETBR), the sustained biochemical response (SBR), and the adverse events were analyzed. The ETVR and SVR were 94.1% and 89.1%, respectively. The ETBR was 80.2% and the SBR was 96%. Multivariate analysis showed that a body mass index of 25 and over was the only independent factor that affected the SVR (odds ratio=10.5, 95% confidence interval: 2.006-54.948, p=0.005). Twenty patients (16.5%) dropped out at the end of treatment, and 7 (5.8%) patients discontinued treatment because of treatment-related adverse events. Our study showed that combination therapy with pegylated-interferon and ribavirin as an initial treatment for genotype 2 and 3 chronic hepatitis C is very effective and safe, and that body mass index is an independent risk factor for nonresponse to antiviral treatment in patients with genotype 2 and 3 chronic hepatitis C.
doi:10.4068/cmj.2012.48.1.21
PMCID: PMC3341433  PMID: 22570811
Hepatitis C, chronic; Peginterferon alfa-2a; Ribavirin; Body mass Index
18.  Knee Joint Laxity and Its Cyclic Variation Influence Tibiofemoral Motion during Weight Acceptance 
Purpose
To better understand how sex differences in anterior knee joint laxity (AKL) impact knee joint biomechanics, we examined the consequence of greater absolute baseline (males and females) and cyclic increases in AKL during the menstrual cycle (females) on anterior tibial translation (ATT) as the knee transitioned from non-weight bearing (NWB) to weight bearing (WB) conditions, while also controlling for genu recurvatum (GR).
Methods
Males and females (71F,48M;18-30 years) were measured for AKL and GR, and underwent measurement of ATT. Females were tested on the days of their cycle when AKL was at its minimum (T1) and maximum (T2); males were matched in time to a female with similar AKL. Linear regressions examined relationships between absolute baseline (AKLT1, GRT1) and cyclic changes (Δ=T2-T1; AKLΔ, GRΔ)(females only) in knee laxity with ATT as measured at T1 and T2, and Δ (T2-T1) (females only).
Results
AKL and GR increased in females, but not males, from T1 to T2. Greater AKLT1 and GRT1 predicted greater ATTT1 and ATTT2 in males (R2=21.0, P<.007). The combination of greater AKLT1, AKLΔ and less GRΔ predicted greater ATTT1 and ATTT2 in females (R2=12.5-13.1, P<.05), with AKLΔ being a stronger predictor (coefficient, P-value) of ATTT2 (0.864, P=.027) compared to ATTT1 (0.333, P=.370). AKLΔ was the sole predictor of ATTΔ (R2=.104; 0.740, P=.042).
Conclusions
Greater absolute baseline and cyclic increases in AKL were consistently associated with greater ATT produced by transition of the knee from NWB to WB. As the ACL is the primary restraint to ATT, these findings provide insight into possible mechanisms by which greater AKL may be associated with at risk knee biomechanics during the weight acceptance phase of dynamic tasks.
doi:10.1249/MSS.0b013e3181ed118d
PMCID: PMC2992800  PMID: 20581718
Injury Mechanism; anterior knee laxity; genu recurvatum; knee biomechanics; hormone response; menstrual cycle
19.  Effects of pentacene-doped PEDOT:PSS as a hole-conducting layer on the performance characteristics of polymer photovoltaic cells 
We have investigated the effect of pentacene-doped poly(3,4-ethylenedioxythiophene:poly(4-styrenesulfonate) [PEDOT:PSS] films as a hole-conducting layer on the performance of polymer photovoltaic cells. By increasing the amount of pentacene and the annealing temperature of pentacene-doped PEDOT:PSS layer, the changes of performance characteristics were evaluated. Pentacene-doped PEDOT:PSS thin films were prepared by dissolving pentacene in 1-methyl-2-pyrrolidinone solvent and mixing with PEDOT:PSS. As the amount of pentacene in the PEDOT:PSS solution was increased, UV-visible transmittance also increased dramatically. By increasing the amount of pentacene in PEDOT:PSS films, dramatic decreases in both the work function and surface resistance were observed. However, the work function and surface resistance began to sharply increase above the doping amount of pentacene at 7.7 and 9.9 mg, respectively. As the annealing temperature was increased, the surface roughness of pentacene-doped PEDOT:PSS films also increased, leading to the formation of PEDOT:PSS aggregates. The films of pentacene-doped PEDOT:PSS were characterized by AFM, SEM, UV-visible transmittance, surface analyzer, surface resistance, and photovoltaic response analysis.
doi:10.1186/1556-276X-7-5
PMCID: PMC3265401  PMID: 22221320
electronic materials; polymers; vapor deposition; electrochemical measurement; electrochemical properties
20.  A Comparison of Cyclic Variations in Anterior Knee Laxity, Genu Recurvatum and General Joint Laxity across the Menstrual Cycle 
Changes in anterior knee laxity (AKL), genu recurvatum (GR) and general joint laxity (GJL) were quantified across days of the early follicular and early luteal phases of the menstrual cycle in 66 females, and the similarity in their pattern of cyclic variations examined. Laxity was measured on each of the first 6 days of menses (M1–M6) and the first 8 days following ovulation (L1–L8) over two cycles. The largest mean differences were observed between L5 and L8 for AKL (0.32mm), and between L5 and M1 for GR (0.56°) and GJL (0.26)(P<.013). At the individual level, mean absolute cyclic changes in AKL (1.8±0.7mm, 1.6±0.7mm), GR (2.8±1.0°, 2.4±1.0°) and GJL (1.1±1.1, 0.7±1.0) were more apparent, with minimum, maximum and delta values being quite consistent from month to month (ICC2,3=.51–.98). Although the average daily pattern of change in laxity was quite similar between variables (Spearman correlation range 0.61 and 0.90), correlations between laxity measures at the individual level were much lower (range −0.07 to 0.43). Substantial, similar, and reproducible cyclic changes in AKL, GR and GJL were observed across the menstrual cycle, with the magnitude and pattern of cyclic changes varying considerably among females.
doi:10.1002/jor.21145
PMCID: PMC2947333  PMID: 20872575
joint laxity; menstrual cycle; anterior cruciate ligament; knee
21.  Combination therapy of renal cell carcinoma or breast cancer patients with dendritic cell vaccine and IL-2: results from a phase I/II trial 
Background
Ten cancer patients (Six renal cell carcinoma and four breast cancer patients) were treated in a phase I/II study with a vaccine composed of autologous dendritic cells (DCs) and IL-2 to evaluate the DC vaccine-related toxicity and antigen-specific immune alteration.
Methods
Cancer patients were treated twice with autologous CD34+ hematopoietic stem cell-derived, GM-CSF/IFN-γ-differentiated DCs pulsed with autologous tumor lysate and KLH, by 4-week interval. Following each subcutaneous injection of therapeutic DCs, low-dose (200 MIU) IL-2 was introduced for 14 consecutive days as an immune adjuvant. To determine the DC vaccine-induced immunological alterations, the KLH-specific lymphocyte proliferation, number of IFN-γ secreting T cells (ELISPOT assay), NK activity and the cytokine modulation were measured.
Results
Cultured-DCs expressing HLA-DR, CD11c, CD83, and B7.1/B7.2 produced IL-12p70. After vaccination, the patients tolerated it. Clinical response was observed in one RCC patient as stable disease. However DC-vaccine related antigen-specific immune responses including peripheral blood lymphocyte proliferation and the number of IFN-r secreting cells were induced in six patients without clear correlation with clinical responses. Also NK activity was induced significantly in six patients after vaccination. DC vaccine-related decrease of TGF-β level or increase of IL-12p70 level and decline of CD4+CD25+ T cells were observed in three patients. However only in the RCC patient whose disease stabilized, combination of stimulatory as well as inhibitory immune alterations including induction of IFN-γ secreting T cell with reduction of CD4+ CD25+ T cell were correlated with clinical responses.
Conclusion
Data indicated that DC vaccine combined with IL-2 is well tolerated without major side effects. DC vaccine induced the specific immunity against introduced antigen. Combinatorial alterations of immunological parameters indicating antigen-specific immune induction along with reduction of inhibitory immunity were correlated with clinical responses in DC vaccine treated patients.
doi:10.1186/1479-5876-9-178
PMCID: PMC3213212  PMID: 22013914
Dendritic cell vaccine; Renal cell carcinoma; Breast cancer; Phase I/II trial; Immune response
22.  Tree-Based Position Weight Matrix Approach to Model Transcription Factor Binding Site Profiles 
PLoS ONE  2011;6(9):e24210.
Most of the position weight matrix (PWM) based bioinformatics methods developed to predict transcription factor binding sites (TFBS) assume each nucleotide in the sequence motif contributes independently to the interaction between protein and DNA sequence, usually producing high false positive predictions. The increasing availability of TF enrichment profiles from recent ChIP-Seq methodology facilitates the investigation of dependent structure and accurate prediction of TFBSs. We develop a novel Tree-based PWM (TPWM) approach to accurately model the interaction between TF and its binding site. The whole tree-structured PWM could be considered as a mixture of different conditional-PWMs. We propose a discriminative approach, called TPD (TPWM based Discriminative Approach), to construct the TPWM from the ChIP-Seq data with a pre-existing PWM. To achieve the maximum discriminative power between the positive and negative datasets, the cutoff value is determined based on the Matthew Correlation Coefficient (MCC). The resulting TPWMs are evaluated with respect to accuracy on extensive synthetic datasets. We then apply our TPWM discriminative approach on several real ChIP-Seq datasets to refine the current TFBS models stored in the TRANSFAC database. Experiments on both the simulated and real ChIP-Seq data show that the proposed method starting from existing PWM has consistently better performance than existing tools in detecting the TFBSs. The improved accuracy is the result of modelling the complete dependent structure of the motifs and better prediction of true positive rate. The findings could lead to better understanding of the mechanisms of TF-DNA interactions.
doi:10.1371/journal.pone.0024210
PMCID: PMC3166302  PMID: 21912677
23.  IsoformEx: isoform level gene expression estimation using weighted non-negative least squares from mRNA-Seq data 
BMC Bioinformatics  2011;12:305.
Background
mRNA-Seq technology has revolutionized the field of transcriptomics for identification and quantification of gene transcripts not only at gene level but also at isoform level. Estimating the expression levels of transcript isoforms from mRNA-Seq data is a challenging problem due to the presence of constitutive exons.
Results
We propose a novel algorithm (IsoformEx) that employs weighted non-negative least squares estimation method to estimate the expression levels of transcript isoforms. Validations based on in silico simulation of mRNA-Seq and qRT-PCR experiments with real mRNA-Seq data showed that IsoformEx could accurately estimate transcript expression levels. In comparisons with published methods, the transcript expression levels estimated by IsoformEx showed higher correlation with known transcript expression levels from simulated mRNA-Seq data, and higher agreement with qRT-PCR measurements of specific transcripts for real mRNA-Seq data.
Conclusions
IsoformEx is a fast and accurate algorithm to estimate transcript expression levels and gene expression levels, which takes into account short exons and alternative exons with a weighting scheme. The software is available at http://bioinformatics.wistar.upenn.edu/isoformex.
doi:10.1186/1471-2105-12-305
PMCID: PMC3180389  PMID: 21794104
24.  SINGLE NUCLEOTIDE POLYMORPHISMS INSIDE microRNA TARGET SITES INFLUENCE TUMOR SUSCEPTIBILITY 
Cancer research  2010;70(7):2789-2798.
Single nucleotide polymorphisms (SNPs) associated with polygenetic disorders, such as breast cancer (BC), can create, destroy or modify microRNA (miRNA) binding sites; however, the extent to which SNPs interfere with miRNA gene regulation and affect cancer susceptibility remains largely unknown. We hypothesize that disruption of miRNA target binding by SNPsis a widespread mechanism relevant to cancer susceptibility. In order to test this, we analyzed SNPs known to be associated with BC risk, in silico and in vitro, for their ability to modify miRNA binding sites and miRNA gene regulation and referred to these as target SNPs. We identified rs1982073-TGFB1 and rs1799782-XRCC1 as target SNPs, whose alleles could modulate gene expression by differential interaction with miR-187 and miR-138, respectively. Genome-wide bioinformatics analysis predicted approximately 64% of transcribed SNPs as target SNPs that can modify (increase/decrease) the binding energy of putative miRNA::mRNA duplexes by over 90%. To assess whether target SNPs are implicated in BC susceptibility, we conducted a case-control population study and observed that germline occurrence of rs799917-BRCA1 and rs334348-TGFR1, significantly varies among populations with different risks of developing BC. Luciferase activity of target SNPs allelic variants and protein levels in cancer cell lines with different genotypes showed differential regulation of target genes following over-expression of the two interacting miRNAs (miR-638 and miR-628-5p). Therefore, we propose that transcribed target SNPs alter miRNA gene regulation and consequently protein expression, contributing to the likelihood of cancer susceptibility, by a novel mechanism of subtle gene regulation.
doi:10.1158/0008-5472.CAN-09-3541
PMCID: PMC2853025  PMID: 20332227
Single nucleotide polymorphism; microRNAs; mRNA; BC; tumor susceptibility
25.  Effect of Axial Load on Anterior Tibial Translation when Transitioning from Non-Weight Bearing to Weight Bearing 
Background
While the application of compressive joint loads and thigh muscle activity are associated with anterior tibial translation in vitro, less is known during early load acceptance in-vivo. We investigated the effects of increasing axial loads on anterior tibial translation and thigh muscle activity in healthy knees during transition from non-weight bearing to early weight bearing.
Methods
Participants (11 Male, 11 Female) underwent 20%, 40%, and 60% body weight acceptance trials at 20° knee flexion while electromagnetic sensors measured anterior tibial translation (mm), and surface electromyography recorded quadriceps and hamstring muscle onset times (ms) and amplitudes (% maximal voluntary isometric contraction). Repeated measures ANOVA compared values across loads. Pearson correlations examined relationships between anterior tibial translation and muscle onset times and amplitudes within each load.
Findings
As load increased, anterior tibial translation (Mean (standard deviation)) (20%=4.7(1.7)mm < 40%=7.1(1.9)mm < 60%=8.8(2.1)mm), and quadriceps (20%=23.6(14.9)% maximal voluntary isometric contraction < 40%=32.7(11.8)% maximal voluntary isometric contraction < 60%=41.1(13.5)% maximal voluntary isometric contraction) and hamstring (20%=15.5(15.7)% maximal voluntary isometric contraction < 40%=23.0(16.4)% maximal voluntary isometric contraction < 60%=27.6(19.1)% maximal voluntary isometric contraction) activation increased, while quadriceps (20% = 96.7(28.4)ms > 60% 80.2(21.8)ms) and hamstring (20% = 141.5(65.0)ms & 40% = 126.3(68.8)> 60% 107.6(28.4)ms) onset times decreased (P≤0.05). There were no relationships between anterior tibial translation and muscle activation amplitudes (R = .033–.294) or onset times (R = −.031–.374)(P>.09).
Interpretation
Greater axial loads near full knee extension during early weight acceptance result in greater anterior tibial translation, regardless of faster and stronger activation amplitudes. These findings support injury prevention programs aimed to reduce impact forces as they may in turn reduce anterior tibial translation and corresponding ligamentous strain during dynamic activity.
doi:10.1016/j.clinbiomech.2009.09.004
PMCID: PMC2795012  PMID: 19837495
Knee; ACL; Loading Rate

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