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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  Online monitoring of immunoaffinity-based depletion of high-abundance blood proteins by UV spectrophotometry using enhanced green fluorescence protein and FITC-labeled human serum albumin 
Proteome Science  2010;8:62.
Background
The removal of high-abundance proteins from plasma is an efficient approach to investigating flow-through proteins for biomarker discovery studies. Most depletion methods are based on multiple immunoaffinity methods available commercially including LC columns and spin columns. Despite its usefulness, high-abundance depletion has an intrinsic problem, the sponge effect, which should be assessed during depletion experiments. Concurrently, the yield of depletion of high-abundance proteins must be monitored during the use of the depletion column. To date, there is no reasonable technique for measuring the recovery of flow-through proteins after depletion and assessing the capacity for capture of high-abundance proteins.
Results
In this study, we developed a method of measuring recovery yields of a multiple affinity removal system column easily and rapidly using enhanced green fluorescence protein as an indicator of flow-through proteins. Also, we monitored the capture efficiency through depletion of a high-abundance protein, albumin labeled with fluorescein isothiocyanate.
Conclusion
This simple method can be applied easily to common high-abundance protein depletion methods, effectively reducing experimental variations in biomarker discovery studies.
doi:10.1186/1477-5956-8-62
PMCID: PMC3012035  PMID: 21122139
22.  Selective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in mice 
Regulation of the formation and function of bone-resorbing osteoclasts (OCs) is a key to understanding the pathogenesis of skeletal disorders. Gene-targeting studies have shown that the RANK signaling pathway plays a critical role in OC differentiation and function. Although pharmaceutical blockade of RANK may be a viable strategy for preventing bone destruction, RANK is implicated in multiple biological processes. Recently, a cytoplasmic motif of RANK was identified that may be specifically involved in OC differentiation. Here, we developed a cell-permeable inhibitor termed the RANK receptor inhibitor (RRI), which targets this motif. The RRI peptide blocked RANKL-induced OC formation from murine bone marrow–derived macrophages. Furthermore, RRI inhibited the resorptive function of OCs and induced OC apoptosis. Treatment with the peptide impaired downstream signaling of RANK linked to Vav3, Rac1, and Cdc42 and resulted in disruptions of the actin cytoskeleton in differentiated OCs. In addition, RRI blocked inflammation-induced bone destruction and protected against ovariectomy-induced bone loss in mice. These data may be useful in the development of selective therapeutic agents for the treatment of osteoporosis and other bone diseases.
doi:10.1172/JCI36809
PMCID: PMC2662555  PMID: 19258703
23.  Glyceraldehyde-3-phosphate Dehydrogenase is a Cellular Target of the Insulin Mimic Demethylasterriquinone B1 
Journal of medicinal chemistry  2007;50(15):3423-3426.
This study was undertaken to identify cellular proteins that bind an orally active natural product insulin mimic. Phage display cloning was used with a biotinylated derivative of this molecule as bait. Among the proteins identified was glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which has recently been shown to affect insulin receptor signaling. Binding data support a role for human GAPDH as another target of the insulin mimic, which could explain its action as a selective insulin receptor modulator.
doi:10.1021/jm070437i
PMCID: PMC2556249  PMID: 17595071
25.  Extracting unrecognized gene relationships from the biomedical literature via matrix factorizations 
BMC Bioinformatics  2007;8(Suppl 9):S6.
Background
The construction of literature-based networks of gene-gene interactions is one of the most important applications of text mining in bioinformatics. Extracting potential gene relationships from the biomedical literature may be helpful in building biological hypotheses that can be explored further experimentally. Recently, latent semantic indexing based on the singular value decomposition (LSI/SVD) has been applied to gene retrieval. However, the determination of the number of factors k used in the reduced rank matrix is still an open problem.
Results
In this paper, we introduce a way to incorporate a priori knowledge of gene relationships into LSI/SVD to determine the number of factors. We also explore the utility of the non-negative matrix factorization (NMF) to extract unrecognized gene relationships from the biomedical literature by taking advantage of known gene relationships. A gene retrieval method based on NMF (GR/NMF) showed comparable performance with LSI/SVD.
Conclusion
Using known gene relationships of a given gene, we can determine the number of factors used in the reduced rank matrix and retrieve unrecognized genes related with the given gene by LSI/SVD or GR/NMF.
doi:10.1186/1471-2105-8-S9-S6
PMCID: PMC2217664  PMID: 18047707

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