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1.  Metastatic Extramammary Paget's Disease of Scrotum Responds Completely to Single Agent Trastuzumab in a Hemodialysis Patient: Case Report, Molecular Profiling and Brief Review of the Literature 
Extramammary Paget's disease (EMPD) is a rare cancer. Although EMPD is usually noninvasive and treated with local therapy, once metastatic the prognosis of EMPD is poor and treatment options are limited. We report a case of a complete response to single agent trastuzumab in a hemodialysis patient with metastatic Her2/neu overexpressed EMPD of the scrotum. Molecular profiling of his case as well as 12 other EMPD and 8 mammary Paget disease (MPD) cases was completed and revealed multiple biomarker aberrations. Overexpression of Her2 was frequently noted (30%–40%) in both EMPD and MPD patients and when present can be effectively treated with Her2 targeted agents. Trastuzumab therapy can be safely utilized in a hemodialysis patient. In addition, multiple protein overexpression and loss were seen in EMPD including PD-1, PD-L1, PTEN, and AR as well as PIK3CA mutation. These findings may lead to possible therapeutic interventions targeting these pathways in a disease with few effective treatment options.
doi:10.1155/2015/895151
PMCID: PMC4322830
2.  Why summary comorbidity measures such as the Charlson Comorbidity Index and Elixhauser score work 
Medical care  2013;10.1097/MLR.0b013e318297429c.
Background
Comorbidity adjustment is an important component of health services research and clinical prognosis. When adjusting for comorbidities in statistical models, researchers can include comorbidities individually or through the use of summary measures such as the Charlson Comorbidity Index or Elixhauser score. We examined the conditions under which individual versus summary measures are most appropriate.
Methods
We provide an analytic proof of the utility of comorbidity summary measures when used in place of individual comorbidities. We compared the use of the Charlson and Elixhauser scores versus individual comorbidities in prognostic models using a SEER-Medicare data example. We examined the ability of summary comorbidity measures to adjust for confounding using simulations.
Results
We devised a mathematical proof that found that the comorbidity summary measures are appropriate prognostic or adjustment mechanisms in survival analyses. Once one knows the comorbidity score, no other information about the comorbidity variables used to create the score is generally needed. Our data example and simulations largely confirmed this finding.
Conclusions
Summary comorbidity measures, such as the Charlson Comorbidity Index and Elixhauser scores, are commonly used for clinical prognosis and comorbidity adjustment. We have provided a theoretical justification that validates the use of such scores under many conditions. Our simulations generally confirm the utility of the summary comorbidity measures as substitutes for use of the individual comorbidity variables in health services research. One caveat is that a summary measure may only be as good as the variables used to create it.
doi:10.1097/MLR.0b013e318297429c
PMCID: PMC3818341  PMID: 23703645
3.  Urethral Dysfunction in Female Mice with Estrogen Receptor β Deficiency 
PLoS ONE  2014;9(10):e109058.
Estrogen has various regulatory functions in the growth, development, and differentiation of the female urogenital system. This study investigated the roles of ERβ in stress urinary incontinence (SUI). Wild-type (ERβ+/+) and knockout (ERβ−/−) female mice were generated (aged 6–8 weeks, n = 6) and urethral function and protein expression were measured. Leak point pressures (LPP) and maximum urethral closure pressure (MUCP) were assessed in mice under urethane anesthesia. After the measurements, the urethras were removed for proteomic analysis using label-free quantitative proteomics by nano-liquid chromatography–mass spectrometry (LC-MS/MS) analysis. The interaction between these proteins was further analysed using MetaCore. Lastly, Western blot was used to confirm the candidate proteins. Compared with the ERβ+/+ group, the LPP and MUCP values of the ERβ−/− group were significantly decreased. Additionally, we identified 85 differentially expressed proteins in the urethra of ERβ−/− female mice; 57 proteins were up-regulated and 28 were down-regulated. The majority of the ERβ knockout-modified proteins were involved in cell-matrix adhesion, metabolism, immune response, signal transduction, nuclear receptor translational regelation, and muscle contraction and development. Western blot confirmed the up-regulation of myosin and collagen in urethra. By contrast, elastin was down-regulated in the ERβ−/− mice. This study is the first study to estimate protein expression changes in urethras from ERβ−/− female mice. These changes could be related to the molecular mechanism of ERβ in SUI.
doi:10.1371/journal.pone.0109058
PMCID: PMC4183540  PMID: 25275480
4.  Phase 2 Trial of Linifanib (ABT-869) in Patients with Advanced Renal Cell Cancer (RCC) after Sunitinib Failure 
Purpose
This study assessed the efficacy and safety of linifanib in patients with advanced renal cell carcinoma (RCC) who were previously treated with sunitinib.
Materials and Methods
This open-label, multicenter, phase 2 trial of oral linifanib 0.25 mg/kg/day enrolled patients who had prior nephrectomy and adequate organ function. The primary endpoint was objective response rate (ORR) per RECIST by central imaging. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and time to progression (TTP). Safety was also assessed.
Results
Fifty-three patients, median age 61 years (range 40–80) were enrolled (August 2007 to October 2008) across 12 North-American centers. Median number of prior therapies was two (range 1–4); 42 patients (81%) had clear-cell histology. ORR was 13.2%, median PFS was 5.4 months (95% CI: 3.6, 6.0) and TTP was the same; median OS was 14.5 months (95% CI: 10.8, 24.1). The most common treatment-related adverse events (AEs) were diarrhea (74%), fatigue (74%), and hypertension (66%), and the most common treatment-related Grade 3/4 AE was hypertension (40%).
Conclusions
Linifanib demonstrated clinically meaningful activity in patients with advanced RCC after sunitinib failure. At 0.25 mg/kg/day, significant dose modifications were required. An alternative, fixed-dosing strategy is being evaluated in other trials.
doi:10.1016/j.ejca.2011.09.002
PMCID: PMC4167844  PMID: 22078932
Renal cell carcinoma; sunitinib; ABT-869; VEGFR; angiogenesis inhibitors
5.  Cost Concerns of Patients With Cancer 
Journal of Oncology Practice  2013;9(5):251-257.
Cost concerns are common among patients with cancer who have health insurance. Health care providers may alleviate concerns by discussing cost-related concerns with all patients, not only those of lower socioeconomic status or those without insurance.
Purpose:
Health care providers are accustomed to identifying populations for whom cost-related concerns may be a significant barrier, such as the poor, but few empiric data have been collected to substantiate such assumptions, particularly among insured patients.
Methods:
Patients with cancer from academic and community hospitals completed a questionnaire that included closed-ended items concerning demographic variables, optimism, numeracy, and concerns about present and future medical costs. In addition, they answered open-ended questions regarding cost concerns and medical expenses.
Results:
Nearly all (99%) participants were insured. In response to the closed-ended questions, 30.3% of patients reported concern about paying for their cancer treatment, 22.3% reported that their family had made sacrifices to pay for their care, and 8.3% stated that their insurance adequately covered their current health care costs, and 17.3% reported concerns about coverage for their costs in the future. On open-ended questions, 35.3% reported additional expenses, and 47.5% reported concerns about health care costs. None of the assessed patient characteristics proved to be a robust predictor across all cost-related concerns. There was a strong association between the identification of concerns or expenses on the open-ended questions and concerns on closed-ended questions.
Conclusion:
Cost concerns are common among patients with cancer who have health insurance. Health care providers may alleviate concerns by discussing cost-related concerns with all patients, not only those of lower socioeconomic status or those without insurance. A closed-ended screening question may help to initiate these conversations. This may identify potential resources, lower distress, and enable patients to make optimal treatment decisions.
doi:10.1200/JOP.2013.000929
PMCID: PMC3770507  PMID: 23943901
6.  Cancer patients' trade-offs among efficacy, toxicity and out-of-pocket cost in the curative and non-curative setting 
Medical care  2013;51(9):10.1097/MLR.0b013e31829faffd.
Background
When making treatment decisions, cancer patients must make trade-offs among efficacy, toxicity and cost. However little is known about what patient characteristics may influence these trade-offs.
Methods
400 cancer patients reviewed two of three stylized curative and non-curative scenarios that asked them to choose between two treatments of varying levels of efficacy, toxicity and cost. Each scenario which included nine choice sets. Demographics, cost concerns, numeracy and optimism were assessed. Within each scenario, we used latent class methods to distinguish groups with discrete preferences. We then used regressions with group membership probabilities as covariates to identify associations.
Results
Median age was 61 years (range 27-90). 25% were enrolled at a community hospital. and 99% were insured. Three latent classes were identified that demonstrated 1) Preference for survival or aversion to 2) high cost or 3) toxicity. Across all scenarios, patients with higher income were more likely to be in the class that favored survival. Lower income patients were more likely to be in the class that was averse to high cost (p<.05). Similar associations were found between education, employment status, numeracy, cost concerns and latent class.
Conclusions
Even in these stylized scenarios, socioeconomic status (SES) predicted treatment choice. Higher income patients may be more likely to focus on survival while those of lower SES may be more likely to avoid expensive treatment, regardless of survival or toxicity. This raises the possibility that insurance plans with greater cost-sharing may have the unintended consequence of increasing disparities in cancer care.
doi:10.1097/MLR.0b013e31829faffd
PMCID: PMC3857689  PMID: 23872905
7.  Synergistic Effect of Vaginal Trauma and Ovariectomy in a Murine Model of Stress Urinary Incontinence: Upregulation of Urethral Nitric Oxide Synthases and Estrogen Receptors 
Mediators of Inflammation  2014;2014:314846.
The molecular mechanisms underlying stress urinary incontinence (SUI) are unclear. We aimed to evaluate the molecular alterations in mice urethras following vaginal trauma and ovariectomy (OVX). Twenty-four virgin female mice were equally distributed into four groups: noninstrumented control; vaginal distension (VD) group; OVX group; and VD + OVX group. Changes in leak point pressures (LPPs), genital tract morphology, body weight gain, plasma 17β-estradiol level and expressions of neuronal nitric oxide synthase (nNOS), induced nitric oxide synthase (iNOS), and estrogen receptors (ERs—ERα and ERβ) were analyzed. Three weeks after VD, the four groups differed significantly in genital size and body weight gain. Compared with the control group, the plasma estradiol levels were significantly decreased in the OVX and VD + OVX groups, and LPPs were significantly decreased in all three groups. nNOS, iNOS, and ERα expressions in the urethra were significantly increased in the VD and VD + OVX groups, whereas ERβ expression was significantly increased only in the VD + OVX group. These results show that SUI following vaginal trauma and OVX involves urethral upregulations of nNOS, iNOS, and ERs, suggesting that NO- and ER-mediated signaling might play a role in the synergistic effect of birth trauma and OVX-related SUI pathogenesis.
doi:10.1155/2014/314846
PMCID: PMC4166435  PMID: 25258476
8.  The Ubiquitin Ligase Stub1 Negatively Modulates Regulatory T cell Suppressive Activity by Promoting Degradation of the Transcription Factor Foxp3 
Immunity  2013;39(2):10.1016/j.immuni.2013.08.006.
SUMMARY
Regulatory T (Treg) cells suppress inflammatory immune responses and autoimmunity caused by self-reactive T cells. The key Treg cell transcription factor Foxp3 is downregulated during inflammation to allow for the acquisition of effector T cell-like functions. Here, we demonstrate that stress signals elicited by proinflammatory cytokines and lipopolysaccharide lead to the degradation of Foxp3 through the action of the E3 ubiquitin ligase Stub1. Stub1 interacted with Foxp3 to promote its K48-linked polyubiquitination in an Hsp70-dependent manner. Knockdown of endogenous Stub1 or Hsp70 prevented Foxp3 degradation. Furthermore, the overexpression of Stub1 in Treg cells abrogated their ability to suppress inflammatory immune responses in vitro and in vivo, and conferred a T helper 1 (Th1) cell-like phenotype. Our results demonstrate the critical role of the stress-activated Stub1-Hsp70 complex in promoting Treg cell inactivation, thus providing a potential therapeutic target for the intervention against autoimmune disease, infection and cancer.
doi:10.1016/j.immuni.2013.08.006
PMCID: PMC3817295  PMID: 23973223
9.  Time from Prior Chemotherapy Enhances Prognostic Risk Grouping in the Second-line Setting of Advanced Urothelial Carcinoma: A Retrospective Analysis of Pooled, Prospective Phase 2 Trials 
European urology  2012;63(4):717-723.
Background
Outcomes for patients in the second-line setting of advanced urothelial carcinoma (UC) are dismal. The recognized prognostic factors in this context are Eastern Cooperative Oncology Group (ECOG) performance status (PS) >0, hemoglobin level (Hb) <10 g/dl, and liver metastasis (LM).
Objectives
The purpose of this retrospective study of prospective trials was to investigate the prognostic value of time from prior chemotherapy (TFPC) independent of known prognostic factors. Design, setting, and participants: Data from patients from seven prospective trials with available baseline TFPC, Hb, PS, and LM values were used for retrospective analysis (n = 570). External validation was conducted in a second-line phase 3 trial comparing best supportive care (BSC) versus vinflunine plus BSC (n = 352).
Outcome measurements and statistical analysis
Cox proportional hazards regression was used to evaluate the association of factors, with overall survival (OS) and progression-free survival (PFS) being the respective primary and secondary outcome measures.
Results and limitations
ECOG-PS >0, LM, Hb <10 g/dl, and shorter TFPC were significant prognostic factors for OS and PFS on multivariable analysis. Patients with zero, one, two, and three to four factors demonstrated median OS of 12.2, 6.7, 5.1, and 3.0 mo, respectively (concordance statistic = 0.638). Setting of prior chemotherapy (metastatic disease vs perioperative) and prior platinum agent (cisplatin or carboplatin) were not prognostic factors. External validation demonstrated a significant association of TFPC with PFS on univariable and most multivariable analyses, and with OS on univariable analyses. Limitations of retrospective analyses are applicable.
Conclusions
Shorter TFPC enhances prognostic classification independent of ECOG-PS>0, Hb<10 g/ dl, and LM in the setting of second-line therapy for advanced UC. These data may facilitate drug development and interpretation of trials.
doi:10.1016/j.eururo.2012.11.042
PMCID: PMC4127896  PMID: 23206856
Urothelial carcinoma; Second line; Prognosis; Time from prior chemotherapy; Hemoglobin; Liver metastasis; Performance status
10.  Financial Distress in Cancer Patients 
Journal of medicine and the person  2013;11(2):10.1007/s12682-013-0152-3.
Novel diagnostic and therapeutic options offer hope to cancer patients with both localized and advanced disease. However, many of these treatments are often costly and even well-insured patients can face high out-of-pocket costs. Families may also be at risk of financial distress due to lost wages and other treatment-related expenses. Research is needed to measure and characterize financial distress in cancer patients and understand how it affects their quality of life. In addition, health care providers need to be trained to counsel patients and their families so they can make patient-centered treatment decisions that reflect their preferences and values.
doi:10.1007/s12682-013-0152-3
PMCID: PMC3859450  PMID: 24349677
11.  Effect of Flos carthami Extract and α1-Adrenergic Antagonists on the Porcine Proximal Ureteral Peristalsis 
Traditional Chinese medicine (TCM) has been proposed to prevent urolithiasis. In China, Flos carthami (FC, also known as Carthamus tinctorius) (Safflower; Chinese name: Hong Hua/紅花) has been used to treat urological diseases for centuries. We previously performed a screening and confirmed the in vivo antilithic effect of FC extract. Here, ex vivo organ bath experiment was further performed to study the effect of FC extract on the inhibition of phenylepinephrine (PE) (10−4 and 10−3 M) ureteral peristalsis of porcine ureters with several α1-adrenergic antagonists (doxazosin, tamsulosin, and terazosin) as experimental controls. The results showed that doxazosin, tamsulosin, and terazosin dose (approximately 4.5 × 10−6 − 4.5 × 10−1 μg/mL) dependently inhibited both 10−4 and 10−3 M PE-induced ureteral peristalsis. FC extract achieved 6.2% ± 10.1%, 21.8% ± 6.8%, and 24.0% ± 5.6% inhibitions of 10−4 M PE-induced peristalsis at doses of 5 × 103, 1 × 104, and 2 × 104 μg/mL, respectively, since FC extract was unable to completely inhibit PE-induced ureteral peristalsis, suggesting the antilithic effect of FC extract is related to mechanisms other than modulation of ureteral peristalsis.
doi:10.1155/2014/437803
PMCID: PMC4120800  PMID: 25170340
12.  Effects of Acanthopanax senticosus Polysaccharide Supplementation on Growth Performance, Immunity, Blood Parameters and Expression of Pro-inflammatory Cytokines Genes in Challenged Weaned Piglets 
To investigate the effect of dietary Acanthopanax senticosus polysaccharide (ASPS) on growth performance, immunity, blood parameters and mRNA expression of pro-inflammatory cytokines in immunologically challenged piglets, an experiment employing 2×2 factorial arrangement concerning dietary ASPS treatment (0 or 800 mg/kg) and immunological challenge (lipopolysaccharide [LPS] or saline injection) was conducted with 64 crossbred piglets (weaned at 28 d of age, average initial body weight of 7.25±0.21 kg) assigned to two dietary ASPS treatments with 8 replicates of 4 pigs each. Half of the piglets of per dietary treatment were injected with LPS or saline on d 14. Blood samples were obtained at 3 h after immunological injection on d 14 and piglets were slaughtered to obtain spleen samples on d 21. Dietary ASPS did not affect average daily gain (ADG) (p = 0.634), average daily feed intake (ADFI) (p = 0.655), and gain:feed (p = 0.814) prior to LPS challenge. After LPS challenge, for LPS-challenged pigs those fed ASPS had higher ADG and ADFI than the non-supplemented group (p<0.05), and an interaction between LPS×ASPS was observed on the two indices (p<0.05). Dietary ASPS improved lymphocyte proliferation among saline-injected and LPS-injected pigs (p<0.05). Interaction between LPS×ASPS was also revealed on lymphocyte proliferation (p<0.05). Circulatory concentration of IgG was influenced neither by ASPS (p = 0.803) or LPS (p = 0.692), nor their interaction (p = 0.289). Plasma concentration and spleen mRNA expression of interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF)-α were induced to increase (p<0.05) by LPS challenge, in contrast, these indices were decreased by dietary ASPS (p<0.05), and interactions were found on these cytokines (p<0.05). For LPS-challenged pigs, dietary ASPS also reduced the circulating concentration and spleen mRNA expression of IL-1β, IL-6 as well as TNF-α (p<0.05). The interaction between LPS×ASPS was also observed on the circulating concentration of insulin-like growth factor- I, α-acid glycoprotein (α-AGP), nonesterified fatty acid, and glucose (p<0.05). The results of this study demonstrate that dietary ASPS can modulate the release of pro-inflammatory cytokines during immunological challenge, which might enable piglets to achieve better growth performance.
doi:10.5713/ajas.2013.13659
PMCID: PMC4093559  PMID: 25050047
Herbal Extract; Stress; Growth; Cytokines; Metabolism; Weaned Pigs
13.  Hydrogen-Saturated Saline Protects Intensive Narrow Band Noise-Induced Hearing Loss in Guinea Pigs through an Antioxidant Effect 
PLoS ONE  2014;9(6):e100774.
The purpose of the current study was to evaluate hydrogen-saturated saline protecting intensive narrow band noise-induced hearing loss. Guinea pigs were divided into three groups: hydrogen-saturated saline; normal saline; and control. For saline administration, the guinea pigs were given daily abdominal injections (1 ml/100 g) 3 days before and 1 h before narrow band noise exposure (2.5–3.5 kHz 130 dB SPL, 1 h). The guinea pigs in the control group received no treatment. The hearing function was assessed by the auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) recording. The changes of free radicals in the cochlea before noise exposure, and immediately and 7 days after noise exposure were also examined. By Scanning electron microscopy and succinate dehydrogenase staining, we found that pre-treatment with hydrogen-saturated saline significantly reduced noise-induced hair cell damage and hearing loss. We also found that the malondialdehyde, lipid peroxidation, and hydroxyl levels were significantly lower in the hydrogen-saturated saline group after noise trauma, indicating that hydrogen-saturated saline can decrease the amount of harmful free radicals caused by noise trauma. Our findings suggest that hydrogen-saturated saline is effective in preventing intensive narrow band noise-induced hearing loss through the antioxidant effect.
doi:10.1371/journal.pone.0100774
PMCID: PMC4063935  PMID: 24945316
14.  The LRP6 rs2302685 polymorphism is associated with increased risk of myocardial infarction 
Background
Abnormal lipids is one of the critical risk factors for myocardial infarction (MI), however the role of genetic variants in lipid metabolism-related genes on MI pathogenesis still requires further investigation. We herein genotyped three SNPs (LRP6 rs2302685, LDLRAP1 rs6687605, SOAT1 rs13306731) in lipid metabolism-related genes, aimed to shed light on the influence of these SNPs on individual susceptibility to MI.
Methods
Genotyping of the three SNPs (rs2302685, rs6687605 and rs13306731) was performed in 285 MI cases and 650 control subjects using polymerase chain reaction–ligation detection reaction (PCR–LDR) method. The association of these SNPs with MI and lipid profiles was performed with SPSS software.
Results
Multivariate logistic regression analysis showed that C allele (OR = 1.62, P = 0.039) and the combined CT/CC genotype (OR = 1.67, P = 0.035) of LRP6 rs2302685 were associated with increased MI risk, while the other two SNPs had no significant effect. Further stratified analysis uncovered a more evident association with MI risk among younger subjects (≤60 years old). Fascinatingly, CT/CC genotype of rs2302685 conferred increased LDL-C levels compared to TT genotype (3.0 mmol/L vs 2.72 mmol/L) in younger subjects.
Conclusions
Our data provides the first evidence that LRP6 rs2302685 polymorphism is associated with an increased risk of MI in Chinese subjects, and the association is more evident among younger individuals, which probably due to the elevated LDL-C levels.
doi:10.1186/1476-511X-13-94
PMCID: PMC4059096  PMID: 24906453
LRP6; Single nucleotide polymorphism; Myocardial infarction; Risk
15.  Anti-angiogenesis in prostate cancer: knocked down but not out 
Asian Journal of Andrology  2014;16(3):372-377.
Angiogenesis is a very complex physiological process, which involves multiple pathways that are dependent on the homeostatic balance between the growth factors (stimulators and inhibitors). This tightly controlled process is stimulated by angiogenic factors, which are present within the tumor and surrounding tumor-associated stromal cells. The dependence of tumor propagation, invasion and metastasis on angiogenesis makes the inhibitors of new blood vessel formation attractive drugs for treating the malignancies. Angiogenesis can be disrupted by several distinct mechanisms: by inhibiting endothelial cells, by interrupting the signaling pathways or by inhibiting other activators of angiogenesis. This strategy has shown therapeutic benefit in several types of solid tumors, leading to Food and Drug Administration (FDA) approval of anti-angiogenic agents in the treatment of kidney, non-small cell lung, colon and brain cancers. Although no angiogenesis inhibitors have been approved for patients with metastatic prostate cancer, therapies that target new blood vessel formation are still an emerging and promising area of prostate cancer research.
doi:10.4103/1008-682X.125903
PMCID: PMC4023362  PMID: 24759579
angiogenesis; clinical trials; prostate cancer
16.  Reply to S. Buti and S. Culine 
Journal of Clinical Oncology  2013;31(12):1615-1616.
doi:10.1200/JCO.2012.47.8255
PMCID: PMC3625713  PMID: 23734370
17.  Epigenetic Regulation of TNFA Expression in Periodontal Disease 
Journal of periodontology  2013;84(11):1606-1616.
Background
Tumor necrosis factor-alpha (TNF-α) plays a central role in the molecular pathogenesis of periodontal disease. However, the epigenetic regulation attributable to microbial and inflammatory signals at the biofilm gingival interface are poorly understood. In this study, we investigated the DNA methylation alteration within the TNFA promoter in human gingival biopsies from different stages of periodontal disease, and explored the regulatory mechanism of TNFA transcription by DNA methylation.
Methods
Gingival biopsies were harvested from 17 chronic periodontitis patients and 18 subjects with periodontal health. Another 11 subjects participated in an experimentally induced gingivitis study, and gingival biopsies were collected at the baseline, induction, and resolution phase. To confirm that TNFA promoter methylation modulated TNFA transcription we treated THP.1 cells with a DNA methyltransferase inhibitor, 5-aza-2-deoxycytidine and used a RAW 294.7 cell line transfected with a TNFA promoter-specific luciferase reporter system with or without methlyaiton,
Results
In gingival biopsies from subjects with severe chronic periodontitis two individual CpG sites within the TNFA promoter (at -163bp and -161bp) displayed increased methylation in periodontitis samples as compared to gingival health (16.1±5.1% vs. 11.0±4.6%, p=0.02, 19.8±4.1% vs. 15.4±3.6%, p=0.04, respectively). The methylation level at -163bp was inversely associated with the transcription level of TNFA (p=0.018). However, no significant difference in the TNFA promoter methylation pattern was observed in samples biopsied during the induction or resolution phase of experimentally induced gingivitis, which represented a reversible periodontal lesion. THP.1 cells treated with 5-aza-2-deoxycytidine demonstrated a time-dependent increase in TNFA messenger level. We also found that the luciferase activity decreased 2.6 fold in a construct containing an in vitro methylated TNFA promoter as compared to the unmethylated insert (p=0.03).
Conclusion
Although the biopsy samples represented a mixed cell population, the change in promoter methylation status in chronic periodontal disease suggested that DNA methylation may be an important regulatory mechanism in controlling TNFA transcriptional expression in disease.
doi:10.1902/jop.2013.120294
PMCID: PMC3986590  PMID: 23368949
18.  CD4+CXCR5+ follicular helper T cells in salivary gland promote B cells maturation in patients with primary Sjogren’s syndrome 
Objective: To examine amount of CD4+CXCR5+Tfh cells and B cells subsets in salivary gland and peripheral blood from patients with primary Sjogren’s syndrome (pSS) and to analyze whether the frequency of CD4+CXCR5+Tfh cells is associated with pSS pathologic process. Methods: The percentages of CD4+CXCR5+Tfh cells and B cell subsets were examined by flow cytometry. B-lymphocyte chemoattraetant (BLC; also called CXCL13), IL-21, IL-6 from the serum of pSS patients was assessed by polymerase chain reaction–enzyme-linked immunosorbent assay (ELISA). Results: The percentages of CD4+CXCR5+Tfh cells in peripheral blood were increased in pSS patients, but decreased after treatment with glucocorticoid and/or immunosuppressive drugs. Abnormal B cell subsets appeared in salivary and peripheral blood of pSS patients. The frequency of salivary CD4+CXCR5+Tfh cells was positively correlated with CD19+CD27+ memory B cells and CD19+CD27high plasma cells. Also increase of salivary CD19+CD27high plasma cells was positively associated with serum ANA titer of pSS patients. Conclusions: CD4+CXCR5+Tfh cells are significantly increased in salivary and peripheral blood in pSS patients with aberrant CD19+CD27+ memory B cells and CD19+CD27high plasma cells, suggesting that CD4+CXCR5+Tfh cells may contribute to the pathogenesis of pSS by promoting the maturation of B cells.
PMCID: PMC4069915  PMID: 24966908
Sjogren’s syndrome; follicular helper T cell; B cell; germinal center
19.  Cloud computing for detecting high-order genome-wide epistatic interaction via dynamic clustering 
BMC Bioinformatics  2014;15:102.
Backgroud
Taking the advan tage of high-throughput single nucleotide polymorphism (SNP) genotyping technology, large genome-wide association studies (GWASs) have been considered to hold promise for unravelling complex relationships between genotype and phenotype. At present, traditional single-locus-based methods are insufficient to detect interactions consisting of multiple-locus, which are broadly existing in complex traits. In addition, statistic tests for high order epistatic interactions with more than 2 SNPs propose computational and analytical challenges because the computation increases exponentially as the cardinality of SNPs combinations gets larger.
Results
In this paper, we provide a simple, fast and powerful method using dynamic clustering and cloud computing to detect genome-wide multi-locus epistatic interactions. We have constructed systematic experiments to compare powers performance against some recently proposed algorithms, including TEAM, SNPRuler, EDCF and BOOST. Furthermore, we have applied our method on two real GWAS datasets, Age-related macular degeneration (AMD) and Rheumatoid arthritis (RA) datasets, where we find some novel potential disease-related genetic factors which are not shown up in detections of 2-loci epistatic interactions.
Conclusions
Experimental results on simulated data demonstrate that our method is more powerful than some recently proposed methods on both two- and three-locus disease models. Our method has discovered many novel high-order associations that are significantly enriched in cases from two real GWAS datasets. Moreover, the running time of the cloud implementation for our method on AMD dataset and RA dataset are roughly 2 hours and 50 hours on a cluster with forty small virtual machines for detecting two-locus interactions, respectively. Therefore, we believe that our method is suitable and effective for the full-scale analysis of multiple-locus epistatic interactions in GWAS.
doi:10.1186/1471-2105-15-102
PMCID: PMC4021249  PMID: 24717145
Cloud computing; Genome-wide association studies; Dynamic clustering
20.  Development of systemic lupus erythematosus in NZM 2328 mice in the absence of any single BAFF receptor 
Arthritis and rheumatism  2013;65(4):1043-1054.
Objective
To determine the necessity for any individual BAFF receptor in the development of SLE.
Methods
Bcma, Taci, and Br3 null mutations were introgressed into NZM 2328 mice. NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice were evaluated for lymphocyte phenotype and BAFF receptor expression by flow cytometry, B cell responsiveness to BAFF by in vitro culture, serum BAFF and total IgG and IgG anti-dsDNA levels by ELISA, renal immunopathology by immunofluorescence and histopathology, and clinical disease.
Results
NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice failed to surface-express BCMA, TACI, and BR3, respectively. Transitional and follicular B cells from NZM.Br3−/− mice were much less responsive to BAFF than the corresponding cells from wild-type (WT), NZM.Bcma−/−, or NZM.Taci−/− mice. In comparison to WT mice, NZM.Bcma−/− and NZM.Taci−/− mice harbored increased spleen B cells, T cells, and plasma cells (PC), whereas serum total IgG and IgG anti-dsDNA levels were similar. Despite their paucity of B cells, NZM.Br3−/− mice harbored increased T cells and WT-like numbers of PC and levels of IgG anti-dsDNA. Serum BAFF levels were increased in NZM.Taci−/− and NZM.Br3−/− mice but were decreased in NZM.Bcma−/− mice. Despite their phenotypic differences, renal immunopathology and clinical disease in NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice were at least as severe as in WT mice.
Conclusions
Any single BAFF receptor, including BR3, is dispensable to development of SLE in NZM mice. Development of disease in NZM.Br3−/− mice demonstrates that BAFF/BCMA and/or BAFF/TACI interactions contribute to SLE and that profound, life-long reduction in B cells does not guarantee protection from SLE.
doi:10.1002/art.37846
PMCID: PMC3618582  PMID: 23334904
21.  A Phase I Study of Temsirolimus and Bryostatin-1 in Patients With Metastatic Renal Cell Carcinoma and Soft Tissue Sarcoma 
The Oncologist  2014;19(4):354-355.
Background.
Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) complex 1, is approved for the treatment of metastatic renal cell carcinoma (RCC). Bryostatin-1 inhibits protein kinase C, a downstream effector of mTOR complex 2. We observed antitumor effects with the combination of temsirolimus and bryostatin-1 in RCC cell lines.
Methods.
Four cohorts of patients received weekly bryostatin-1 (20 μg/m2) with temsirolimus (10, 15, 25, or 37.5 mg) in 28-day cycles.
Results.
Thirty patients received a total of 138 cycles across four dose levels. Twenty-five patients had RCC (17 clear cell, 7 papillary, and 1 unclassified). Two sarcoma patients with prior cytotoxic therapy experienced dose-limiting toxicity at 15 mg of temsirolimus (grade 3 neutropenia and grade 3 hypophosphatemia). Subsequently, patients with prior cytotoxic therapy were excluded. Two additional dose-limiting toxicities were noted with 37.5 mg of temsirolimus (grade 3 neutropenia and grade 3 creatinine elevation). Consequently, the maximum tolerated dose was defined as temsirolimus at 25 mg and bryostatin-1 at 20 μg/m2 every 28 days. Of the 25 RCC patients, 3 patients had partial responses that lasted for 14 months, 28 months, and ≥80 months, respectively. Partial responses were seen in both clear cell and papillary histology.
Conclusion.
This combination of 37.5 mg of temsirolimus with 20 μg/m2 of bryostatin-1 was reasonably safe and well tolerated. Durable responses were observed in 3 of 25 patients with RCC.
doi:10.1634/theoncologist.2014-0020
PMCID: PMC3983829  PMID: 24674872
22.  Treatment of Stress Urinary Incontinence by Cinnamaldehyde, the Major Constituent of the Chinese Medicinal Herb Ramulus Cinnamomi 
Stress urinary incontinence (SUI) is a common disorder in middle-aged women and the elderly population. Although surgical treatment of SUI has progressed, pharmacological therapies remain unelucidated. We screened potential herbal medicines against SUI with an ex vivo organ bath assay. Ramulus Cinnamomi and its major constituent cinnamaldehyde cause a high contractile force of the urethra and a low contractile force of blood vessels. Cinnamaldehyde dose-dependently reduced lipopolysaccharide-induced nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells. In the vaginal distension- (VD-) induced SUI model in mice, cinnamaldehyde significantly reversed the VD-induced SUI physical signs and reduced blood pressure. Cinnamaldehyde may offer therapeutic potential against SUI without the possible side effect of hypertension. The modulation of several SUI-related proteins including myosin, iNOS, survival motor neuron (SMN) protein, and superoxide dismutase 3 (SOD3) may play some crucial roles in the therapeutic approach against SUI. This information may offer clues to the pathogenesis of SUI and open additional avenues for potential therapy strategies.
doi:10.1155/2014/280204
PMCID: PMC3966347  PMID: 24711852
23.  The Functional Influences of Common ABCB1 Genetic Variants on the Inhibition of P-glycoprotein by Antrodia cinnamomea Extracts 
PLoS ONE  2014;9(2):e89622.
Antrodia cinnamomea is a traditional healthy food that has been demonstrated to possess anti-inflammatory, antioxidative, and anticacer effects. The purpose of this study was to evaluate whether the ethanolic extract of A. cinnamomea (EEAC) can affect the efflux function of P-glycoprotein (P-gp) and the effect of ABCB1 genetic variants on the interaction between EEAC and P-gp. To investigate the mechanism of this interaction, Flp-In™-293 cells stably transfected with various genotypes of human P-gp were established and the expression of P-gp was confirmed by Western blot. The results of the rhodamine 123 efflux assay demonstrated that EEAC efficiently inhibited wild-type P-gp function at an IC50 concentration of 1.51±0.08 µg/mL through non-competitive inhibition. The IC50 concentrations for variant-type 1236T-2677T-3435T P-gp and variant-type 1236T-2677A-3435T P-gp were 5.56±0.49 µg/mL and 3.33±0.67 µg/mL, respectively. In addition, the inhibition kinetics of EEAC also changed to uncompetitive inhibition in variant-type 1236T-2677A-3435T P-gp. The ATPase assay revealed that EEAC was an ATPase stimulator and was capable of reducing verapamil-induced ATPase levels. These results indicate that EEAC may be a potent P-gp inhibitor and higher dosages may be required in subjects carrying variant-types P-gp. Further studies are required to translate this basic knowledge into clinical applications.
doi:10.1371/journal.pone.0089622
PMCID: PMC3934917  PMID: 24586917
24.  Use of Adjuvant Trastuzumab in Women with Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer by Race/Ethnicity and Education within the National Comprehensive Cancer Network 
Cancer  2012;119(4):839-846.
Purpose
Trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive breast cancer is highly efficacious yet costly and time-intensive, and few data are available about its utilization. We examined receipt and completion of adjuvant trastuzumab by race/ethnicity and education for women with HER2-positive disease.
Methods
Using the National Comprehensive Cancer Network (NCCN) Breast Cancer Outcomes Database, we identified 1,109 women diagnosed with stage I–III, HER2-positive breast cancer during September 2005 through December 2008 who were followed for ≥1 year. We assessed the association of race/ethnicity and education with receipt of trastuzumab, and among women who initiated trastuzumab, with completion of >270 days of therapy, using multivariable logistic regression.
Results
The cohort was 75% white, 8% black, and 9% Hispanic; 20% attained a high school degree or less. Most women (83%) received trastuzumab, with no significant differences by race/ethnicity or SES. Among women initiating trastuzumab, 73% of black women vs. 87% of white women (p=.007) and 70% of women with less than high school education vs. 90% of women with a college degree completed >270 days of therapy (p=.006). In adjusted analyses, black (vs. white) women and those without a high school degree (vs. college degree) had lower odds of completing therapy (odds ratio [OR]=.45, 95% confidence interval [CI]=.27–.74 and OR=0.27, 95% CI=.14–.51, respectively).
Conclusion
We observed differences in trastuzumab completion by race and educational attainment for women treated at NCCN centers. Efforts to assure appropriate utilization of trastuzumab and understand treatment barriers are needed and could lead to improved outcomes.
doi:10.1002/cncr.27831
PMCID: PMC3565006  PMID: 23011924
breast cancer; disparities; trastuzumab; race; socioeconomic status
25.  Advanced Imaging Modalities in Early Stage Breast Cancer: Preoperative Use in the United States Medicare Population 
Annals of surgical oncology  2012;20(1):102-110.
INTRODUCTION
Guidelines for breast cancer staging exist, but adherence remains unknown. This study evaluates patterns of imaging in early-stage breast cancer usually reserved for advanced disease.
METHODS
Surveillance Epidemiology and End Results data linked to Medicare claims from 1992–2005 were reviewed for stage I/II breast cancer patients. Claims were searched for preoperative performance of CT, PET, and bone scans, and brain MRIs (“advanced imaging”).
RESULTS
There were 67,874 stage I/II breast cancer patients; 18.8% (n=12,740) had preoperative advanced imaging. The proportion of patients having CTs, PET scans and brain MRIs increased from 5.7% to 12.4% (p<0.0001), 0.8% to 3.4% (p<0.0001) and 0.2% to 1.1% (p=0.008), respectively, from 1992–2005. Bone scans declined from 20.1% to 10.7% (p<0.0001). “Breast cancer” (174.x) was the only diagnosis code associated with 62.1% of PET scans, 37.7% of bone scans, 24.2% of CTs, and 5.1% of brain MRIs. ≥1 symptom or metastatic site was suggested for 19.6% of bone scans, 13.0% of CTs, 13.0% of PET scans and 6.2% of brain MRIs. Factors associated (p<0.05) with use of all modalities were urban setting, breast MRI and ultrasound. Breast MRI was the strongest predictor (p<0.0001) of bone scan (OR1.63, 95%CI 1.44–1.86), Brain MRI (OR1.74, 95%CI 1.15–2.63), CT (OR2.42, 95%CI 2.12–2.76), and PET (OR5.71, 95%CI 4.52–7.22).
CONCLUSION
Aside from bone scans, performance of advanced imaging is increasing in early-stage Medicare breast cancer patients, with limited rationale provided by coded diagnoses. In light of existing guidelines and increasing scrutiny about healthcare costs, greater reinforcement of current indications is warranted.
doi:10.1245/s10434-012-2571-4
PMCID: PMC3923372  PMID: 22878617

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