Johns Hopkins Singapore

Singapore, Singapore

Johns Hopkins Singapore

Singapore, Singapore
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Murray P.G.,University of Birmingham | Fan Y.,Chinese University of Hong Kong | Davies G.,University of Birmingham | Ying J.,Chinese University of Hong Kong | And 17 more authors.
American Journal of Pathology | Year: 2010

The malignant Hodgkin/Reed-Sternberg (HRS) cells of Hodgkin lymphoma (HL) are believed to derive from germinal center (GC) B cells, but lack expression of a functional B cell receptor. As apoptosis is the normal fate of B-cell receptor - negative GC B cells, mechanisms that abrogate apoptosis are thus critical in HL development, such as epigenetic disruption of certain pro-apoptotic cancer genes including tumor suppressor genes. Identifying methylated genes elucidates oncogenic mechanisms and provides valuable biomarkers; therefore, we performed a chemical epigenetic screening for methylated genes in HL through pharmacological demethylation and expression profiling. IGSF4/CADM1/TSLC1, a pro-apoptotic cell adhesion molecule of the immunoglobulin superfamily, was identified together with other methylated targets. In contrast to its expression in normal GC B cells, IGSF4 was down-regulated and methylated in HL cell lines, most primary HL, and microdissected HRS cells of 3/5 cases, but not in normal peripheral blood mononuclear cells and seldom in normal lymph nodes. We also detected IGSF4 methylation in sera of 14/18 (78%) HL patients but seldom in normal sera. Ectopic IGSF4 expression decreased HL cells survival and increased their sensitivity to apoptosis. IGSF4 induction that normally follows heat shock stress treatment was also abrogated in methylated lymphoma cells. Thus, our data demonstrate that IGSF4 silencing by CpG methylation provides an anti-apoptotic signal to HRS cells important in HL pathogenesis. Copyright © American Society for Investigative Pathology.

Low J.S.W.,Johns Hopkins Singapore | Low J.S.W.,National University of Singapore | Tao Q.,Johns Hopkins Singapore | Tao Q.,Sidney Kimmel Comprehensive Cancer Center | And 17 more authors.
Oncogene | Year: 2011

The critical 8p22 tumor suppressor deleted in liver cancer 1 (DLC1) is frequently inactivated by aberrant CpG methylation and/or genetic deletion and implicated in tumorigeneses of multiple tumor types. Here, we report the identification and characterization of its new isoform, DLC1 isoform 4 (DLC1-i4). This novel isoform encodes an 1125-aa (amino acid) protein with distinct N-terminus as compared with other known DLC1 isoforms. Similar to other isoforms, DLC1-i4 is expressed ubiquitously in normal tissues and immortalized normal epithelial cells, suggesting a role as a major DLC1 transcript. However, differential expression of the four DLC1 isoforms is found in tumor cell lines: Isoform 1 (longest) and 3 (short thus probably nonfunctional) share a promoter and are silenced in almost all cancer and immortalized cell lines, whereas isoform 2 and 4 utilize different promoters and are frequently downregulated. DLC1-i4 is significantly downregulated in multiple carcinoma cell lines, including 2/4 nasopharyngeal, 8/16 (50%) esophageal, 4/16 (25%) gastric, 6/9 (67%) breast, 3/4 colorectal, 4/4 cervical and 2/8(25%) lung carcinoma cell lines. The functional DLC1-i4 promoter is within a CpG island and is activated by wild-type p53. CpG methylation of the DLC1-i4 promoter is associated with its silencing in tumor cells and was detected in 38-100% of multiple primary tumors. Treatment with 5-aza-2′-deoxycytidine or genetic double knockout of DNMT1 and DNMT3B led to demethylation of the promoter and reactivation of its expression, indicating a predominantly epigenetic mechanism of silencing. Ectopic expression of DLC1-i4 in silenced tumor cells strongly inhibited their growth and colony formation. Thus, we identified a new isoform of DLC1 with tumor suppressive function. The differential expression of various DLC1 isoforms suggests interplay in modulating the complex activities of DLC1 during carcinogenesis. © 2011 Macmillan Publishers Limited All rights reserved.

PubMed | National University of Singapore and Johns Hopkins Singapore
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

217 Background: Recently Abiraterone (A) and Enzalutamide (E), new drugs with different novel mechanisms of action, have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC) based on the COU-AA-301 and AFFIRM phase III trials, after docetaxel failure. The lack of direct comparative trials has introduced a new treatment dilemma for the practicing oncologist: is one drug more effective than the other?We performed an indirect comparative effectiveness analysis between E and A using the results of the AFFIRM and COU-AA-301 pivotal trials. Due to the lack of study-to-study replication of comparisons, these indirect comparisons are subject to the assumption that the relative effects of each drug relative to placebo are the same across studies.1) Overall survival (OS)- the respective hazard ratios (95% confidence intervals {CI}) in the AFFIRM and COU-AA-301 trials for OS for E vs. placebo and A vs. placebo were 0.63 (0.53-0.75) and 0.66 (0.56-0.79). The indirect estimate of the hazard ratio (HR) (95% CI; p-value) for E vs. A was 0.96 (0.75-1.22; 0.72) 2) Time to PSA progression- the respective HR(95% CI) in the AFFIRM and COU-AA-301 trials for time to PSA progression for E vs. placebo and A vs. placebo were 0.25 (0.20-0.30) and 0.58 (0.46-0.73). The indirect estimate of the HR (95% CI; p-value) for E vs. A was 0.43 (0.32-0.58; 4.3 10In this indirect comparative effectiveness analysis, E appears to be more effective than A in terms of time to PSA progression, rPFS and PSA response. OS was not different.

Li L.,Chinese University of Hong Kong | Ying J.,Chinese University of Hong Kong | Ying J.,Peking Union Medical College | Li H.,Chinese University of Hong Kong | And 9 more authors.
Oncogene | Year: 2012

Genetic alterations of 16q21-q22, the locus of a 6-cadherin cluster, are frequently involved in multiple tumors, suggesting the presence of critical tumor suppressor genes (TSGs). Using 1 Mb array comparative genomic hybridization (aCGH), we refined a small hemizygous deletion (1 Mb) at 16q21-22.1, which contains a single gene Cadherin-11 (CDH11, OB-cadherin). CDH11 was broadly expressed in human normal adult and fetal tissues, while its silencing and promoter CpG methylation were frequently detected in tumor cell lines, but not in immortalized normal epithelial cells. Aberrant methylation was also frequently detected in multiple primary tumors. CDH11 silencing could be reversed by pharmacologic or genetic demethylation, indicating an epigenetic mechanism. Ectopic expression of CDH11 strongly suppressed tumorigenecity and induced tumor cell apoptosis. Moreover, CDH11 was found to inhibit Wnt/Β-catenin and AKT/Rho A signaling, as well as actin stress fiber formation, thus further inhibiting tumor cell migration and invasion. CDH11 also inhibited epithelial-to-mesenchymal transition and downregulated stem cell markers. Thus, our work identifies CDH11 as a functional tumor suppressor and an important antagonist of Wnt/Β-catenin and AKT/Rho A signaling, with frequent epigenetic inactivation in common carcinomas. © 2012 Macmillan Publishers Limited. All rights reserved.

Zachara N.E.,Johns Hopkins University | Molina H.,Johns Hopkins University | Wong K.Y.,Johns Hopkins Singapore | Pandey A.,Johns Hopkins University | Hart G.W.,Johns Hopkins University
Amino Acids | Year: 2011

The modification of nuclear, mitochondrial, and cytoplasmic proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) is a dynamic and essential post-translational modification of metazoans. Numerous forms of cellular injury lead to elevated levels of O-GlcNAc in both in vivo and in vitro models, and elevation of O-GlcNAc levels before, or immediately after, the induction of cellular injury is protective in models of heat stress, oxidative stress, endoplasmic reticulum (ER) stress, hypoxia, ischemia reperfusion injury, and trauma hemorrhage. Together, these data suggest that O-GlcNAc is a regulator of the cellular stress response. However, the molecular mechanism(s) by which O-GlcNAc regulates protein function leading to enhanced cell survival have not been identified. In order to determine how O-GlcNAc modulates stress tolerance in these models we have used stable isotope labeling with amino acids in cell culture to determine the identity of proteins that undergo O-GlcNAcylation in response to heat shock. Numerous proteins with diverse functions were identified, including NF-90, RuvB-like 1 (Tip49α), RuvB-like 2 (Tip49β), and several COPII vesicle transport proteins. Many of these proteins bind double-stranded DNA-dependent protein kinase (PK), or double-stranded DNA breaks, suggesting a role for O-GlcNAc in regulating DNA damage signaling or repair. Supporting this hypothesis, we have shown that DNA-PK is O-GlcNAc modified in response to numerous forms of cellular stress. © 2010 Springer-Verlag.

Verma A.,Tan Tock Seng Hospital | Lim A.Y.H.,Tan Tock Seng Hospital | Tai D.Y.H.,Tan Tock Seng Hospital | Goh S.K.,Johns Hopkins Singapore | And 4 more authors.
Medicine (United States) | Year: 2015

To study number of procedures and time to diagnose lung cancer and factors affecting the timeliness of clinching this diagnosis. Retrospective cohort study of lung cancer patients who consecutively underwent diagnostic bronchoscopy in 1 year (October 2013 to September 2014). Out of 101 patients diagnosed with lung cancer from bronchoscopy, average time interval between first abnormal computed tomogram (CT) scan-to-1st procedure, 1st procedure-to-diagnosis, and 1st abnormal CT scan-to-diagnosis was 1626, 1119, and 2733 days, respectively. These intervals were significantly longer in those requiring repeat procedures. Multivariate analysis revealed inconclusive 1st procedure to be the predictor of prolonged (30 days) CT scan to diagnosis time (P=0.04). Twenty-nine patients (28.7%) required repeat procedures (n=63). Reasons behind repeating the procedures were inadequate procedure (n=14), inaccessibility of lesion (n=9), inappropriate procedure (n=5), mutation analysis (n=2), and others (n=2). Fifty had visible endo-bronchial lesion, 20 had positive bronchus sign, and 83 had enlarged mediastinal/hilar lymph-nodes or central masses adjacent to the airways. Fewer procedures, and shorter procedure to diagnosis time, were observed in those undergoing convex probe endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) (P=0.04). Most patients exhibit enlarged mediastinal lymph node or mass adjacent to the central airway accessible by convex probe EBUS-TBNA. Hence, combining it with conventional bronchoscopic techniques such as bronchoalveolar lavage, brush, and forceps biopsy increases detection rate, and reduces number of procedures and time to establish diagnosis. This may translate into cost and resource savings, timeliness of diagnosis, greater patient satisfaction, and conceivably better outcomes. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

PubMed | Johns Hopkins Singapore
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

20662 Background: The efficacy and toxicity of Pemetrexed (P) in Asian patients is unknown.Retrospective review of patients treated with P in a single institution between July 2005 and November 2007. Medical records, radiologic and laboratory data were reviewed. RECIST were used to assess efficacy independently of the treating physicians assessment. National Cancer Institute CTCAE v3.0 were used for the description of adverse events.Forty-three patients received P: 37 had NSCLC and 6 had mesothelioma. Patients with NSCLC had a median age of 60 years (range, 45 to 89), and were predominantly male (29 men and 8 women), ethnic Chinese (32 patients) and smokers (22 patients). Histology was as follows: NSCLC, 19; adenocarcinoma, 12; squamous cell carcinoma, 4; bronchioalveolar and large cell, 1 each. Twenty-four patients had stage IV at diagnosis, 12 had stage III and 1 had stage II. All had received at least one prior regimen (median 1, range 1 to 4): Carboplatin and Gemcitabine, 21 patients; Carboplatin, Irinotecan and Paclitaxel, 9; Gefitinib, 9; Carboplatin and Paclitaxel, 6; Erlotinib, 2; Gemcitabine and Cisplatin, Single agent paclitaxel, Carboplatin and Docetaxel, Cisplatin and Etoposide, 1 patient each. Twenty-nine individuals had an ECOG PS of 0 or 1. Patients received a median of 2 cycles (total, 95; range 1 to 12). Grade 3 and 4 adverse events were as follows: anemia, 3 patients; pneumonia, 2 patients; neutropenic fever, 1 patient; thrombocytopenia, 1 patient. Five (14%) patients had an objective response (1 CR, 4 PR) and 13 (35%) had stable disease. Median Time to Treatment Failure was 8 weeks. Median overall survival was 80 weeks. The median age for patients with mesothelioma was 46.5 years (range 29 to 73). Five men and one woman (4 ethnic Chinese, 1 Indian and 1 Arab) received a median of 4 cycles (total 30, range 1 to 15) of Pemetrexed in combination with cisplatin. Three patients had a PR, 2 had SD and one had progressed at the time of first evaluation. Grade 3 and 4 toxicity was as follows: leukocytopenia, neutropenia, and thrombocytopenia, 1 patient.Pemetrexed is safe and active in the treatment of Asian patients with NSCLC and mesothelioma. [Table: see text].

PubMed | University of Porto, Federal University of São Paulo and Johns Hopkins Singapore
Type: Journal Article | Journal: Future oncology (London, England) | Year: 2016

Concomitant chemoradiotherapy (with cisplatin or carboplatin) is an option of definitive treatment for squamous head and neck cancer. We aimed to perform a meta-analysis comparing those two platinum agents.We carried out a systematic search on English literature between 1990 and 17 April 2015 according to the Cochrane review guidelines.Five of 60 studies fulfilled inclusion criteria with 491 patients. There was no difference in response rate. Cisplatin tends to be more active systemically than carboplatin, without statistically significance; 5-year survival rate: 30 and 27%, respectively (p = 0.33).Despite the trend to improved outcomes in using cisplatin, carboplatin is also active and can be a reasonable option to treat patients.

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