Genetic diversity of Streptococcus pneumoniae causing meningitis and sepsis in Singapore during the first year of PCV7 implementation

Streptococcus pneumoniae is a major cause of sepsis, meningitis and respiratory disease worldwide. Pneumococcal conjugate vaccines (PCVs) have now been implemented in many countries worldwide, including Singapore. To evaluate the effectiveness of these vaccines, pneumococcal surveillance studies are required. Detailed and unified pneumococcal epidemiology data are currently scarce in South East Asia. Thus, we present data on invasive pneumococcal (IPD) isolates from Singapore that could assist in evaluating the effectiveness of pneumococcal vaccine in Singapore. One hundred and fifty-nine invasive pneumococcal disease isolates were received by the National Public Health Laboratory in Singapore between June 2009 and August 2010. Isolates were characterized using serotyping and multilocus sequence typing. Twenty-four different serotypes were found, the most common of which were 19A, 3, 7F, 23F, 6B, 14, 8 and 19F (in rank order). One hundred and two sequence types were observed, of which 38 were novel due to new alleles or new combinations of already existing alleles. Based on the Simpson’s Index of Diversity, serotypes 3, 6B and 19A were the most genetically diverse. Novel sequence types were more prevalent among conjugate vaccine serotypes 3, 19F and 23F and non-conjugate vaccine serotype 8, serogroup 15 and in non-typable isolates. We have demonstrated considerable genetic diversity among invasive pneumococci before and during the widespread use of conjugate vaccines in Singapore. Approximately half of all novel IPD clones identified in this study were non-conjugate vaccine serotypes. Although PCVs would target the most common serotypes, the high genetic diversity in non-vaccine serotypes would require further surveillance studies

Characterization of the epigenetic modification patterns of pluripotent stem cell genes in human cancers

Poster Session B - abstractThe 1st AACR Special Conference on Stem Cells, Development, and Cancer, Vancouver, B.C., Canada, 3-6 March 2011

Seroprevalence of vaccine-preventable diseases among children and adolescents in Singapore: Results from the National Paediatric Seroprevalence Survey 2018

10.1016/j.ijid.2019.12.015International Journal of Infectious Diseases92234-24

A phase II study of the efficacy and safety of the combination therapy of the MEK inhibitor refametinib (BAY 86-9766) plus sorafenib for Asian patients with unresectable hepatocellular carcinoma

Purpose: There is an unmet need for treatment options in hepatocellular carcinoma (HCC). Sorafenib is currently the only approved systemic treatment for HCC. Refametinib, an oral, allosteric MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in vitro and in vivo. A phase II study evaluated efficacy and safety of refametinib plus sorafenib in Asian patients with HCC (NCT01204177). Experimental Design: Eligible patients received twice-daily refametinib 50 mg plus twice-daily sorafenib 200 mg (morning)/400 mg (evening), with dose escalation to sorafenib 400 mg twice daily from cycle 2 if no grade ≥2 hand-foot skin reaction, fatigue, or gastrointestinal toxicity occurred. Primary efficacy endpoint: disease control rate. Secondary endpoints: time to progression, overall survival, pharmacokinetic assessment, biomarker analysis, safety, and tolerability. Results: Of 95 enrolled patients, 70 received study treatment. Most patients had liver cirrhosis (82.9%) and hepatitis B viral infection (75.7%). Disease control rate was 44.8% (primary efficacy analysis; n = 58). Median time to progression was 122 days, median overall survival was 290 days (n = 70). Best clinical responders had RAS mutations; majority of poor responders had wild-type RAS. Most frequent drug-related adverse events were diarrhea, rash, aspartate aminotransferase elevation, vomiting, and nausea. Dose modifications due to adverse events were necessary in almost all patients. Conclusions: Refametinib plus sorafenib showed antitumor activity in patients with HCC and was tolerated at reduced doses by most patients. Frequent dose modifications due to grade 3 adverse events may have contributed to limited treatment effect. Patients with RAS mutations appear to benefit from refametinib/sorafenib combination. Clin Cancer Res; 20(23); 5976–85. ©2014 AAC

Gold(III) compound is a novel chemocytotoxic agent for hepatocellular carcinoma

Recently, a series of gold(III) meso-tetraarylporphyrins that are stable against demetallation in physiological conditions have been synthesized. In the present study, the antitumor effects of one of these compounds, gold(III) meso-tetraarylporphyrin 1a (gold-1a) was investigated in an orthotopic rat hepatocellular carcinoma (HCC) model as well as using a HCC cell line. The rat HCC model was induced by injection of rat hepatoma cells, McA-RH7777, into the left lobe of the liver. Seven days after tumor cell inoculation, gold-1a was injected directly into the tumor nodule at different doses, followed by the same doses via intraperitoneal injection twice a week. Gold-1a administration significantly prolonged the survival of HCC-bearing rats. Importantly, gold-la induced necrosis as well as apoptosis in the tumor tissues, but not in the normal liver tissues. Furthermore, gold-1a treatment neither caused significant drop in body weight of the rats nor affected plasma aspartate aminotransferase level. In the in vitro studies, we observed that gold-la treatment inhibited the proliferation of McA-RH7777 cells. Gold-1a upregulated genes that increase apoptosis, stabilize p53, decrease proliferation and downregulated genes playing roles in angiogenesis, invasion, and metabolism, as demonstrated by microarray. In particular, the compound upregulated 2 members of the growth arrest and DNA damage (Gadd) inducible gene family, Gadd34 and Gadd153. Suppression of Gadd34 and Gadd153 in McA-RH7777 cells by small hairpin RNA reduced the gold-1a-induced apoptosis and growth inhibition, indicating that gold-1a mediated its effects via upregulation of Gadd34 and Gadd153. Results from our study demonstrated that gold-1a might be a novel promising chemocytotoxic agent for treating HCC. © 2005 Wiley-Liss. Inc.link_to_OA_fulltex

Kringle 1 Domain of Human Hepatocyte Growth Factor (HGFK1) Inhibits the Growth and Metastasis of Hepatocellular Carcinoma in Rats

Objective: We have previously shown that recombinant protein of kringle 1 domain of human hepatocyte growth factor (HGFK1) inhibits the proliferation of bovine aortic endothelial (BAE) cells. Here we investigate the in vivo efficacy of long term expression of HGFK1 in cancer gene therapy for hepatocellular carcinoma (HCC) using the adenoassociated virus (serotype 2) carrying the HGFK1 gene (rAAV-HGFK1). Methods: Preclinical animal studies were conducted using an established orthotopic Buffalo rat HCC model. HCC was induced by injection of 1.0×106 rat hepatoma cells, McA-RH7777, into the left lobe of the liver. Ten days after tumor cell inoculation, surgeries were performed to confirm the tumor formation. Then rAAV-HGFKl (1.2×1012 v.p.), rAAV-EGFP (1.2×1012 v.p.) or PBS were injected directly into the tumor nodule (0.2×1012 v.p.) followed by portal vein (1.0×1012 v.p.) injection. Results: We first showed that infection by rAAV-HGFKl produced significant anti-angiogenesis effect as demonstrated by reduced proliferation and microvascular tube formation of mouse microvascular endothelial cells in vitro in the cell culture system. The in vivo efficacy of rAAV-HGFK1 was then evaluated in the rat model of HCC. Results from our study demonstrated for the first time that a long term expression of HGFK1 significantly prolonged the median survival rate of the HCC bearing rats from 30 days to 49 days. More importantly rAAV-HGFK1 inhibited tumor growth and completely prevented lung and peritoneal metastasis. Conclusion: Long term expression of HGFK1 might be a novel promising treatment for HCC and other cancers.link_to_subscribed_fulltex

Results of TRACER: a phase II randomized, double-blinded, multicenter Asian study investigating the combination of transcatheter arterial chemoembolization (TACE) and oral everolimus in localised unresectable hepatocellular carcinoma (HCC)

This journal suppl. entitled: The 7th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2016). Advancing HCC Management through Multi-Disciplinary Approach. Hong Kong, SAR (China), July 8-10, 2016: Abstract

The kringle 1 domain of hepatocyte growth factor has antiangiogenic and antitumor cell effects on hepatocellular carcinoma

The kringle 1 domain of human hepatocyte growth factor (HGFK1) was previously shown to inhibit bovine aortic endothelial cell proliferation, suggesting that it might be an antiangiogenic molecule. Here, we evaluated the in vivo efficacy of a recombinant adenoassociated virus carrying HGFK1 (rAAV-HGFK1) for the treatment of hepatocellular carcinoma (HCC) in a rat orthotopic HCC model and explored its molecular mechanisms in vitro in both endothelial and tumor cells. We first showed that rAAV-HGFK1 treatment significantly prolonged the survival time of rats transplanted with tumor cells. Treatment with rAAV-HGFK1 inhibited tumor growth, decreased tumor microvessel density, and completely prevented intrahepatic, lung, and peritoneal metastasis in this in vivo model. In vitro, rAAVHGFK1 exhibited both antiangiogenic and antitumor cell effects, inhibiting the proliferation of both murine microvascular endothelial cells (MEC) and tumor cells, and inducing apoptosis and G 0-G 1 phase arrest in these cells. To our surprise, rAAV-HGFK1 did not act through the hepatocyte growth factor/hepatocyte growth factor receptor pathway. Instead, it worked mainly through epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling, with more minor contributions from vascular endothelial growth factor/vascular endothelial growth factor receptor and β fibroblast growth factor (bFGF)/β fibroblast growth factor receptor (bFGFR) signaling. In both MECs and tumor cells, rAAV-HGFK1 acted through two pathways downstream of EGFR, namely inhibition of extracellular signal-regulated kinase activation and stimulation of p38 mitogen-activated protein kinase/c-Jun-NH 2-kinase activation. These results suggest for the first time that HGFK1 exerts both antiangiogenic and antitumor cell activities mainly through EGF/EGFR signaling, and may thus be considered as a novel therapeutic strategy for the treatment of HCC. ©2008 American Association for Cancer Research.link_to_OA_fulltex