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Sabapathy K.,Humphrey Oei Institute of Cancer Research | Sabapathy K.,National University of Singapore
Progress in Molecular Biology and Translational Science | Year: 2012

The c-Jun-NH 2-terminal kinase (JNK) signaling pathway plays a critical role in regulating cell fate, being implicated in a multitude of diseases ranging from cancer to neurological and immunological/inflammatory conditions. Not surprisingly, therefore, it has been sought after for therapeutic intervention, and its inhibition has been shown to ameliorate many pathological conditions in experimental systems, paving the way for initial clinical trials. However, the fundamental problem in fully harnessing the potential provided by the JNK pathway has been the lack of specificity, due to the multiple JNK forms that are involved in multiple cellular processes in various cell types. Moreover, lack of sufficient knowledge of all JNK-interacting proteins and substrates has also hindered progress. This review will therefore focus on the role of the JNKs in human diseases and appraise the efforts to inhibit JNK signaling to ameliorate disease conditions, assessing potential challenges and providing insights into possible future directions to efficiently target this pathway for therapeutic use. © 2012 Elsevier Inc. Source

Hui K.M.,Humphrey Oei Institute of Cancer Research | Linn Y.C.,Singapore General Hospital
Journal of Biomedicine and Biotechnology | Year: 2010

Cytokine-induced killer (CIK) cells are polyclonal T effector cells generated when cultured under cytokine stimulation. CIK cells exhibit potent, non-MHC-restricted cytolytic activities against susceptible tumor cells of both autologous and allogeneic origins. Over the past 20 years, CIK cells have evolved from experimental observations into early clinical studies with encouraging preliminary efficacy towards susceptible autologous and allogeneic tumor cells in both therapeutic and adjuvant settings. This paper is our attempt to summarize the available published literature related to CIK cells. Looking into the future, we anticipate that the continuous therapeutic application of CIK cells will likely be developed along two major directions: overcoming the challenge to organize large prospective randomized clinical trials to define the roles of CIK cells in cancer immunotherapy and expanding its spectrum of cytotoxicity towards resistant tumor cells through experimental manipulations. © 2010 Y. C. Linn and K. M. Hui. Source

Huynh H.,Humphrey Oei Institute of Cancer Research
Expert Opinion on Emerging Drugs | Year: 2010

Importance of the field: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Although patients with early-stage disease have a good prognosis, there has been no effective therapy available for those with advanced disease. Despite the death risk of patients with advanced HCC being reduced with sorafenib therapy, many patients eventually turn out to be refractory to this therapy. Thus, treatment of HCC remains an urgent health concern. Areas covered in this review: Recent improvement in understanding the pathophysiology of HCC at the molecular level has fostered the development of molecular targeted therapies that specifically block the disrupted pathways. What the reader will gain: This review summarizes the preclinical and clinical data from 2004 to 2009 on the efficacy and safety of the emerging drug for the treatment of HCC, including small molecule inhibitors (erlotinib, sunitinib, sorafenib, vandetanib, cediranib, brivanib and dovitinib) and the rationale for combination therapies for patients with advanced HCC. Take home message: Understanding the mechanisms of action, safety and efficacy of these new agents and new methods of combining these drugs may help prolong overall survival of patients with HCC and reduce disease recurrence after surgery or ablative therapies. © 2010 Informa UK Ltd. Source

Slagle B.L.,Baylor College of Medicine | Andrisani O.M.,Purdue University | Bouchard M.J.,Drexel University | Lee C.G.L.,National University of Singapore | And 3 more authors.
Hepatology | Year: 2015

Chronic infection with hepatitis B virus (HBV) is a risk factor for developing hepatocellular carcinoma (HCC). The life cycle of HBV is complex and has been difficult to study because HBV does not infect cultured cells. The HBV regulatory X protein (HBx) controls the level of HBV replication and possesses an HCC cofactor role. Attempts to understand the mechanism(s) that underlie HBx effects on HBV replication and HBV-associated carcinogenesis have led to many reported HBx activities that are likely influenced by the assays used. This review summarizes experimental systems commonly used to study HBx functions, describes limitations of these experimental systems that should be considered, and suggests approaches for ensuring the biological relevance of HBx studies. © 2014 by the American Association for the Study of Liver Diseases. Source

Lal S.,Humphrey Oei Institute of Cancer Research
Pharmacogenomics Journal | Year: 2016

This study investigated the impact of ABCB5, ABCC5 and RLIP76 polymorphisms on doxorubicin pharmacokinetics in Asian breast cancer patients (N=62). Direct sequencing was performed to screen for previously identified ABCC5 polymorphisms as well as polymorphisms in the exons and exon–intron boundaries of ABCB5 and RLIP76 genes. Genotype–phenotype correlations were analyzed using Mann–Whitney U-test. The homozygous variant allele at the ABCC5 g.+7161G>A (rs1533682) locus was significantly associated with higher doxorubicin clearance (g.+7161AA vs g.+7161GG, CL/BSA (Lh-1m-2): 30.34 (25.41–33.60) vs 22.46 (15.04–49.4), P=0.04). Homozygosity for the reference allele at the ABCC5 g.-1679T>A locus was associated with significantly higher doxorubicinol exposure (g.-1679TT vs g.-1679TA, AUC0-∞/dose/BSA (hm-5): 15.48 (6.18–67.17) vs 8.88 (3.68–21.71), P=0.0001). No significant influence of the three newly identified ABCB5 polymorphisms (c.2T>C, c.343A>G and c.1573G>A) on doxorubicin pharmacokinetics was observed. No polymorphisms were identified in the RLIP76 gene. These findings suggest that ABCC5 polymorphisms may explain partially the interpatient variability in doxorubicin disposition.The Pharmacogenomics Journal advance online publication, 15 March 2016; doi:10.1038/tpj.2016.17. © 2016 Macmillan Publishers Limited Source

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