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1.  Improving Bladder Cancer Imaging Using 3T Functional Dynamic Contrast-Enhanced MRI 
Investigative radiology  2014;49(6):390-395.
Objectives
To assess the capability of T2-weighted MRI (T2W-MRI) and the additional diagnostic value of Dynamic Contrast-Enhanced MRI (DCE-MRI) using multi-transmit 3T in the localization of bladder cancer.
Materials and Methods
This prospective study was approved by the local Institutional Review Board. Thirty–six patients were included in the study and provided informed consent. MRI scans were performed with T2W-MRI and DCE-MRI on a 3T multi-transmit system. Two observers (with 12 and 25 years of experience) independently interpreted T2W-MRI prior to DCE-MRI data (maps of pharmacokinetic parameters) to localize bladder tumors. The pathological examination of cystectomy bladder specimens was used as a reference gold standard. The McNemar test was performed to evaluate the differences in sensitivity, specificity, and accuracy. Kappa scores were calculated to assess interobserver agreement.
Results
The sensitivity, specificity, and accuracy of the localization with T2W-MRI alone were 81% (29/36), 63% (5/8) and 77% (34/44) for observer 1, and 72% (26/36), 63% (5/8), and 70% (31/44) for observer 2. With additional DCE-MRI available, these values were 92% (33/36), 75% (6/8), and 89% (39/44) for observer 1, and 92% (33/36), 63% (5/8), and 86% (38/44) for observer 2. DCE-MRI significantly (P < 0.01) improved the sensitivity and accuracy for observer 2. For the twenty-three patients treated with chemotherapy, DCE-MRI also significantly (P < 0.02) improved the sensitivity and accuracy of bladder cancer localization with T2W-MRI alone for observer 2. Kappa scores were 0.63 for T2W-MRI alone, and 0.78 for additional DCE-MRI. Out of seven sub-centimeter malignant tumors, four (57%) were identified on T2W images and six (86%) on DCE maps. Out of eleven malignant tumors within the bladder wall thickening, six (55%) were found on T2W images and ten (91%) on DCE maps.
Conclusions
Compared to conventional T2W-MRI alone, the addition of DCE-MRI improved interobserver agreement as well as the localization of small malignant tumors and those within bladder wall thickening.
doi:10.1097/RLI.0000000000000022
PMCID: PMC4326253  PMID: 24637583
3T MRI; DCE-MRI; bladder cancer localization; bladder wall thickening; sub-centimeter tumors
2.  Hypofractionated intensity modulated radiotherapy with temozolomide in newly diagnosed glioblastoma multiforme 
We conducted a phase I study to determine (a) the maximum tolerated dose of peri-radiation therapy temozolomide (TMZ) and (b) the safety of a selected hypofractionated intensity modulated radiation therapy (HIMRT) regimen in glioblastoma multiforme (GBM) patients. Patients with histological diagnosis of GBM, Karnofsky performance status (KPS)≥60 and adequate bone marrow function were eligible for the study. All patients received peri-radiation TMZ; 1 week before the beginning of radiation therapy (RT), 1 week after RT and for 3 weeks during RT. Standard 75 mg/m2/day dose was administered to all patients 1 week post-RT. Dose escalation was commenced at level I: 50 mg/m2/day, level II: 65 mg/m2/day and level III: 75 mg/m2/day for 4 weeks. HIMRT was delivered at 52.5 Gy in 15 fractions to the contrast enhancing lesion (or surgical cavity) plus the surrounding edema plus a 2 cm margin. Six men and three women with a median age of 67 years (range, 44–81) and a median KPS of 80 (range, 80–90) were enrolled. Three patients were accrued at each TMZ dose level. Median follow-up was 10 months (range, 1–15). Median progression free survival was 3.9 months (95% confidence interval [CI]: 0.9–7.4; range, 0.9–9.9 months) and the overall survival 12.7 months (95% CI: 2.5–17.6; range, 2.5–20.7 months). Time spent in a KPS ≥70 was 8.1 months (95% CI: 2.4–15.6; range, 2.4–16 months). No instance of irreversible grade 3 or higher acute toxicity was noted. HIMRT at 52.5 Gy in 15 fractions with peri-RT TMZ at a maximum tolerated dose of 75 mg/m2/day for 5 weeks is well tolerated and is able to abate treatment time for these patients.
doi:10.1016/j.jocn.2013.09.005
PMCID: PMC4299456  PMID: 24380758
Concurrent; Glioblastoma multiforme; Hypofractionated; Temozolomide
3.  Clinicopathologic predictors of recurrence and overall survival in adenoid cystic carcinoma of the head and neck: A single institutional experience at a tertiary care center 
Head & neck  2014;36(12):1705-1711.
Background
The purpose of this study was to determine factors that impact recurrence and long-term survival of head and neck adenoid cystic carcinoma (ACC).
Methods
We conducted a retrospective review of 87 patients with head and neck ACC who were evaluated between 1992 and 2009. Staining for Ki-67, p53, α-estrogen receptor (αER), and progesterone receptor (PR) was performed.
Results
Forty men (46%) and 47 women (54%) were included in this study. Median follow-up for patients was 98 months. Five-year recurrence-free and overall survival (OS) rates were 56% and 81%, respectively. Ki-67 and p53 expression was observed in 5 (6%) and 2 (2%) patients, respectively. αER and PR were all negative. The most important determinants of disease-free survival (DFS) were perineural invasion (PNI; p = .001) and female sex (p = .027). Disease site (major vs minor salivary gland) was the only predictor of worse OS on multivariate analysis.
Conclusion
Perineural invasion, female sex, and disease site were the most consistent predictors of poor outcome in head and neck ACC.
doi:10.1002/hed.23523
PMCID: PMC4299584  PMID: 24166847
adenoid cystic carcinomas; head and neck; prognostic factors; disease-free survival; overall survival
4.  Amide Proton Transfer MR Imaging of Prostate Cancer: A Preliminary Study 
Purpose
To evaluate the capability of amide proton transfer (APT) MR imaging for detection of prostate cancer that typically shows a higher tumor cell proliferation rate and cellular density leading to an MRI-detectable overall elevated mobile protein level in higher grade tumors.
Materials and Methods
Twelve patients with biopsy-proven prostate cancer were imaged on a 3 Tesla MR imaging system before prostatectomy. APT-MR images were acquired by means of a single-slice single-shot turbo spin echo sequence with a saturation prepulse preparation using 33 different frequency offsets (−8 to 8 ppm, interval 0.5 ppm). For quantification we used the APT ratio (APTR) based on the asymmetry of the magnetization transfer ratio at 3.5 ppm in respect to the water signal. Tumor and peripheral zone benign regions of interest (ROIs) were delineated based on whole mount pathology slides after prostatectomy.
Results
APTR in prostate cancer ROIs was 5.8% 6 3.2%, significantly higher than that in the peripheral zone benign regions (0.3% ± 3.2%, P = 0.002).
Conclusion
APT-MR imaging is feasible in prostate cancer detection and has the potential to discriminate between cancer and noncancer tissues.
doi:10.1002/jmri.22480
PMCID: PMC4287206  PMID: 21563248
amide proton transfer; chemical exchange saturation transfer; prostate cancer; mobile protein level; molecular imaging
5.  Characterization of BRCA1 Ring Finger Variants of Uncertain Significance 
The majority of pathogenic mutations in BRCA1 result in a truncated protein. Although most missense changes in BRCA1 are of unknown functional significance, a handful of deleterious missense mutations have been identified. The majority of these occur in splice sites or highly conserved protein domains. Previously, we developed a predictive model, VUS Predict, to classify BRCA variants of uncertain significance as neutral or deleterious. It uses evolutionary prediction algorithms together with clinical information from cancer pathology reports and BRCA genetic testing results. Because of the higher probability that missense changes occurring in conserved BRCA1 domains are of pathogenic significance, we identified all individuals in our cohort who had been tested for BRCA1 and BRCA2 mutations who had missense changes in the BRCA1 ring finger domain and sought to classify those changes. We applied VUS Predict to three previously uncharacterized variants and four missense changes known to be deleterious. Two variants, L22S and T37K, were predicted to be deleterious and one variant, K45Q, was predicted to be neutral by VUS Predict. The mutations C39R, C44Y, C44S and C61G were confirmed as deleterious.
doi:10.1007/s10549-009-0438-6
PMCID: PMC4283813  PMID: 19543972
BRCA1; variants of uncertain significance; ring finger domain; mutation characterization
6.  Effect of spleen operation on antiviral treatment in hepatitis C virus-related cirrhotic patients 
World Journal of Gastroenterology : WJG  2014;20(41):15387-15397.
AIM: To investigate the impact of spleen operation (SO) on interferon-α (IFN-α)-based antiviral treatment in patients with hepatitis C virus (HCV)-related cirrhosis.
METHODS: Studies were systematically identified by searching electronic databases including MEDLINE, Cochrane Library, Elsevier, and Embase up to September 30, 2013, and relevant clinical studies were reviewed. Sustained virological response (SVR) rate and adherence to therapy were taken as the endpoints of interest.
RESULTS: A total of 603 patients from 16 studies were included in the systematic review. Of 372 patients who underwent SO followed by antiviral treatment, the total SVR rate was 39.5%. SVR was associated with HCV genotypes 2/3 (OR = 10.84; 95%CI: 5.47-21.47; P < 0.00001). IFN-α dose needed to be reduced in 29.4%, and IFN-α-based therapy was discontinued in 11.5% of patients. Analysis of controlled studies showed that SVRs were achieved in 34.1% of patients with SO and 31.1% of patients without SO. SO had no effect on the SVR rate in cirrhotic patients with genotype 1 HCV infection (OR = 1.28; 95%CI: 0.51-3.22; P = 0.60), but improved the SVR rate in patients with genotypes 2/3 infection, though the difference was not significant (OR = 0.36; 95%CI: 0.13-1.02; P = 0.05).
CONCLUSION: SO combined with IFN-α-based antiviral therapy may be suitable in cirrhotic patients with genotypes 2/3 HCV infection, but not in those with genotype 1 infection.
doi:10.3748/wjg.v20.i41.15387
PMCID: PMC4223274  PMID: 25386089
Hepatitis C virus cirrhosis; Interferon, Ribavirin; Splenectomy; Partial splenic embolization
7.  Phenotypes of Th lineages generated by the commonly used activation with anti-CD3/CD28 antibodies differ from those generated by the physiological activation with the specific antigen 
Cellular & molecular immunology  2014;11(3):305-313.
T-helper (Th) lineages have been generated in vitro by activating CD4 cells with anti-CD3/CD28 antibodies during polarization. Physiologically, however, the generation of Th lineages is by activation with the specific antigen presented by antigen-presenting cells (APC). Here, we used TCR-transgenic mice to compare the phenotypes of Th1, Th9 and Th17 lineages when generated by either one of the two activation modes. Lineage Th cells specific against hen egg lysozyme (HEL), were adoptively transferred into recipient mice transgenically expressing HEL in their lens. Remarkable differences were found between lineages of Th1, Th9, or Th17, generated by either one of the two modes in their capacities to migrate to and proliferate in the recipient spleen and, importantly, to induce inflammation in the recipient mouse eyes. Substantial differences were also observed between the lineage pairs in their transcript expression profiles of certain chemokines and chemokine receptors. Surprisingly, however, close similarities were observed between the transcript expression profiles of lineages of the three phenotypes, activated by the same mode. Furthermore, Th cell lineages generated by the two activation modes differed considerably in their pattern of gene expression, as monitored by microarray analysis, but exhibited commonality with lineages of other phenotypes generated by the same activation mode. This study thus shows that (i) Th lineages generated by activation with anti-CD3/CD28 antibodies differ from lineages generated by antigen/APC and (ii) the mode of activation determines to a large extent the expression profile of major transcripts.
doi:10.1038/cmi.2014.8
PMCID: PMC4011984  PMID: 24583715
Eye; Inflammation; Microarray; T cell differentiation
8.  Oncolytic adenovirus encoding tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits the growth and metastasis of triple-negative breast cancer 
Cancer Biology & Therapy  2013;14(11):1016-1023.
Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising cancer therapeutic target due to its selective apoptosis-inducing effect in cancer cells. To efficiently deliver TRAIL to the tumor cells, an oncolytic adenovirus (p55-hTERT-HRE-TRAIL) carrying the TRAIL coding sequence was constructed. In the present study, we aimed to investigate the effect of p55-hTERT-HRE-TRAIL on the growth and metastasis of triple-negative breast cancer (TNBC). We observed that infection of the recombinant adenovirus resulted in expression of TRAIL and massive cell death in a TNBC cell line MDA-MB-231. This effect is much weaker in MCF-10A, which is a normal breast cell line. Administration of P55-HTERT-HRE-TRAIL significantly reduced orthotopic breast tumor growth and extended survival in a metastatic model. Our results suggest the oncolytic adenovirus armed with P55-HTERT-HRE-TRAIL, which exhibited enhanced anti-tumor activity and improved survival, is a promising candidate for virotherapy of TNBC.
doi:10.4161/cbt.26043
PMCID: PMC3925656  PMID: 24025362
tumor necrosis factor-related apoptosis inducing ligand (TRAIL); triple-negative breast cancer (TNBC); adenovirus; virotherapy
9.  Autoimmune and autoinflammatory mechanisms in uveitis 
Seminars in immunopathology  2014;36(5):581-594.
The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8+ T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders.
doi:10.1007/s00281-014-0433-9
PMCID: PMC4186974  PMID: 24858699
Uveitis; Autoimmunity; Autoinflammation; Macrophages; T lymphocytes; Immunotherapy
10.  Negative Regulation of Hif1a Expression and TH17 Differentiation by Hypoxia Regulated miR-210 
Nature immunology  2014;15(4):393-401.
MicroRNA-210 (miR-210) is a signature microRNA of hypoxia. We found robust increase (>100-fold) of miR-210 abundance in activated T cells, especially in the TH17 lineage. Hypoxia synergized with T cell receptor (TCR)–CD28 stimulation to accelerate and increase the magnitude of Mir210 expression. Mir210 was directly regulated by HIF-1α, a key regulator of TH17 polarization. Surprisingly, Hif1a was identified as a miR-210-target, suggesting negative-feedback by miR-210 to inhibit HIF-1α protein expression. Deletion of Mir210 promoted TH17 differentiation under conditions with limited oxygen. In experimental colitis, miR-210 reduced Hif1a transcript abundance, reduced the proportion of cells producing inflammatory cytokines and controlled disease severity. Our study identifies miR-210 as an important regulator of T cell differentiation in hypoxia, which can limit immunopathology.
doi:10.1038/ni.2846
PMCID: PMC3996831  PMID: 24608041
11.  Transcription factor Achaete-Scute homologue 2 initiates T follicular helper cell development 
Nature  2014;507(7493):513-518.
In immune responses, activated T cells migrate to B cell follicles and develop to T follicular helper (Tfh) cells, a new subset of CD4+ T cells specialized in providing help to B lymphocytes in the induction of germinal centers 1,2. Although Bcl6 has been shown to be essential in Tfh cell function, it may not regulate the initial migration of T cells 3 or the induction of Tfh program as exampled by C-X-C chemokine receptor type 5 (CXCR5) upregulation 4. Here, we show that Achaete-Scute homologue 2 (Ascl2), a basic helix-loop-helix (bHLH) transcription factor 5, is selectively upregulated in its expression in Tfh cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6 and downregulates C-C chemokine receptor 7 (CCR7) expression in T cells in vitro and accelerates T cell migration to the follicles and Tfh cell development in vivo. Genome-wide analysis indicates that Ascl2 directly regulates Tfh-related genes while inhibits expression of Th1 and Th17 genes. Acute deletion of Ascl2 as well as blockade of its function with the Id3 protein in CD4+ T cells results in impaired Tfh cell development and the germinal center response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances Tfh cell generation. Thus, Ascl2 directly initiates Tfh cell development.
doi:10.1038/nature12910
PMCID: PMC4012617  PMID: 24463518
12.  Finding Candidate Drugs for Hepatitis C Based on Chemical-Chemical and Chemical-Protein Interactions 
PLoS ONE  2014;9(9):e107767.
Hepatitis C virus (HCV) is an infectious virus that can cause serious illnesses. Only a few drugs have been reported to effectively treat hepatitis C. To have greater diversity in drug choice and better treatment options, it is necessary to develop more drugs to treat the infection. However, it is time-consuming and expensive to discover candidate drugs using experimental methods, and computational methods may complement experimental approaches as a preliminary filtering process. This type of approach was proposed by using known chemical-chemical interactions to extract interactive compounds with three known drug compounds of HCV, and the probabilities of these drug compounds being able to treat hepatitis C were calculated using chemical-protein interactions between the interactive compounds and HCV target genes. Moreover, the randomization test and expectation-maximization (EM) algorithm were both employed to exclude false discoveries. Analysis of the selected compounds, including acyclovir and ganciclovir, indicated that some of these compounds had potential to treat the HCV. Hopefully, this proposed method could provide new insights into the discovery of candidate drugs for the treatment of HCV and other diseases.
doi:10.1371/journal.pone.0107767
PMCID: PMC4166673  PMID: 25225900
13.  Sodium ferulate lowers portal pressure in rats with secondary biliary cirrhosis through the RhoA/Rho-kinase signaling pathway: A preliminary study 
Cirrhotic rats show higher expression levels of hepatic RhoA and Rho-kinase than normal healthy rats, and the activation of this signaling pathway leads to portal hypertension. Sodium ferulate (SF) has been shown to decrease the production of geranylgeranyl pyrophosphate (GGPP), a substance essential for RhoA activation. In the present study, to investigate the effects of SF on fibrosis, portal hypertension and the RhoA/Rho-kinase pathway, hepatic cirrhosis was induced in rats by bile duct ligation. Liver function and fibrogenesis-related biochemical parameters, the hepatic hydroxyproline content, the pathological characteristics of the liver sections and the levels of hepatic α-smooth muscle actin (α-SMA; by immunohistochemistry) were analyzed to assess effects of SF on hepatic fibrosis. In addition, hepatic RhoA, Rho-kinase and endothelial nitric oxide synthase (eNOS) expression was examined by immunohistochemistry. Apoptosis in the SF-treated and SF + GGPP-treated rat primary hepatic stellate cells (HSCs) and a human stellate cell line (LX-2) was examined by flow cytometry. Intrahepatic resistance and responsiveness to the α1-adrenoceptor agonist, methoxamine, were investigated by in situ liver perfusion. Treatment with SF did not affect fibrosis-related biochemical parameters or the hydroxyproline content; however, SF reduced the histological evidence of fibrosis and hepatocyte damage. The SF-treated rats had a significantly lower expression of α-SMA and Rho-kinase, as well as an increased hepatic eNOS content; however, SF did not affect RhoA expression. The SF-treated HSCs had a significantly increased apoptotic rate compared to the untreated rats. Following the addition of GGPP, the rate apoptotic rate decreased. SF reduced basal intrahepatic resistance and the responsiveness of hepatic vascular smooth muscle to methoxamine. Therefore, our data demonstrate that SF reduces fibrogenesis, decreases portal pressure in cirrhotic rats and inhibits the activation of the RhoA/Rho-kinase signaling pathway.
doi:10.3892/ijmm.2014.1905
PMCID: PMC4199412  PMID: 25174394
portal hypertension; sodium ferulate; cirrhosis; bile duct ligation; RhoA; Rho-kinase; methoxamine; endothelial nitric oxide synthase; fibrosis
14.  Specific Biomimetic Hydroxyapatite Nanotopographies Enhance Osteoblastic Differentiation and Bone Graft Osteointegration 
Tissue Engineering. Part A  2013;19(15-16):1704-1712.
Impaired healing of cortical bone grafts represents a significant clinical problem. Cadaveric bone grafts undergo extensive chemical processing to decrease the risk of disease transmission; however, these processing techniques alter the bone surface and decrease the osteogenic potential of cells at the healing site. Extensive work has been done to optimize the surface of bone grafts, and hydroxyapatite (HAP) and nanotopography both increase osteoblastic differentiation. HAP is the main mineral component of bone and can enhance osteoblastic differentiation and bone implant healing in vivo, while nanotopography can enhance osteoblastic differentiation, adhesion, and proliferation. This is the first study to test the combined effects of HAP and nanotopographies on bone graft healing. With the goal of identifying the optimized surface features to improve bone graft healing, we tested the hypothesis that HAP-based nanotopographic resurfacing of bone grafts improves integration of cortical bone grafts by enhancing osteoblastic differentiation. Here we show that osteoblastic cells cultured on processed bones coated with specific-scale (50–60 nm) HAP nanotopographies display increased osteoblastic differentiation compared to cells on uncoated bone, bones coated with poly-l-lactic acid nanotopographies, or other HAP nanotopographies. Further, bone grafts coated with 50–60-nm HAP exhibited increased formation of new bone and improved healing, with mechanical properties equivalent to live autografts. These data indicate the potential for specific HAP nanotopographies to not only increase osteoblastic differentiation but also improve bone graft incorporation, which could significantly increase patient quality of life after traumatic bone injuries or resection of an osteosarcoma.
doi:10.1089/ten.tea.2012.0560
PMCID: PMC3700012  PMID: 23510012
15.  A Phase I/II Study of Etanercept and Rituximab in Patients with Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma 
Leukemia  2009;23(5):912-918.
Rituximab has modest activity in relapsed Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) but is associated with TNF-α release that can cause CLL proliferation and inhibit apoptosis. We examined whether disruption of TNF-α by etanercept improves response to rituximab in CLL. Eligible patients had previously treated CLL with performance status 0–3. Patients received etanercept 25 mg subcutaneously twice weekly (weeks 1–5) and rituximab 375 mg/m2 intravenously thrice weekly (weeks 2–5) using a phase I/II design. Primary endpoints were response and toxicity. The 36 enrolled patients had a median of 2 prior treatments; 50% were fludarabine-refractory, and 22% had del(17p13.1). Of the 34 response-evaluable patients, ten (29%) responded, including 9 partial responses and 1 complete remission. Response was not affected by prior rituximab nor fludarabine-refractory status, but no patients with del(17p13.1) responded. Median PFS for responders was 9.0 months (range 1–43). Ten patients have had treatment-free intervals exceeding 12 months, including four who have remained untreated for 32, 43, 46 and 56 months. Adverse events were mild, including mild infusion reactions, transient cytopenias and grade 3 infections in 14%. The combination of etanercept and thrice weekly rituximab produces durable remissions in non-del(17p13.1) CLL patients and is well tolerated.
doi:10.1038/leu.2008.385
PMCID: PMC4099250  PMID: 19225537
Rituximab; Etanercept; chronic lymphocytic leukemia
16.  Genetic and Epigenetic Regulation in Age-related Macular Degeneration 
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the older population worldwide. While strong genetic risk factors have been associated with AMD etiology, environmental influences through epigenetic regulation are also likely to play a role. Recent advances in epigenetic studies have resulted in the development of numerous epigenetic drugs for the treatment of cancer and inflammation. Here, we review the current literature on the genetic and epigenetic mechanisms of AMD and suggest that understanding the cooperation of epigenetic and genetic mechanisms will greatly advance the clinical management of AMD.
PMCID: PMC3755470  PMID: 23997991
17.  The transcription factors Thpok and LRF are necessary and partly redundant for T helper cell differentiation 
Immunity  2012;37(4):622-633.
Summary
T helper (Th) cells are critical for defenses against infection and recognize peptides bound to Class II Major Histocompatibility Complex (MHC-II) molecules. Although transcription factors have been identified that direct helper cells into specific effector fates, whether a ‘master’ regulator controls the developmental program common to all Th cells remains unclear. Here we showed that the two transcription factors Thpok and LRF share this function. Although disruption of both factors did not prevent the generation of MHC II-specific T cells, these cells failed to express Th cell genes or undergo Th cell differentiation in vivo. In contrast, T cells lacking Thpok only displayed LRF-dependent functions and contributed to multiple effector responses, both in vitro and in vivo, with the notable exception of Th2 cell responses that control extra-cellular parasites. These findings identify the Thpok-LRF pair as a core node of Th cell differentiation and function.
doi:10.1016/j.immuni.2012.06.019
PMCID: PMC4050670  PMID: 23041065
18.  A phase I study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors 
Investigational new drugs  2012;31(3):685-695.
Summary
Purpose
Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G.
Experimental Design
Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m2 over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured.
Results
Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m2 (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome.
Conclusions
This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure.
doi:10.1007/s10637-012-9863-1
PMCID: PMC3646991  PMID: 22847785
Triapine; Gemcitabine; Phase I; Clinical Trial
19.  Overexpression of IL-17RC associated with ocular sarcoidosis 
Background
Sarcoidosis is a chronic inflammatory disease with a systemic granulomatous disorder affecting multiple organs including the eye. Both CD4+ T cell and macrophage have been linked to the pathogenesis of the disease.
Methods
The expression of IL-17RC was measured using FACS,immunohistochemistry and real-time PCR. Serum level of IL-17 was detected using ELISA.
Results
An elevated expression of IL-17RC on CD8+ T cells in peripheral blood was found in patients with ocular sarcoidosis as compared to healthy controls. Interestingly, we found a significant increase in the serum level of IL-17 in patients with ocular sarcoidosis as compared to healthy controls, which may be responsible for the induction of IL-17RC on CD8+ cells. In addition, IL-17RC appeared only in the retinal tissue of the patient with clinically active sarcoidosis.
Conclusions
Our results suggested a potential involvement of IL-17RC+CD8+ T cells in pathogenesis of ocular sarcoidosis.
doi:10.1186/1479-5876-12-152
PMCID: PMC4059456  PMID: 24885153
Ocular sarcoidosis; IL-17RC; CD8
20.  Autoimmune and autoinflammatory mechanisms in uveitis 
Seminars in Immunopathology  2014;36(5):581-594.
The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8+ T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders.
doi:10.1007/s00281-014-0433-9
PMCID: PMC4186974  PMID: 24858699
Uveitis; Autoimmunity; Autoinflammation; Macrophages; T lymphocytes; Immunotherapy
21.  Phenotypes of Th lineages generated by the commonly used activation with anti-CD3/CD28 antibodies differ from those generated by the physiological activation with the specific antigen 
Cellular and Molecular Immunology  2014;11(3):305-313.
T-helper (Th) lineages have been generated in vitro by activating CD4 cells with anti-CD3/CD28 antibodies during polarization. Physiologically, however, the generation of Th lineages is by activation with the specific antigen presented by antigen-presenting cells (APC). Here, we used T-cell receptor (TCR)-transgenic mice to compare the phenotypes of Th1, Th9 and Th17 lineages when generated by either one of the two activation modes. Lineage Th cells specific against hen egg lysozyme (HEL), were adoptively transferred into recipient mice transgenically expressing HEL in their lens. Remarkable differences were found between lineages of Th1, Th9 or Th17, generated by either one of the two modes in their capacities to migrate to and proliferate in the recipient spleen and, importantly, to induce inflammation in the recipient mouse eyes. Substantial differences were also observed between the lineage pairs in their transcript expression profiles of certain chemokines and chemokine receptors. Surprisingly, however, close similarities were observed between the transcript expression profiles of lineages of the three phenotypes, activated by the same mode. Furthermore, Th cell lineages generated by the two activation modes differed considerably in their pattern of gene expression, as monitored by microarray analysis, but exhibited commonality with lineages of other phenotypes generated by the same activation mode. This study thus shows that (i) Th lineages generated by activation with anti-CD3/CD28 antibodies differ from lineages generated by antigen/APC; and (ii) the mode of activation determines to a large extent the expression profile of major transcripts.
doi:10.1038/cmi.2014.8
PMCID: PMC4011984  PMID: 24583715
Eye; Inflammation; Microarray; T-cell differentiation
22.  Lipotoxic Effect of p21 on Free Fatty Acid-Induced Steatosis in L02 Cells 
PLoS ONE  2014;9(4):e96124.
Nonalcoholic fatty liver disease (NAFLD) is increasingly regarded as a hepatic manifestation of metabolic syndrome. Though with high prevalence, the mechanism is poorly understood. This study aimed to investigate the effects of p21 on free fatty acid (FFA)-induced steatosis in L02 cells. We therefore analyzed the L02 cells with MG132 and siRNA treatment for different expression of p21 related to lipid accumulation and lipotoxicity. Cellular total lipid was stained by Oil Red O, while triglyceride content, cytotoxicity assays, lipid peroxidation markers and anti-oxidation levels were measured by enzymatic kits. Treatment with 1 mM FFA for 48 hr induced magnificent intracellular lipid accumulation and increased oxidative stress in p21 overload L02 cells compared to that in p21 knockdown L02 cells. By increasing oxidative stress and peroxidation, p21 accelerates FFA-induced lipotoxic effect in L02 cells and might provide information about potentially new targets for drug development and treatments of NAFLD.
doi:10.1371/journal.pone.0096124
PMCID: PMC4005739  PMID: 24788149
23.  Intercellular Adhesion Molecule 1 Mediates Migration of Th1 and Th17 Cells Across Human Retinal Vascular Endothelium 
Purpose.
Autoimmune inflammation of the retina causes vision loss in the majority of affected individuals. Th1 or Th17 cells initiate the disease on trafficking from the circulation into the eye across the retinal vascular endothelium. We investigated the ability of human Th1- and Th17-polarized cells to cross a simulated human retinal endothelium, and examined the role of IgG superfamily members in this process.
Methods.
Th1- and Th17-polarized cell populations were generated from human peripheral blood CD4+ T cells, using two Th1- and Th17-polarizing protocols. Transendothelial migration assays were performed over 18 hours in Boyden chambers, after seeding the transwell membrane with human retinal endothelial cells. In some assays intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), or activated leukocyte cell adhesion molecule (ALCAM) blocking antibody, or isotype- and concentration-matched control antibody, was added to the upper chambers.
Results.
Th1- and Th17-polarized cells migrated equally efficiently across the human retinal endothelial monolayer. The percentage of IL-17+ IFN-γ− Th17-polarized cells was reduced following migration. Blocking ICAM-1, but not VCAM-1 or ALCAM, significantly reduced migration of Th1- and Th17-polarized cells for a majority of human donors.
Conclusions.
Taken in the context of other literature on transendothelial migration, our results illustrate the importance of investigating the specific tissue and vascular endothelium when considering helper T cell migration in autoimmune inflammation. Our findings further indicate that while generalizations about involvement of specific adhesion molecules in uveitis and other autoimmune disease may be possible, these may not apply to individual patients universally. The observations are relevant to the use of adhesion blockade for therapeutic purposes.
This work shows that human Th1- and Th17-polarized cells migrate equally efficiently across human retinal vascular endothelium, and that ICAM-1 is involved in coordinating the movement of both cell subsets.
doi:10.1167/iovs.13-12058
PMCID: PMC3808099  PMID: 24022011
uveitis; retina; endothelial cell; Th1 cell; Th17 cell
24.  Hepatitis C virus core antigen, an earlier and stronger predictor on sustained virological response in patients with genotype 1 HCV infection 
BMC Gastroenterology  2014;14:47.
Background
Earlier kinetics of serum HCV core antigen (HCVcAg) and its predictive value on sustained virological response (SVR) were investigated in patients with genotype 1 HCV infection during antiviral treatment.
Methods
In a multi-centered, randomized and positive drug-controlled phase IIb clinical trial on type Y peginterferon α-2b ( NCT01140997), forty-eight CHC patients who participated in pharmacokinetics were randomly divided into 4 cohorts and treated with PegIFNα (type Y peginterferon α-2b 90 μg, 135 μg, 180 μg and PegIFNα-2a 180 μg, respectively, once a week) and ribavirin (< 75 kg, 1000 mg daily and ≥ 75 kg, 1200 mg daily) for 48 weeks, and then followed up for 24 weeks. 32 patients infected with genotype 1 HCV and completed the whole process were included in this study. HCV RNAs were detected at baseline, and weeks 4, 12, 24, 48 and 72 using Cobas TaqMan. ARCHITECT HCVcAg was performed at 24, 48, 72, 96, 120 and 144 h in addition to the above time points. The receiver operating curves (ROCs) were performed to study the predictive values of HCVcAg decline on SVR.
Results
Following antiviral treatment, serum HCVcAg levels rapidly declined within the first week and correlated well with corresponding HCV RNA at baseline, weeks 4, 12, 24, 48 and 72 (rs = 0.969, 0.928, 0.999, 0.983, 0.985 and 0.946, respectively, P < 0.001). All of the areas under the receiver operating curves (AUROCs) were more than 0.80 and showed good predictive power on SVR at 24, 48, 72, 96, 120 and 144 h. The144 h was the best predictive time point of HCVcAg decline on SVR because of its largest AUROC (more than 0.90).
Conclusions
Early kinetics of serum HCVcAg predicts SVR very well in genotype 1 CHC patients during antiviral treatment, and its reduction value at 144 h is an earlier and stronger predictor on SVR than rapid virological response and early virological response. (TRN: NCT01140997).
doi:10.1186/1471-230X-14-47
PMCID: PMC3995626  PMID: 24625322
Hepatitis C; HCV core antigen; Antiviral treatment; Interferon-α
25.  The Role of Macrophage Class A Scavenger Receptors in a Laser-Induced Murine Choroidal Neovascularization Model 
Purpose.
Laser-induced choroidal neovascularization (CNV) is a widely used model to mimic many features of CNV resulting from wet AMD. Macrophages have been implicated in the pathogenesis of AMD. Class A scavenger receptors, scavenger receptor-A (SR-A) and macrophage receptor with collagenous domain (MARCO), are expressed on macrophages and are associated with macrophage function. The goal of this study is to examine the role of macrophage scavenger receptors in immune cell recruitment and the formation of CNV.
Methods.
Laser photocoagulation was performed in wild-type and knockout mice with deletion of SR-A (SR-A−/−), MARCO (MARCO−/−), or both SR-A and MARCO double knockout (DKO). Immune cell recruitment at different time points and CNV lesions at 14 days after laser treatment were evaluated through immunostaining and confocal microscopy. Microarray analysis was performed in eyes 1 day after laser injury.
Results.
Wild-type eyes showed higher chemokine/receptor expression compared with knockout eyes after laser injury. Scavenger receptor deficiency markedly impaired the recruitment of neutrophils and macrophages to CNV lesions at 1- and 3-days post laser injury, respectively. Significantly reduced CNV volumes were found in the eyes from scavenger receptor knockout mice compared with wild-type mice.
Conclusions.
The deficiency of scavenger receptors impairs the formation of CNV and immune cell recruitment. Our findings suggest a potential role for scavenger receptors in contributing to CNV formation and inflammation in AMD.
Class A scavenger receptor deficiency impairs immune cell recruitment and the formation of choroidal neovascularization (CNV). This suggests that scavenger receptors may contribute to CNV formation and inflammation seen in AMD.
doi:10.1167/iovs.12-11380
PMCID: PMC3771553  PMID: 23927892
AMD; CNV; macrophages; scavenger receptors

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