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Li J.,Erasmus Medical Center | Hernanda P.Y.,Wijaya Kusuma University of Surabaya | Bramer W.M.,Erasmus University Rotterdam | Peppelenbosch M.P.,Erasmus Medical Center | And 2 more authors.
PLoS ONE | Year: 2015

Several studies have reported that metformin can reduce the risk of hepatocellular carcinoma (HCC) in diabetes patients. However, the direct anti-HCC effects of metformin have hardly been studied in patients, but have been extensively investigated in animal models of HCC. We therefore performed a systematic review and meta-analysis of animal studies evaluating the effects of metformin on HCC. Methods We collected the relevant studies by searching EMBASE, Medline (OvidSP), Web of Science, Scopus, PubMed Publisher, and Google Scholar. Studies were included according to the following inclusion criteria: HCC, animal study, and metformin intervention. Study quality was assessed using SYRCLE's risk of bias tool. A meta-analysis was performed for the outcome measures: tumor growth (tumor volume, weight and size), tumor number and incidence. Results The search resulted in 573 references, of which 13 could be included in the review and 12 included in the meta-analysis. The study characteristics of the included studies varied considerably. Two studies used rats, while the others used mice. Only one study used female animals, nine used male, and three studies didn't mention the gender of animals in their experiments. The quality of the included studies was low to moderate based on the assessment of their risk of bias. The meta-analysis showed that metformin significantly inhibited the growth of HCC tumour (SMD -2.20[-2.96,-1.43]; n=16), but no significant effect on the number of tumors (SMD-1.05[-2.13,0.03]; n=5) or the incidence of HCC was observed (RR 0.62[0.33,1.16]; n=6). To investigate the potential sources of significant heterogeneities found in outcome of tumor growth (I2=81%), subgroup analyses of scales of growth measures and of types of animal models used were performed. Conclusion Metformin appears to have a direct anti-HCC effect in animal models. Although the intrinsic limitations of animal studies, this systematic review could provide an important reference for future preclinical animal trials of good quality and clinical development. Source

Sciortino R.,AusAID | Sciortino R.,Mahidol University | Marjadi B.,Wijaya Kusuma University of Surabaya
Reproductive Health Matters | Year: 2010

A case study of Muhammadiyah's Islamic charitable health services in the islands of Java and Sumatra, Indonesia, was undertaken in 2008, to assess the impact of privatization of health care on this socially-oriented service provider, especially in terms of access for the poor. Findings presented here relate primarily to the effects on Muhammadiyah's maternal and child health and contraceptive services. In order to survive and thrive amidst private and public competitors, Muhammadiyah's primary care units, mostly consisting of maternal and child health centres and maternity clinics, when not closed altogether, have been directed toward providing curative hospital services, and more expensive and sometimes unnecessary treatment. A shift in the patient population away from the poor has also occurred, as market pressures transform this charitable enterprise into a commercial one, prejudicing reproductive health care and reducing access for those most in need. An improved stewardship role by government is needed to regulate the private sector, along with serious thinking about the future of primary and preventive care and health promotion, including for comprehensive reproductive health care. The neglect of these core primary care elements in Indonesia may worsen as privatization proceeds and profit considerations become more pressing with increased competition. © 2010 Reproductive Health Matters. Source

Hernanda P.Y.,Erasmus Medical Center | Hernanda P.Y.,Wijaya Kusuma University of Surabaya | Chen K.,Erasmus Medical Center | Chen K.,Zhejiang Sci-Tech University | And 19 more authors.
Oncogene | Year: 2015

Further understanding of the molecular biology and pathogenesis of hepatocellular carcinoma (HCC) is crucial for future therapeutic development. SMAD4, recognized as an important tumor suppressor, is a central mediator of transforming growth factor beta (TGFB) and bone morphogenetic protein (BMP) signaling. This study investigated the role of SMAD4 in HCC. Nuclear localization of SMAD4 was observed in a cohort of 140 HCC patients using tissue microarray. HCC cell lines were used for functional assay in vitro and in immune-deficient mice. Nuclear SMAD4 levels were significantly increased in patient HCC tumors as compared with adjacent tissues. Knockdown of SMAD4 significantly reduced the efficiency of colony formation and migratory capacity of HCC cells in vitro and was incompatible with HCC tumor initiation and growth in mice. Knockdown of SMAD4 partially conferred resistance to the anti-growth effects of BMP ligand in HCC cells. Importantly, simultaneous elevation of SMAD4 and phosphorylated SMAD2/3 is significantly associated with poor patient outcome after surgery. Although high levels of SMAD4 can also mediate an antitumor function by coupling with phosphorylated SMAD1/5/8, this signaling, however, is absent in majority of our HCC patients. In conclusion, this study revealed a highly non-canonical tumor-promoting function of SMAD4 in HCC. The drastic elevation of nuclear SMAD4 in sub-population of HCC tumors highlights its potential as an outcome predictor for patient stratification and a target for personalized therapeutic development. © 2015 Macmillan Publishers Limited All rights reserved. Source

Chen K.,Erasmus Medical Center | Chen K.,Zhejiang Sci-Tech University | Cao W.,Erasmus Medical Center | Li J.,Erasmus Medical Center | And 9 more authors.
Molecular Medicine | Year: 2015

As uncontrolled cell proliferation requires nucleotide biosynthesis, inhibiting enzymes that mediate nucleotide biosynthesis constitutes a rational approach to the management of oncological diseases. In practice, however, results of this strategy are mixed and thus elucidation of the mechanisms by which cancer cells evade the effect of nucleotide biosynthesis restriction is urgently needed. Here we explored the notion that intrinsic differences in cancer cell cycle velocity are important in the resistance toward inhibition of inosine monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA). In short-term experiments, MPA treatment of fast-growing cancer cells effectively elicited G0/G1 arrest and provoked apoptosis, thus inhibiting cell proliferation and colony formation. Forced expression of a mutated IMPDH2, lacking a binding site for MPA but retaining enzymatic activity, resulted in complete resistance of cancer cells to MPA. In nude mice subcutaneously engrafted with HeLa cells, MPA moderately delayed tumor formation by inhibiting cell proliferation and inducing apoptosis. Importantly, we developed a lentiviral vector-based Tet-on label-retaining system that enables to identify, isolate and functionally characterize slow-cycling or so-called label-retaining cells (LRCs) in vitro and in vivo. We surprisingly found the presence of LRCs in fast-growing tumors. LRCs were superior in colony formation, tumor initiation and resistance to MPA as compared with fast-cycling cells. Thus, the slow-cycling compartment of cancer seems predominantly responsible for resistance to MPA. © 2015, Uninversity of Michigan. All rights reserved. Source

Witono Y.,University of Jember | Widjanarko S.B.,Brawijaya University | Mujianto,Wijaya Kusuma University of Surabaya | Rachmawati D.T.,Brawijaya University
International Journal on Advanced Science, Engineering and Information Technology | Year: 2015

The aims of this study was to investigate the amino acid (AAs) composition of over fermented tempeh (OFT), the hydrolysates and the seasoning product that hydrolyzed by calotropin from Calotropis gigantea. OFT was hydrolyzed by 0.15% calotropin at 55°C for 3 hours. The hydrolysates was mixed with 13.3% glucose; 13.3% salt, and 13.3% of caramelized sugar, and then boiled for 10 min to make the seasoning. AAs compositions of OFT, the hydrolysates of OFT (HOFT), and the seasoning product of OFT (SOFT) were identified by HPLC. Seventeen AAs have identified and computed. HOFT contained the highest AAs 377.71 mg/100 g, followed by OFT 136.14 mg/100 g and SOFT 60.22 mg/100 g. The highest amount of AAs in all samples was glutamic acid. These results indicate that the hydrolysis of OFT by calotropin increase the AAs compounds and can be applied as seasoning. Source

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