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1.  Adiponectin Receptor Signaling on Dendritic Cells Blunts Antitumor Immunity 
Cancer research  2014;74(20):5711-5722.
Immune escape is a fundamental trait of cancer. Dendritic cells (DC) that interact with T cells represent a crucial site for the development of tolerance to tumor antigens, but there remains incomplete knowledge about how DC-tolerizing signals evolve during tumorigenesis. In this study, we show that DCs isolated from patients with metastatic or locally advanced breast cancer express high levels of the adiponectin receptors AdipoR1 and AdipoR2, which are sufficient to blunt antitumor immunity. Mechanistic investigations of ligand–receptor interactions on DCs revealed novel signaling pathways for each receptor. AdipoR1 stimulated IL10 production by activating the AMPK and MAPKp38 pathways, whereas AdipoR2 modified inflammatory processes by activating the COX-2 and PPARγ pathways. Stimulation of these pathways was sufficient to block activation of NF-κB in DC, thereby attenuating their ability to stimulate antigen-specific T-cell responses. Together, our findings reveal novel insights into how DC-tolerizing signals evolve in cancer to promote immune escape. Furthermore, by defining a critical role for adiponectin signaling in this process, our work suggests new and broadly applicable strategies for immunometabolic therapy in patients with cancer.
PMCID: PMC4314963  PMID: 25261236
2.  Aging and insulin signaling differentially control normal and tumorous germline stem cells 
Aging Cell  2014;14(1):25-34.
Aging influences stem cells, but the processes involved remain unclear. Insulin signaling, which controls cellular nutrient sensing and organismal aging, regulates the G2 phase of Drosophila female germ line stem cell (GSC) division cycle in response to diet; furthermore, this signaling pathway is attenuated with age. The role of insulin signaling in GSCs as organisms age, however, is also unclear. Here, we report that aging results in the accumulation of tumorous GSCs, accompanied by a decline in GSC number and proliferation rate. Intriguingly, GSC loss with age is hastened by either accelerating (through eliminating expression of Myt1, a cell cycle inhibitory regulator) or delaying (through mutation of insulin receptor (dinR) GSC division, implying that disrupted cell cycle progression and insulin signaling contribute to age-dependent GSC loss. As flies age, DNA damage accumulates in GSCs, and the S phase of the GSC cell cycle is prolonged. In addition, GSC tumors (which escape the normal stem cell regulatory microenvironment, known as the niche) still respond to aging in a similar manner to normal GSCs, suggesting that niche signals are not required for GSCs to sense or respond to aging. Finally, we show that GSCs from mated and unmated females behave similarly, indicating that female GSC–male communication does not affect GSCs with age. Our results indicate the differential effects of aging and diet mediated by insulin signaling on the stem cell division cycle, highlight the complexity of the regulation of stem cell aging, and describe a link between ovarian cancer and aging.
PMCID: PMC4326914  PMID: 25470527
aging; cell cycle; GSCs; IGF; tumor; tumor stem cell
3.  Genetic Polymorphisms of Metabolic Enzymes and the Pharmacokinetics of Indapamide in Taiwanese Subjects 
The AAPS Journal  2013;16(2):206-213.
To understand the genetic makeup and impact on pharmacokinetics (PK) in the Taiwanese population, we analyzed the pharmacogenetic (PG) profile and demonstrated its effects on enzyme metabolism using indapamide as an example. A multiplex mass spectrometry method was used to examine the single nucleotide polymorphism (SNP) profile of eight major phases I and II metabolic enzymes in 1,038 Taiwanese subjects. A PG/PK study was conducted in 24 healthy subjects to investigate the possible effects of 28 SNPs on drug biotransformation. Among the genetic profile analyzed, eight SNPs from CYP2A6, CYP2C19, CYP2D6, CYP2E1, CYP3A5, and UGT2B7 showed higher variant frequencies than those previously reported in Caucasians or Africans. For instance, we observed 14.7% frequency of the SNP rs5031016 (I471T) from CYP2A6 in Taiwanese, whereas 0% variation was reported in Caucasians and Africans. The PG/PK study of indapamide demonstrated that the polymorphic SNPs CYP2C9 rs4918758 and CYP2C19 rs4244285 appeared to confer lowered enzyme activity, as indicated by increased Cmax (25% ∼ 64%), increased area under the plasma level-time curves (30∼76%), increased area under the time infinity (43% ∼ 80%), and lower apparent clearance values than PK for wild-type indapamide. Our results reinforce the biochemical support of CYP2C19 in indapamide metabolism and identify a possible new participating enzyme CYP2C9. The PG/PK approach contributed toward understanding the genetic makeup of different ethnic groups and associations of enzymes in drug metabolism. It could be used to identify two genetic markers that enable to differentiate subjects with varied PK outcomes of indapamide.
PMCID: PMC3933584  PMID: 24357089
indapamide; metabolic enzymes; pharmacogenetics; pharmacokinetics; SNPs
4.  Notch Signaling Mediates the Age-Associated Decrease in Adhesion of Germline Stem Cells to the Niche 
PLoS Genetics  2014;10(12):e1004888.
Stem cells have an innate ability to occupy their stem cell niche, which in turn, is optimized to house stem cells. Organ aging is associated with reduced stem cell occupancy in the niche, but the mechanisms involved are poorly understood. Here, we report that Notch signaling is increased with age in Drosophila female germline stem cells (GSCs), and this results in their removal from the niche. Clonal analysis revealed that GSCs with low levels of Notch signaling exhibit increased adhesiveness to the niche, thereby out-competing their neighbors with higher levels of Notch; adhesiveness is altered through regulation of E-cadherin expression. Experimental enhancement of Notch signaling in GSCs hastens their age-dependent loss from the niche, and such loss is at least partially mediated by Sex lethal. However, disruption of Notch signaling in GSCs does not delay GSC loss during aging, and nor does it affect BMP signaling, which promotes self-renewal of GSCs. Finally, we show that in contrast to GSCs, Notch activation in the niche (which maintains niche integrity, and thus mediates GSC retention) is reduced with age, indicating that Notch signaling regulates GSC niche occupancy both intrinsically and extrinsically. Our findings expose a novel role of Notch signaling in controlling GSC-niche adhesion in response to aging, and are also of relevance to metastatic cancer cells, in which Notch signaling suppresses cell adhesion.
Author Summary
Aging is frequently associated with a decline in the size of stem cell pools, but little is known regarding the molecular mechanisms underlying this process. Here, we report that Notch signaling is increased in GSCs as they age, and this promotes their removal from the niche in an E-cadherin dependent manner. In contrast to GSCs, niche cells exhibit decreased Notch signaling with age; Notch signaling in these cells controls niche integrity, and consequently GSC retention. While Notch signaling in the niche is regulated by insulin signaling, Notch signaling in GSCs is controlled by Sex lethal, an RNA-binding protein. These results imply that Notch signaling is regulated in a cell-type-dependent manner, and coordination between GSCs and their niche facilitates the removal of cells from the niche during the aging process.
PMCID: PMC4270478  PMID: 25521289
5.  Effects of Maternal LPS Exposure during Pregnancy on Metabolic Phenotypes in Female Offspring 
PLoS ONE  2014;9(12):e114780.
It is increasingly recognized that intra-uterine growth restriction (IUGR) is associated with an increased risk of metabolic disorders in late life. Previous studies showed that mice exposed to LPS in late gestation induced fetal IUGR. The present study investigated the effects of maternal LPS exposure during pregnancy on metabolic phenotypes in female adult offspring. Pregnant mice were intraperitoneally injected with LPS (50 µg/kg) daily from gestational day (GD)15 to GD17. After lactation, female pups were fed with standard-chow diets (SD) or high-fat diets (HFD). Glucose tolerance test (GTT) and insulin tolerance test (ITT) were assessed 8 and 12 weeks after diet intervention. Hepatic triglyceride content was examined 12 weeks after diet intervention. As expected, maternal LPS exposure during pregnancy resulted in fetal IUGR. Although there was an increasing trend on fat mass in female offspring whose dams were exposed to LPS during pregnancy, maternal LPS exposure during pregnancy did not elevate the levels of fasting blood glucose and serum insulin and hepatic triglyceride content in female adult offspring. Moreover, maternal LPS exposure during pregnancy did not alter insulin sensitivity in adipose tissue and liver in female adult offspring. Further analysis showed that maternal LPS exposure during pregnancy did not exacerbate HFD-induced glucose tolerance and insulin resistance in female adult offspring. In addition, maternal LPS exposure during pregnancy did not aggravate HFD-induced elevation of hepatic triglyceride content in female adult offspring. In conclusion, LPS-induced IUGR does not alter metabolic phenotypes in adulthood.
PMCID: PMC4257726  PMID: 25479255
6.  Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application 
Through epithelial-mesenchymal transition (EMT), cancer cells acquire enhanced ability of migration and invasion, stem cell like characteristics and therapeutic resistance. Notch signaling regulates cell-cell connection, cell polarity and motility during organ development. Recent studies demonstrate that Notch signaling plays an important role in lung cancer initiation and cross-talks with several transcriptional factors to enhance EMT, contributing to the progression of non-small cell lung cancer (NSCLC). Correspondingly, blocking of Notch signaling inhibits NSCLC migration and tumor growth by reversing EMT. Clinical trials have showed promising effect in some cancer patients received treatment with Notch1 inhibitor. This review attempts to provide an overview of the Notch signal in NSCLC: its biological significance and therapeutic application.
PMCID: PMC4267749  PMID: 25477004
Notch signaling; Epithelial-mesenchymal transition (EMT); Cancer stem cells (CSCs); Non-small-cell lung cancer (NSCLC); Gamma secretase inhibitor
7.  Orally Administered Melatonin Prevents Lipopolysaccharide-Induced Neural Tube Defects in Mice 
PLoS ONE  2014;9(11):e113763.
Lipopolysaccharide (LPS) has been associated with adverse pregnant outcomes, including fetal demise, intra-uterine growth restriction (IUGR), neural tube defects (NTDs) and preterm delivery in rodent animals. Previous studies demonstrated that melatonin protected against LPS-induced fetal demise, IUGR and preterm delivery. The aim of the present study was to investigate the effects of melatonin on LPS-induced NTDs. All pregnant mice except controls were intraperitoneally injected with LPS (25 µg/kg) daily from gestational day (GD)8 to GD12. Some pregnant mice were orally administered with melatonin (MT, 50 mg/kg) before each LPS injection. A five-day LPS injection resulted in 27.5% of fetuses with anencephaly, exencephaly or encephalomeningocele. Additional experiment showed that maternal LPS exposure significantly down-regulated placental proton-coupled folate transporter (pcft) and disturbed folate transport from maternal circulation through the placentas into the fetus. Interestingly, melatonin significantly attenuated LPS-induced down-regulation of placental pcft. Moreover, melatonin markedly improved the transport of folate from maternal circulation through the placentas into the fetus. Correspondingly, orally administered melatonin reduced the incidence of LPS-induced anencephaly, exencephaly or encephalomeningocele. Taken together, these results suggest that orally administered melatonin prevents LPS-induced NTDs through alleviating LPS-induced disturbance of folate transport from maternal circulation through the placenta into the fetus.
PMCID: PMC4242665  PMID: 25420102
8.  Genetic characterization of Greek population isolates reveals strong genetic drift at missense and trait-associated variants 
Nature Communications  2014;5:5345.
Isolated populations are emerging as a powerful study design in the search for low-frequency and rare variant associations with complex phenotypes. Here we genotype 2,296 samples from two isolated Greek populations, the Pomak villages (HELIC-Pomak) in the North of Greece and the Mylopotamos villages (HELIC-MANOLIS) in Crete. We compare their genomic characteristics to the general Greek population and establish them as genetic isolates. In the MANOLIS cohort, we observe an enrichment of missense variants among the variants that have drifted up in frequency by more than fivefold. In the Pomak cohort, we find novel associations at variants on chr11p15.4 showing large allele frequency increases (from 0.2% in the general Greek population to 4.6% in the isolate) with haematological traits, for example, with mean corpuscular volume (rs7116019, P=2.3 × 10−26). We replicate this association in a second set of Pomak samples (combined P=2.0 × 10−36). We demonstrate significant power gains in detecting medical trait associations.
Isolated populations can increase power to detect low frequency and rare risk variants associated with complex phenotypes. Here, the authors identify variants associated with haematological traits in two isolated Greek populations that would be difficult to detect in the general population, due to their low frequency.
PMCID: PMC4242463  PMID: 25373335
9.  PRDI-BF1-RIZ domain of retinoblastoma protein-interacting zinc finger gene 1 induces apoptosis and exerts anticancer activity in esophageal squamous cell carcinoma cells 
Oncology Letters  2014;9(1):341-346.
The present study examined the role of the PRDI-BF1-RIZ (PR) domain of tumor suppressor retinoblastoma protein-interacting zinc finger gene 1 (RIZ1) as an anticancer domain and its ability to induce apoptosis in esophageal squamous cell carcinoma (ESCC) cells. The TE13 ESCC cell line was transfected with pcDNA3.1(+) eukaryotic expression vectors bearing the open reading frames of either the human RIZ1 gene or the PR domain, and the mRNA and protein expression levels were then detected using quantitative reverse transcription polymerase chain reaction and western blotting, respectively. The rate of apoptosis was determined by flow cytometry and the cell invasion ability was determined by an invasion assay. RIZ1 and the PR domain induced apoptosis and reduced the cell invasion ability (P<0.01). These findings indicate that the RIZ1 gene possesses anticancer activity in the PR domain, which may be important in inhibiting the development of ESCC.
PMCID: PMC4246629  PMID: 25435989
retinoblastoma protein-interacting zinc finger gene 1; PRDI-BF1-RIZ domain; esophageal squamous cell carcinoma
10.  Chiral Cationic Polyamines for Chiral Microcapsules and siRNA Delivery 
Bioorganic & medicinal chemistry letters  2013;23(21):10.1016/j.bmcl.2013.08.083.
PMCID: PMC3853371  PMID: 24035095
11.  Regional Variation of Distal Esophagus Distensibility Assessed Using the Functional Luminal Imaging Probe (FLIP) 
This study aimed to evaluate the spatial variation of esophageal distensibility in normal subjects using a novel multichannel functional luminal imaging probe (FLIP).
Ten healthy subjects (4 male, age 21–49 years) were evaluated during endoscopy with a high-resolution impedance planimetry probe (FLIP) positioned through the esophagogastric junction (EGJ) and distal 10cm of the esophageal body. Stepwise bag distensions using 5 ml increments from 0 to 60 mL were conducted and simultaneous measurements of cross-sectional area (CSA) and the associated intrabag pressure from each subject were analyzed using a customized MATLAB™ program. The distensibility along the esophagus was determined and compared between the EGJ and interval locations at 2–5 cm and 6–10 cm above the EGJ.
The pressure-CSA relationship was nearly linear among sites at lower pressures (0 to 7.5 mmHg) and reached a distension plateau at pressures ranging from 8 to 24 mmHg. The location of greatest distensibility was 4 cm above the EGJ. Although the CSAs of individual recording loci were not significantly different, there was a significant difference between the mean CSAs when comparing the region 2 to 5 cm proximal to EGJ to that 6 to 10 cm proximal to the EGJ.
There were significant regional differences in distensibility along the distal esophagus with lower values in the proximal part compared to more distal part. The greatest distensibility was noted to occur at about 4 cm above the EGJ in close proximity to the location of the contractile deceleration point and phrenic ampulla.
PMCID: PMC3793325  PMID: 23965159
cross-sectional area; esophageal distensibility; functional imaging; impedance planimetry
12.  Levenberg-Marquardt Method for the Eigenvalue Complementarity Problem 
The Scientific World Journal  2014;2014:307823.
The eigenvalue complementarity problem (EiCP) is a kind of very useful model, which is widely used in the study of many problems in mechanics, engineering, and economics. The EiCP was shown to be equivalent to a special nonlinear complementarity problem or a mathematical programming problem with complementarity constraints. The existing methods for solving the EiCP are all nonsmooth methods, including nonsmooth or semismooth Newton type methods. In this paper, we reformulate the EiCP as a system of continuously differentiable equations and give the Levenberg-Marquardt method to solve them. Under mild assumptions, the method is proved globally convergent. Finally, some numerical results and the extensions of the method are also given. The numerical experiments highlight the efficiency of the method.
PMCID: PMC4230238  PMID: 25530996
13.  Effect of carbon dioxide pneumoperitoneum on human renal cell carcinoma proliferation and metastasis in an orthotropic xenograft nude mouse model 
Archives of Medical Science : AMS  2014;10(5):1041-1046.
This study aimed to explore the effect of carbon dioxide (CO2) pneumoperitoneum on tumor proliferation and metastasis in an orthotropic xenograft nude mice model of human renal cell carcinoma (RCC) and evaluate the safety of CO2 pneumoperitoneum laparoscopy for treating RCC.
Material and methods
RCC 786-0 cells were injected to establish an orthotropic xenograft model. Fifty nude mice were given orthotropic inoculations and randomized to five groups: group A (control); group B (CO2 pneumoperitoneum for 2 h); group C (CO2 pneumoperitoneum for 4 h); group D (CO2 pneumoperitoneum for 4 h and 24 h after waking); group E (CO2 pneumoperitoneum for 4 h and 48 h after waking). The proliferation status was observed in RCC specimens by immunohistochemical staining for Ki67. The protein levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were examined by western blotting.
All groups showed similar Ki67-positive staining in RCC samples (p > 0.05). The relative expression of HIF-1α and VEGF gradually increased in both group B and group C, as compared with group A, but only the difference between group C and group A reached statistical significance (p < 0.05). The protein levels of HIF-1α and VEGF decreased in both group D and group E, as compared with group B and group C; however, the differences between group D, group E, and group A did not reach statistical significance (p > 0.05).
In an orthotropic xenograft nude mice model of RCC, CO2 pneumoperitoneum has no effect on expression of the cellular proliferation marker Ki67. However, CO2 pneumoperitoneum rapidly induces transient expression of HIF-1α and VEGF. Thus, CO2 pneumoperitoneum laparoscopy may be a safe method for treating RCC.
PMCID: PMC4223147  PMID: 25395958
carbon dioxide pneumoperitoneum; renal cell carcinoma; tumor proliferation; hypoxia-inducible factor-1α; vascular endothelial growth factor
14.  Low-Dose Chemotherapy of Hepatocellular Carcinoma through Triggered-Release from Bilayer-Decorated Magnetoliposomes 
Low-dose (LD) chemotherapy is a promising treatment strategy that may be improved by controlled delivery. Polyethylene glycol-stabilized bilayer-decorated magnetoliposomes (dMLs) have been designed as a stimuli-responsive LD chemotherapy drug delivery system and tested in vitro using Huh-7 hepatocellular carcinoma cell line. The dMLs contained hydrophobic superparamagnetic iron oxide nanoparticles within the lipid bilayer and doxorubicin hydrochloride (DOX, 2 µM) within the aqueous core. Structural analysis by cryogenic transmission electron microscopy and dynamic light scattering showed that the assemblies were approximately 120 nm in diameter. Furthermore, the samples consisted of a mixture of dMLs and bare liposomes (no nanoparticles), which provided dual burst and spontaneous DOX release profiles, respectively. Cell viability results show that the cytotoxicity of DOX-loaded dMLs was similar to that of bare dMLs (~10%), which indicates that spontaneous DOX leakage had little cytotoxic effect. However, when subjected to a physiologically acceptable radiofrequency (RF) electromagnetic field, cell viability was reduced up to 40% after 8 h and complete cell death was observed after 24 h. The therapeutic mechanism was intracellular RF-triggered DOX release from the dMLs and not intracellular hyperthermia due to nanoparticle heating via magnetic losses.
PMCID: PMC3995871  PMID: 24549047
magnetoliposome; SPIO nanoparticle; hepatocellular carcinoma; drug delivery; magnetic nanoparticle; stimuli responsive
15.  Maternal LPS Exposure during Pregnancy Impairs Testicular Development, Steroidogenesis and Spermatogenesis in Male Offspring 
PLoS ONE  2014;9(9):e106786.
Lipopolysaccharide (LPS) is associated with adverse developmental outcomes including embryonic resorption, fetal death, congenital teratogenesis and fetal growth retardation. Here, we explored the effects of maternal LPS exposure during pregnancy on testicular development, steroidogenesis and spermatogenesis in male offspring. The pregnant mice were intraperitoneally injected with LPS (50 µg/kg) daily from gestational day (GD) 13 to GD 17. At fetal period, a significant decrease in body weight and abnormal Leydig cell aggregations were observed in males whose mothers were exposed to LPS during pregnancy. At postnatal day (PND) 26, anogenital distance (AGD), a sensitive index of altered androgen action, was markedly reduced in male pups whose mothers were exposed to LPS daily from GD13 to GD 17. At PND35, the weight of testes, prostates and seminal vesicles, and serum testosterone (T) level were significantly decreased in LPS-treated male pups. At adulthood, the number of sperm was significantly decreased in male offspring whose mothers were exposed to LPS on GD 13–17. Maternal LPS exposure during gestation obviously diminished the percent of seminiferous tubules in stages I–VI, increased the percent of seminiferous tubules in stages IX–XII, and caused massive sloughing of germ cells in seminiferous tubules in mouse testes. Moreover, maternal LPS exposure significantly reduced serum T level in male mice whose mothers were exposed to LPS challenge during pregnancy. Taken together, these results suggest that maternal LPS exposure during pregnancy disrupts T production. The decreased T synthesis might be associated with LPS-induced impairments for spermatogenesis in male offspring.
PMCID: PMC4177809  PMID: 25255222
16.  Rare cause of upper gastrointestinal bleeding owing to hepatic cancer invasion: A case report 
World Journal of Gastroenterology : WJG  2014;20(35):12704-12708.
Upper gastrointestinal bleeding refers to bleeding that arises from the gastrointestinal tract proximal to the ligament of Treitz. The primary reason for gastrointestinal bleeding associated with hepatocellular carcinoma is rupture of a varicose vein owing to pericardial hypotension. We report a rare case of gastrointestinal bleeding with hepatocellular carcinoma in a patient who presented with recurrent gastrointestinal bleeding. The initial diagnosis was gastric cancer with metastasis to the multiple lymph nodes of the lesser curvature. The patient underwent exploratory laparotomy, which identified two lesions in the gastric wall. Total gastrectomy and hepatic local excision was then performed. Pathological results indicated that the hepatocellular carcinoma had invaded the stomach directly, which was confirmed immunohistochemically. The patient is alive with a disease-free survival of 1 year since the surgery. Hepatocellular carcinoma with gastric invasion should be considered as a rare cause of upper gastrointestinal bleeding in hepatocellular carcinoma patients, especially with lesions located in the left lateral hepatic lobe. Surgery is the best solution.
PMCID: PMC4168114  PMID: 25253981
Bleeding; Cancer; Gastrointestinal tract; Liver; Neoplasm invasion
17.  5-mehtyltetrahydrofolate rescues alcohol-induced neural crest cell migration abnormalities 
Molecular Brain  2014;7(1):67.
Alcohol is detrimental to early development. Fetal alcohol spectrum disorders (FASD) due to maternal alcohol abuse results in a series of developmental abnormalities including cranial facial dysmorphology, ocular anomalies, congenital heart defects, microcephaly and intellectual disabilities. Previous studies have been shown that ethanol exposure causes neural crest (NC) apoptosis and perturbation of neural crest migration. However, the underlying mechanism remains elusive. In this report we investigated the fetal effect of alcohol on the process of neural crest development in the Xenopus leavis.
Pre-gastrulation exposure of 2-4% alcohol induces apoptosis in Xenopus embryo whereas 1% alcohol specifically impairs neural crest migration without observing discernible apoptosis. Additionally, 1% alcohol treatment considerably increased the phenotype of small head (43.4% ± 4.4%, total embryo n = 234), and 1.5% and 2.0% dramatically augment the deformation to 81.2% ± 6.5% (n = 205) and 91.6% ± 3.0% (n = 235), respectively (P < 0.05). Significant accumulation of Homocysteine was caused by alcohol treatment in embryos and 5-mehtyltetrahydrofolate restores neural crest migration and alleviates homocysteine accumulation, resulting in inhibition of the alcohol-induced neurocristopathies.
Our study demonstrates that prenatal alcohol exposure causes neural crest cell migration abnormality and 5-mehtyltetrahydrofolate could be beneficial for treating FASD.
PMCID: PMC4172781  PMID: 25223405
Alcohol; 5-mehtyltetrahydrofolate; Neural crest; FASD; Xenopus
18.  Evaluation of a standardized treatment regimen of anti-tuberculosis drugs for patients with multi-drug-resistant tuberculosis (STREAM): study protocol for a randomized controlled trial 
Trials  2014;15(1):353.
In contrast to drug-sensitive tuberculosis, the guidelines for the treatment of multi-drug-resistant tuberculosis (MDR-TB) have a very poor evidence base; current recommendations, based on expert opinion, are that patients should be treated for a minimum of 20 months. A series of cohort studies conducted in Bangladesh identified a nine-month regimen with very promising results. There is a need to evaluate this regimen in comparison with the currently recommended regimen in a randomized controlled trial in a variety of settings, including patients with HIV-coinfection.
STREAM is a multi-centre randomized trial of non-inferiority design comparing a nine-month regimen to the treatment currently recommended by the World Health Organization in patients with MDR pulmonary TB with no evidence on line probe assay of fluoroquinolone or kanamycin resistance. The nine-month regimen includes clofazimine and high-dose moxifloxacin and can be extended to 11 months in the event of delay in smear conversion. The primary outcome is based on the bacteriological status of the patients at 27 months post-randomization. Based on the assumption that the nine-month regimen will be slightly more effective than the control regimen and, given a 10% margin of non-inferiority, a total of 400 patients are required to be enrolled. Health economics data are being collected on all patients in selected sites.
The results from the study in Bangladesh and cohorts in progress elsewhere are encouraging, but for this regimen to be recommended more widely than in a research setting, robust evidence is needed from a randomized clinical trial. Results from the STREAM trial together with data from ongoing cohorts should provide the evidence necessary to revise current recommendations for the treatment for MDR-TB.
Trial registration
This trial was registered with (registration number: ISRCTN78372190) on 14 October 2010.
PMCID: PMC4164715  PMID: 25199531
Multi-drug-resistant tuberculosis; Multicenter randomized trial; Non-inferiority; Shorter treatment duration
19.  Programmable chemical controllers made from DNA 
Nature nanotechnology  2013;8(10):755-762.
Biological organisms use complex molecular networks to navigate their environment and regulate their internal state. The development of synthetic systems with similar capabilities could lead to applications such as smart therapeutics or fabrication methods based on self-organization. To achieve this, molecular control circuits need to be engineered to perform integrated sensing, computation and actuation. Here we report a DNA-based technology for implementing the computational core of such controllers. We use the formalism of chemical reaction networks as a 'programming language', and our DNA architecture can, in principle, implement any behaviour that can be mathematically expressed as such. Unlike logic circuits, our formulation naturally allows complex signal processing of intrinsically analogue biological and chemical inputs. Controller components can be derived from biologically synthesized (plasmid) DNA, which reduces errors associated with chemically synthesized DNA. We implement several building-block reaction types and then combine them into a network that realizes, at the molecular level, an algorithm used in distributed control systems for achieving consensus between multiple agents.
PMCID: PMC4150546  PMID: 24077029
20.  Preparation of High Purity Crystalline Silicon by Electro-Catalytic Reduction of Sodium Hexafluorosilicate with Sodium below 180°C 
PLoS ONE  2014;9(8):e105537.
The growing field of silicon solar cells requires a substantial reduction in the cost of semiconductor grade silicon, which has been mainly produced by the rod-based Siemens method. Because silicon can react with almost all of the elements and form a number of alloys at high temperatures, it is highly desired to obtain high purity crystalline silicon at relatively low temperatures through low cost process. Here we report a fast, complete and inexpensive reduction method for converting sodium hexafluorosilicate into silicon at a relatively low reaction temperature (∼200°C). This temperature could be further decreased to less than 180°C in combination with an electrochemical approach. The residue sodium fluoride is dissolved away by pure water and hydrochloric acid solution in later purifying processes below 15°C. High purity silicon in particle form can be obtained. The relative simplicity of this method might lead to a low cost process in producing high purity silicon.
PMCID: PMC4143305  PMID: 25153509
21.  Determinants of the Over-Anticoagulation Response during Warfarin Initiation Therapy in Asian Patients Based on Population Pharmacokinetic-Pharmacodynamic Analyses 
PLoS ONE  2014;9(8):e105891.
To clarify pharmacokinetic-pharmacodynamic (PK-PD) factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time-courses of the plasma S-warfarin concentration, Cp(S), and coagulation and anti-coagulation (INR) responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S) to estimate the clearance of S-warfarin, CL(S), and that between Cp(S) and the normal prothrombin concentration (NPT) as a coagulation marker for estimation of IC50. We also analyzed the non-linear relationship between NPT inhibition and the increase in INR to derive the non-linear index λ. Population analyses accurately predicted the time-courses of Cp(S), NPT and INR. Multivariate analysis showed that CYP2C9*3 mutation and body surface area were predictors of CL(S), that VKORC1 and CYP4F2 polymorphisms were predictors of IC50, and that baseline NPT was a predictor of λ. CL(S) and λ were significantly lower in patients with INR≥4 than in those with INR<4 (190 mL/h vs 265 mL/h, P<0.01 and 3.2 vs 3.7, P<0.01, respectively). Finally, logistic regression analysis revealed that CL(S), ALT and hypertension contributed significantly to INR≥4. All these results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S), might be critical determinants of the over-anticoagulation response during warfarin initiation in Asians.
Trial Registration NCT02065388
PMCID: PMC4141831  PMID: 25148255
22.  A Novel Compound NSC745885 Exerts an Anti-Tumor Effect on Tongue Cancer SAS Cells In Vitro and In Vivo 
PLoS ONE  2014;9(8):e104703.
Oral squamous cell carcinoma (OSCC) is a prevalent cancer, especially in developing countries. Anthracyclines and their anthraquinone derivatives, such as doxorubicin, exhibit a cell growth inhibitory effect and have been used as anti-cancer drugs for many years. However, the cardiotoxicity of anthracycline antibiotics is a major concern in their clinical application. NSC745885 is a novel compound synthesized from 1,2-diaminoanthraquinone, which subsequently reacts with thionyl chloride and triethylamine. The present study aimed to investigate the anti-oral cancer potential and the safety of NSC745885.
We investigated the anti-cancer potential of NSC745885 in oral squamous carcinoma cell lines and in an in vivo oral cancer xenograft mouse model. The expression of apoptotic related genes were evaluated by real-time RT-PCR and western bloting, and the in vivo assessment of apoptotic marker were measured by immunohistochemical staining. The anti-tumor efficiency and safety between doxorubicin and NSC745885 were also compared.
Our results demonstrated that NSC745885 exhibits anti-oral cancer activity through the induction of apoptosis in cancer cells and in tumor-bearing mice, and this treatment did not induce marked toxicity in experimental mice. This compound also exhibits a comparable anti-tumor efficiency and a higher safety in experimental mice when compared to doxorubicin.
The data of this study provide evidence for NSC745885 as a potential novel therapeutic drug for the treatment of human OSCC.
PMCID: PMC4134221  PMID: 25127132
23.  Chromogranin A is a reliable serum diagnostic biomarker for pancreatic neuroendocrine tumors but not for insulinomas 
Pancreatic neuroendocrine tumors (PNETs) are a group of rare tumors. Chromogranin A (CgA) was considered as the most practical and useful serum tumor marker in PNET patients. But peripheral blood levels of CgA are not routinely tested in Chinese patients with PNETs. This study was to assess the diagnostic value of CgA in Chinese patients with PNETs especially in patients with insulinomas.
Eighty-nine patients with PNETs including 57 insulinomas and 32 non-insulinoma PNETs as well as 86 healthy participants were enrolled in this study between September 2003 and June 2013. Serum levels of CgA were measured by ELISA method. Expression of CgA protein was detected in 26 PNET tissues including 14 insulinomas by immunohistochemical staining.
Serum levels of CgA in 89 PNET patients were significantly higher than that in healthy controls (P = 7.2 × 10−9). Serum levels of CgA in 57 patients with insulinomas (median 64.8 ng/ml, range 25–164) were slightly higher than the levels in healthy controls (median 53.4 ng/ml, range 39–94) but much lower than the levels in 32 patients with non-insulinoma PNETs (median 193 ng/ml, range 27–9021), P = 0.001. The serum CgA levels were reduced in 16 of 17 patients with insulinomas after tumor resection. ROC curve showed that CgA values at 60 ng/ml distinguished patients with insulinomas from healthy controls but its sensitivity and specificity were 66.7% and 73.3%, respectively. In contrast, CgA values at 74 ng/ml distinguished patients with non-insulinoma PNETs from healthy controls, and the sensitivity and specificity were 65.6% and 91.9%, respectively. Except for two insulinomas with negative staining of CgA, 12 insulinoma tissues showed positive staining of CgA.
CgA is a reliable serum diagnostic biomarker for PNETs but not for insulinomas.
PMCID: PMC4130880  PMID: 25099181
24.  Accurate Parameter Estimation for Unbalanced Three-Phase System 
The Scientific World Journal  2014;2014:539420.
Smart grid is an intelligent power generation and control console in modern electricity networks, where the unbalanced three-phase power system is the commonly used model. Here, parameter estimation for this system is addressed. After converting the three-phase waveforms into a pair of orthogonal signals via the α β-transformation, the nonlinear least squares (NLS) estimator is developed for accurately finding the frequency, phase, and voltage parameters. The estimator is realized by the Newton-Raphson scheme, whose global convergence is studied in this paper. Computer simulations show that the mean square error performance of NLS method can attain the Cramér-Rao lower bound. Moreover, our proposal provides more accurate frequency estimation when compared with the complex least mean square (CLMS) and augmented CLMS.
PMCID: PMC4138947  PMID: 25162056
25.  Using regression models to determine the poroelastic properties of cartilage 
Journal of biomechanics  2013;46(11):1921-1927.
The feasibility of determining biphasic material properties using regression models was investigated. A transversely isotropic poroelastic finite element model of stress relaxation was developed and validated against known results. This model was then used to simulate load intensity for a wide range of material properties. Linear regression equations for load intensity as a function of the five independent material properties were then developed for nine time points (131, 205, 304, 390, 500, 619, 700, 800, and 1000 s) during relaxation. These equations illustrate the effect of individual material property on the stress in the time history. The equations at the first four time points, as well as one at a later time (five equations) could be solved for the five unknown material properties given computed values of the load intensity. Results showed that four of the five material properties could be estimated from the regression equations to within 9% of the values used in simulation if time points up to 1000 s are included in the set of equations. However, reasonable estimates of the out of plane Poisson's ratio could not be found. Although all regression equations depended on permeability, suggesting that true equilibrium was not realized at 1000 s of simulation, it was possible to estimate material properties to within 10% of the expected values using equations that included data up to 800 s. This suggests that credible estimates of most material properties can be obtained from tests that are not run to equilibrium, which is typically several thousand seconds.
PMCID: PMC3786438  PMID: 23796400
Stress relaxation; Poroelasticity; Transversely isotropic; Linear regression

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