Prognostic Role of Adjuvant Chemotherapy in Node-Negative (N0), Triple-Negative (TN), Medullary Breast Cancer (MBC) in the Korean Population

Background

Despite the favorable prognosis for medullary breast cancer (MBC), the guidelines for the use of adjuvant chemotherapy for MBC have not been clearly established. This study investigated the prognostic role of adjuvant chemotherapy in Korean patients with node-negative (N0), triple-negative (TN) MBC patients.

Methods

We included data from 252 patients with N0 TN MBC, obtained from the Korean Breast Cancer Registry database. Patients were categorized as those who did not undergo adjuvant chemotherapy (group I) or those who did (group II). Clinicopathological characteristics, breast cancer-specific survival (BCSS), and overall survival (OS) were compared between the groups. In addition, a subgroup analysis for survival based on tumor size was conducted.

Results

A total of 252 N0 TN MBC patients with tumor sizes >1 cm who were diagnosed between April 1997 and March 2011 were enrolled. The median age was 44.95 years (range, 25–72 years), and the median follow-up period was 93.94 months (range, 23–195 months). Overall, the BCSS and OS in group II (97.3% and 97.3%, respectively) were significantly better compared with those in group I (89.2% and 86.2%, respectively). In the subgroup analysis, in patients with tumors >2 cm in size, those in group II had significant better BCSS and OS (97.5% and 97.5%, respectively) compared with those in group I (78.3% and 73.9%, respectively). In contrast in those with tumors 1–2 cm in size, there were no significant differences in BCSS and OS between the groups (both 97.1% for group I, and 95.2% and 92.9%, respectively for group II). Multivariate analysis revealed that adjuvant chemotherapy significantly improved BCSS (P = 0.009) and OS (P = 0.007), but only for patients with larger tumors (>2 cm).

Conclusions

In patients with N0 TN MBC, adjuvant chemotherapy had a significant clinical survival benefit, but only in those with tumors >2 cm.     

Comparative acute toxicity of gallium(III), antimony(III), indium(III), cadmium(II), and copper(II) on freshwater swamp shrimp (Macrobrachium nipponense)

Background

Acute toxicity testing were carried out the freshwater swamp shrimp, Macrobrachium nipponense, as the model animal for the semiconductor applied metals (gallium, antimony, indium, cadmium, and copper) to evaluate if the species is an suitable experimental animal of pollution in aquatic ecosystem.

Results

The static renewal test method of acute lethal concentrations determination was used, and water temperature was maintained at 24.0 ± 0.5°C. Data of individual metal obtained from acute toxicity tests were determined using probit analysis method. The median lethal concentration (96-h LC₅₀) of gallium, antimony, indium, cadmium, and copper for M. nipponense were estimated as 2.7742, 1.9626, 6.8938, 0.0539, and 0.0313 mg/L, respectively.

Conclusions

Comparing the toxicity tolerance of M. nipponense with other species which exposed to these metals, it is obviously that the M. nipponense is more sensitive than that of various other aquatic animals.     

Comparison of Body Mass Index (BMI), Body Adiposity Index (BAI), Waist Circumference (WC), Waist-To-Hip Ratio (WHR) and Waist-To-Height Ratio (WHtR) as Predictors of Cardiovascular Disease Risk Factors in an Adult Population in Singapore

Background

Excess adiposity is associated with cardiovascular disease (CVD) risk factors such as hypertension, diabetes mellitus and dyslipidemia. Amongst the various measures of adiposity, the best one to help predict these risk factors remains contentious. A novel index of adiposity, the Body Adiposity Index (BAI) was proposed in 2011, and has not been extensively studied in all populations. Therefore, the purpose of this study is to compare the relationship between Body Mass Index (BMI), Waist Circumference (WC), Waist-to-Hip Ratio (WHR), Waist-to-Height Ratio (WHtR), Body Adiposity Index (BAI) and CVD risk factors in the local adult population.

Methods and Findings

This is a cross sectional study involving 1,891 subjects (Chinese 59.1% Malay 22.2%, Indian 18.7%), aged 21–74 years, based on an employee health screening (2012) undertaken at a hospital in Singapore. Anthropometric indices and CVD risk factor variables were measured, and Spearman correlation, Receiver Operating Characteristic (ROC) curves and multiple logistic regressions were used. BAI consistently had the lower correlation, area under ROC and odd ratio values when compared with BMI, WC and WHtR, although differences were often small with overlapping 95% confidence intervals. After adjusting for BMI, BAI did not further increase the odds of CVD risk factors, unlike WC and WHtR (for all except hypertension and low high density lipoprotein cholesterol). When subjects with the various CVD risk factors were grouped according to established cut-offs, a BMI of ≥23.0 kg/m² and/or WHtR ≥0.5 identified the highest proportion for all the CVD risk factors in both genders, even higher than a combination of BMI and WC.

Conclusions

BAI may function as a measure of overall adiposity but it is unlikely to be better than BMI. A combination of BMI and WHtR could have the best clinical utility in identifying patients with CVD risk factors in an adult population in Singapore.     

Further regional localization of the genes for human acid alpha glucosidase (GAA), peptidase D (PEPD), and alpha mannosidase B (MANB) by somatic cell hybridization

Summary We have further regionally localized the gene for human acid alpha glucosidase (GAA) to 17q21q23 by examinaiton of hybrid clones derived from a fusion between human fibroblasts carrying a 17/19 balanced translocation (17pter17q23::19p13.319pter; 19qterp13.3::17q2317qter) and a mouse line deficient in thymidine kinase. These hybrids were constantly maintained in HAT selective media in order to select for the presence of the human thymidine kinase gene on the intact chromosome 17 (17q21-q22) or the 17/19 (17pter17q23::19p13.319pter) translocation chromosome. We detected human GAA by rocket immunoelectrophoresis, using a human specific heterologous antibody raised against human acid alpha glucosidase (GAA) (Honig et al. 1984). Three secondary clones, which contained the 17/19 translocation and no intact chromosome 17 or 19, were still positive for GAA. Two of these secondary clones contained the distal portion of the 17/19 translocation chromosome, with a break in the band 17q21 (probably at 17q21.2), attached to a mouse chromosome. Combined with earlier results (Weil et al. 1979; Nickel et al. 1982; Honig et al. 1984), the gene for GAA can be assigned to 17q21.217q23. Additionally, these clones were negative for human peptidase D (PEPD), alpha mannosidase B (MANB), and phosphohexose isomerase (PHI). Combined with previous results (Ingram et al. 1977; Bruns et al. 1979), these results exclude the genes for PEPD and MANB from 19pter19p13.3 and confirm the exclusion of the gene for PHI from this segment of chromosome 19 (Wilson et al. 1984; Ingram et al. 1977).     

A family of polyamino phenolic macrocyclic ligands. Acid-base and coordination properties towards Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and Pb(II) ions

The acid-base and coordination properties towards Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and Pb(II) of four polyamino-phenol macrocycles 15-hydroxy-3,6,9-triazabicyclo[9.3.1]pentadeca-11,13,1¹⁵-triene L1, 18-hydroxy-3,6,9,12-tetraazabicyclo[12.3.1]octadeca-14,16,1¹⁸-triene L2, 21-hydroxy-3,6,9,12,15-pentaazabicyclo[15.3.1]enaicosa-17,19,1²¹-triene L3 and 24-hydroxy-3,6,9,12,15,18-hexaazabicyclo[18.3.1]tetraicosa-20,22,1²⁴-triene L4 are reported. The protonation and stability constants were determined by means of potentiometric measurements in 0.15 mol dm⁻³ NMe₄Cl aqueous solution at 298.1 K. L1 forms highly unsaturated Co(II), Cu(II), Zn(II) and Cd(II) mononuclear complexes that are prone to give dimeric dinuclear species with [(MH₋₁L1)₂]²⁺ stoichiometry, in solution. L2 forms stable Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and Pb(II) mononuclear complexes that can coordinate external species as OH⁻ anion, giving hydroxylated complexes at alkaline pH. L3 forms stable Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and Pb(II) mononuclear complexes and Co(II), Ni(II), Cu(II) and Zn(II) dinuclear [M₂H₋₁L3]³⁺ species. L4 forms stable mono- and dinuclear Co(II), Cu(II), Zn(II) and Cd(II) complexes, but only mononuclear species with Pb(II). The effect of macrocyclic size is considered in the discussion of results.     

Exploration of serum biomarkers for predicting the response to Inchinkoto (ICKT), a Japanese traditional herbal medicine

Introduction

In patients with obstructive jaundice, biliary drainage sometimes fails to result in improvement. A pharmaceutical-grade choleretic herbal medicine, Inchinkoto (ICKT), has been proposed to exert auxiliary effects on biliary drainage; however, its effects are variable among patients.

Objectives

The aim of this study is to explore serum biomarkers that are associated with pharmaceutical efficacy of ICKT.

Methods

Obstructive jaundice patients who underwent external biliary decompression were enrolled (n?=?37). ICKT was given orally 3 times a day at daily dose of 7.5 g. Serum and bile samples were collected before, 3 h after, and 24 h after ICKT administration. The concentrations of total bilirubin, direct bilirubin, and total bile acid in bile specimens were measured. Metabolites in serum samples were comprehensively profiled using LC–MS/MS and GC–MS/MS. Pharmacokinetic analysis of major ICKT components was also performed.

Results

ICKT administration significantly decreased serum ALT and increased bile volume after 24 h. The serum concentrations of ICKT components were not well correlated with the efficacy of ICKT. However, the ratio of 2-hydroxyisobutyric acid to arachidonic acid and the ratio of glutaric acid to niacinamide, exhibited good performance as biomarkers for the efficacy of ICKT on bile flow and ALT, respectively. Additionally, comprehensive correlation analysis revealed that serum glucuronic acid was highly correlated with serum total bilirubin, suggesting that this metabolite may be deeply involved in the pathogenesis of jaundice.

Conclusions

The present study indicates that ICKT is efficacious and provides candidates for predicting ICKT efficacy. Further validation studies are warranted.

     

3-Deazaneplanocin A (DZNep), an Inhibitor of the Histone Methyltransferase EZH2, Induces Apoptosis and Reduces Cell Migration in Chondrosarcoma Cells

Objective

Growing evidences indicate that the histone methyltransferase EZH2 (enhancer of zeste homolog 2) may be an appropriate therapeutic target in some tumors. Indeed, a high expression of EZH2 is correlated with poor prognosis and metastasis in many cancers. In addition, 3-Deazaneplanocin A (DZNep), an S-adenosyl-L homocysteine hydrolase inhibitor which induces EZH2 protein depletion, leads to cell death in several cancers and tumors. The aim of this study was to determine whether an epigenetic therapy targeting EZH2 with DZNep may be also efficient to treat chondrosarcomas.

Methods

EZH2 expression was determined by immunohistochemistry and western-blot. Chondrosarcoma cell line CH2879 was cultured in the presence of DZNep, and its growth and survival were evaluated by counting adherent cells periodically. Apoptosis was assayed by cell cycle analysis, Apo2.7 expression using flow cytometry, and by PARP cleavage using western-blot. Cell migration was assessed by wound healing assay.

Results

Chondrosarcomas (at least with high grade) highly express EZH2, at contrary to enchondromas or chondrocytes. In vitro, DZNep inhibits EZH2 protein expression, and subsequently reduces the trimethylation of lysine 27 on histone H3 (H3K27me3). Interestingly, DZNep induces cell death of chondrosarcoma cell lines by apoptosis, while it slightly reduces growth of normal chondrocytes. In addition, DZNep reduces cell migration.

Conclusion

These results indicate that an epigenetic therapy that pharmacologically targets EZH2 via DZNep may constitute a novel approach to treat chondrosarcomas.     

Stability assessment of a new antithrombotic small peptide,Arg-Gly-Asp-Trp-Arg (RGDWR), and its derivative

Objective

To assess the stabilities of Arg-Gly-Asp-Trp-Arg (RGDWR, designated as RWR), a new patented antithrombotic small peptide, and its derivative with ω-aminocaprylic acid on its N-terminus (ωRWR).

Results

RWR in rat plasma was decreased by between 32 and 48% after 4 h incubation on ice, indicating its instability in plasma. In contrast, ωRWR in plasma remained at 96–107%. Concentration changes were within 6.2% for ωRWR after storage in various conditions. ωRWR is therefore stable in rat plasma, as well as under different storage methods. Furthermore, ω-aminocaprylic acid added onto the RWR peptide did not affect its antiplatelet aggregation activity.

Conclusions

A novel small peptide, ωRWR, has been developed with a good stability for possible antithrombotic use.

     

HDM2 antagonist MI-219 (spiro-oxindole), but not Nutlin-3 (cis-imidazoline), regulates p53 through enhanced HDM2 autoubiquitination and degradation in human malignant B-cell lymphomas

Background

Lymphomas frequently retain wild-type (wt) p53 function but overexpress HDM2, thereby compromising p53 activity. Therefore, lymphoma is a suitable model for studying the therapeutic value of disrupting the HDM2-p53 interaction by small-molecule inhibitors (SMIs). HDM2 have been developed and are under various stages of preclinical and clinical investigation. Previously, we examined the anti-lymphoma activity of MI-319, the laboratory grade of a new class of HDM2 SMI, the spiro-oxindole, in follicular lymphoma. Since then, MI-219, the clinical grade has become readily available. This study further examines the preclinical effects and mechanisms of MI-219 in a panel of human lymphoma cell lines as well as a cohort of patient-derived B-lymphcytes for its potential clinical use.

Results

Preclinical assessment of MI-219 was evaluated by means of an in vitro and ex vivo approach and compared to Nutlin-3, the gold standard. Characterization of p53 activity and stability were assessed by quantitative PCR, Western blot, and immunoprecipitation. Biological outcome was measured using Trypan blue exclusion assay, Annexin V/PI, PARP and caspase-3 cleavage. Surprisingly, the overall biological effects of Nutlin-3 were more delayed (48 h) while MI-219 triggered an earlier response (12-24 h), predominantly in the form of apoptotic cell death. Using a cell free autoubiquitination assay, neither agent interfered with HDM2 E3 ligase function. MI-219 was more effective in upregulating wt-p53 stabilization compared to Nutlin-3. MI-219, but not Nutlin-3, enhanced the autoubiquitination and degradation of HDM2.

Conclusions

Our data reveals unexpected differences between MI-219 and the well-studied Nutlin-3 in lymphoma cell lines and patient samples. We suggest a novel mechanism for MI-219 that alters the functional activity of HDM2 through enhanced autoubiquitination and degradation. Additionally, this mechanism appears to correspond to biological outcome. Our results provide evidence that different classes of HDM2 SMIs elicit molecular events that extend beyond HDM2-p53 dissociation which may be of biological and potentially therapeutic importance.     

Life cycle assessment of single use thermoform boxes made from polystyrene (PS), polylactic acid, (PLA), and PLA/starch: cradle to consumer gate

Purpose

Currently, the bio-based plastics have been drawing considerable attention from the packaging industry as a sustainable solution for replacing petroleum-based plastics in order to reduce the accumulation of plastic waste in the environment. This work has benchmarked the environmental impact of bio-based against petroleum-based plastics for single use boxes. In this paper, the cradle to consumer gate environmental impact data of these boxes was calculated and reported as part 1. End-of-life options of both bio- and petroleum-based boxes are an important subject which will be further studied for part 2. The energy sources in this work were taken from the Thailand energy database namely: Thai electricity grid mix (TEGM), Thai coal electricity (TCE), Thai natural gas combine cycle (TNGCC), and Thai coal integrated gasification combine cycle (TIGCC).

Methods

The materials studied were polystyrene (PS) derived from petroleum, polylactic acid (PLA) derived from corn, and PLA/cassava starch blend (PLA/starch). The tray with lid (herein after called box) was processed in a plastic manufacturing in Thailand using cast sheet extrusion and then thermoforming techniques. The functional unit is specified as 10,000 units of 8.0?×?10.0?×?2.5 cm of PS, PLA, and PLA/starch boxes which weigh 447.60, 597.60, and 549.56 kg, respectively. Three impact categories; namely global warming potential including direct greenhouse gas, and indirect land use change (LUC) emissions, acidification, and photochemical ozone formation are investigated. Finally, the normalization results including and excluding LUC consideration were compared and reported.

Results and discussion

The results from this study have shown that the total environmental impact including LUC emission of bio-based boxes were different when the various energy sources were supplied throughout the life cycle production stage. It can be seen that the PS box has lower environmental impact than PLA and PLA/starch boxes when TEGM, TCE, TNGCC, and TIGCC were used as energy supplied. LUC of renewable feedstocks, such as corn and cassava, were considered as the biggest impact of absolute scores of PLA and PLA/starch boxes. These results are consistent with Piemonte and Gironi (2010).

Conclusions

PLA and PLA/starch boxes give a slightly higher environmental impact than the PS box by 1.59 and 1.09 times, respectively, when LUC was not accounted in the absolute scores and clean energy TIGCC was used throughout the life cycle.     

Reduction kinetics of Fe(III), Co(III), U(VI), Cr(VI), and Tc(VII) in cultures of dissimilatory metal-reducing bacteria

The reduction kinetics of Fe(III)citrate, Fe(III)NTA, Co(III)EDTA-, U(VI)O(2) (2+), Cr(VI)O(4) (2-), and Tc(VII)O(4) (-) were studied in cultures of dissimilatory metal reducing bacteria (DMRB): Shewanella alga strain BrY, Shewanella putrefaciens strain CN32, Shewanella oneidensis strain MR-1, and Geobacter metallireducens strain GS-15. Reduction rates were metal specific with the following rate trend: Fe(III)citrate > or = Fe(III)NTA > Co(III)EDTA- > UO(2)(2+) > CrO(4)(2-) > TcO(4)(-), except for CrO(4) (2-) when H(2) was used as electron donor. The metal reduction rates were also electron donor dependent with faster rates observed for H(2) than lactate- for all Shewanella species despite higher initial lactate (10 mM) than H2 (0.48 mM). The bioreduction of CrO(4) (2-) was anomalously slower compared to the other metals with H(2) as an electron donor relative to lactate and reduction ceased before all the CrO(4)(2-) had been reduced. Transmission electron microscopic (TEM) and energy-dispersive spectroscopic (EDS) analyses performed on selected solids at experiment termination found precipitates of reduced U and Tc in association with the outer cell membrane and in the periplasm of the bacteria. The kinetic rates of metal reduction were correlated with the precipitation of reduced metal phases and their causal relationship discussed. The experimental rate data were well described by a Monod kinetic expression with respect to the electron acceptor for all metals except CrO(4)(2-), for which the Monod model had to be modified to account for incomplete reduction. However, the Monod models became statistically over-parameterized, resulting in large uncertainties of their parameters. A first-order approximation to the Monod model also effectively described the experimental results, but the rate coefficients exhibited far less uncertainty. The more precise rate coefficients of the first-order model provided a better means than the Monod parameters, to quantitatively compare the reduction rates between metals, electron donors, and DMRB species.     

Modelling the Species Distribution of Flat-Headed Cats (Prionailurus planiceps), an Endangered South-East Asian Small Felid

Background

The flat-headed cat (Prionailurus planiceps) is one of the world''s least known, highly threatened felids with a distribution restricted to tropical lowland rainforests in Peninsular Thailand/Malaysia, Borneo and Sumatra. Throughout its geographic range large-scale anthropogenic transformation processes, including the pollution of fresh-water river systems and landscape fragmentation, raise concerns regarding its conservation status. Despite an increasing number of camera-trapping field surveys for carnivores in South-East Asia during the past two decades, few of these studies recorded the flat-headed cat.

Methodology/Principal Findings

In this study, we designed a predictive species distribution model using the Maximum Entropy (MaxEnt) algorithm to reassess the potential current distribution and conservation status of the flat-headed cat. Eighty-eight independent species occurrence records were gathered from field surveys, literature records, and museum collections. These current and historical records were analysed in relation to bioclimatic variables (WorldClim), altitude (SRTM) and minimum distance to larger water resources (Digital Chart of the World). Distance to water was identified as the key predictor for the occurrence of flat-headed cats (>50% explanation). In addition, we used different land cover maps (GLC2000, GlobCover and SarVision LLC for Borneo), information on protected areas and regional human population density data to extract suitable habitats from the potential distribution predicted by the MaxEnt model. Between 54% and 68% of suitable habitat has already been converted to unsuitable land cover types (e.g. croplands, plantations), and only between 10% and 20% of suitable land cover is categorised as fully protected according to the IUCN criteria. The remaining habitats are highly fragmented and only a few larger forest patches remain.

Conclusion/Significance

Based on our findings, we recommend that future conservation efforts for the flat-headed cat should focus on the identified remaining key localities and be implemented through a continuous dialogue between local stakeholders, conservationists and scientists to ensure its long-term survival. The flat-headed cat can serve as a flagship species for the protection of several other endangered species associated with the threatened tropical lowland forests and surface fresh-water sources in this region.     

LDL-Migration Index (LDL-MI), an Indicator of Small Dense Low-Density Lipoprotein (sdLDL), Is Higher in Non-Alcoholic Steatohepatitis than in Non-Alcoholic Fatty Liver: A Multicenter Cross-Sectional Study

Background

Non-alcoholic fatty liver disease (NAFLD) is associated with increased risks of atherosclerotic diseases, including cardiovascular disease. However, the difference in risk between patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) has not yet been determined. Accumulating evidence has shown that high amounts of small dense low-density lipoprotein (sdLDL) are closely associated with atherosclerotic diseases. This study investigated differences in risk factors for atherosclerotic diseases, especially LDL-migration index (LDL-MI), an indicator of sdLDL, between patients with NAFL and NASH.

Methods

LDL-MI was analyzed in a primary cohort of 156 patients with NAFLD, including 53 with NAFL and 103 with NASH, and a validation cohort of 69 patients with NAFLD, including 25 with NAFL and 44 with NASH.

Results

In the primary cohort, NASH was associated with elevated LDL-MI (p = 0.039). Multiple regression analysis showed that NASH and the non-use of lipid lowering medications were independently correlated with higher LDL-MI in all patients with NAFLD. Among patients not on lipid lowering medications, those with NASH had significantly higher LDL-MI than those with NAFL (p = 0.001). These findings were confirmed in a validation cohort, in that LDL-MI was significantly higher in patients with NASH than with NAFL (p = 0.043).

Conclusion

This study is the first to show that LDL-MI, an indicator of sdLDL, was higher in patients with NASH than with NAFL, suggesting that the risk of atherosclerotic diseases may be higher in NASH than NAFL. Patients with NASH should be followed closely, especially for the progression of liver pathology and atherosclerotic diseases.

Trial Registration

UMIN000009614     

Macrophage derived chemokine (CCL22), thymus and activation-regulated chemokine (CCL17), and CCR4 in idiopathic pulmonary fibrosis

Background

Idiopathic pulmonary fibrosis (IPF) is a chronically progressive interstitial lung disease of unknown etiology. Previously, we have demonstrated the selective upregulation of the macrophage-derived chemokine CCL22 and the thymus activation-regulated chemokine CCL17 among chemokines, in a rat model of radiation pneumonitis/pulmonary fibrosis and preliminarily observed an increase in bronchoalveolar (BAL) fluid CCL22 levels of IPF patients.

Methods

We examined the expression of CCR4, a specific receptor for CCL22 and CCL17, in bronchoalveolar lavage (BAL) fluid cells, as well as the levels of CCL22 and CCL17, to elucidate their pathophysiological roles in pulmonary fibrosis. We also studied their immunohistochemical localization.

Results

BAL fluid CCL22 and CCL17 levels were significantly higher in patients with IPF than those with collagen vascular diseases and healthy volunteers, and there was a significant correlation between the levels of CCL22 and CCL17 in patients with IPF. CCL22 levels in the BAL fluid did not correlate with the total cell numbers, alveolar lymphocytes, or macrophages in BAL fluid. However, the CCL22 levels significantly correlated with the numbers of CCR4-expressing alveolar macrophages. By immunohistochemical and immunofluorescence analysis, localization of CCL22 and CCR4 to CD68-positive alveolar macrophages as well as that of CCL17 to hyperplastic epithelial cells were shown. Clinically, CCL22 BAL fluid levels inversely correlated with DLco/VA values in IPF patients.

Conclusion

We speculated that locally overexpressed CCL22 may induce lung dysfunction through recruitment and activation of CCR4-positive alveolar macrophages.     

Chronic alcohol consumption,type 2 diabetes mellitus,insulin-like growth factor-I (IGF-I), and growth hormone (GH) in ethanol-treated diabetic rats

Aims

Alcohol has deleterious influences on glucose metabolism which may contribute to the development of type 2 diabetes mellitus (T2DM). Insulin-like growth factor I (IGF-I) and growth hormone (GH), which interact with insulin to modulate metabolic control, have been shown to be related to impaired glucose tolerance. This study was conducted to assess the possibility that altered circulating IGF-I and GH levels contribute to the exacerbation of T2DM by alcohol use in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats.

Main method

OLETF rats were pair-fed a Lieber-DeCarli Regular Ethanol diet and LETO rats were pair-fed a control diet for 6 weeks. At 6 weeks, an Intraperitoneal Glucose Tolerance Test (IP-GTT) was performed and IGF-I and GH levels were evaluated.

Key findings

Prior to an IP-GTT, OLETF-Ethanol (O-E) group had significantly a decrease in the mean glucose levels compared to OLETF-Control (O-C) group. At 120 min post IP-GTT, the O-E group had significantly an increase in the mean glucose levels compared to O-C group. The serum IGF-I levels were significantly lower and the serum GH levels were significantly higher in the O-E group than in L-C group.

Significance

These results suggest that IGF-I and GH are prominent in defining the risk and development of T2DM, and may be adversely affected by heavy alcohol use, possibly mediating its diabetogenic effects. Thus, the overall glucose intolerance in the setting of alcoholism may be attributable to inappropriate alteration of IGF-I and GH levels.     

First-in-Human Phase I Study of PRS-050 (Angiocal), an Anticalin Targeting and Antagonizing VEGF-A,in Patients with Advanced Solid Tumors

Background

To report the nonrandomized first-in-human phase I trial of PRS-050, a novel, rationally engineered Anticalin based on human tear lipocalin that targets and antagonizes vascular endothelial growth factor A (VEGF-A).

Methods

Patients with advanced solid tumors received PRS-050 at 0.1 mg/kg to 10 mg/kg by IV in successive dosing cohorts according to the 3+3 escalation scheme. The primary end point was safety.

Results

Twenty-six patients were enrolled; 25 were evaluable. Two patients experienced dose-limiting toxicity, comprising grade (G) 3 hypertension and G3 pyrexia, respectively. The maximum tolerated dose was not reached. Most commonly reported treatment-emergent adverse events (AEs) included chills (52%; G3, 4%), fatigue (52%; G3, 4%), hypertension (44%; G3, 16%), and nausea (40%, all G1/2). No anti–PRS-050 antibodies following multiple administration of the drug were detected. PRS-050 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately 6 days. Free VEGF-A was detectable at baseline in 9/25 patients, becoming rapidly undetectable after PRS-050 infusion for up to 3 weeks. VEGF-A/PRS-050 complex was detectable for up to 3 weeks at all dose levels, including in patients without detectable baseline-free VEGF-A. We also detected a significant reduction in circulating matrix metalloproteinase 2, suggesting this end point could be a pharmacodynamic (PD) marker of the drug’s activity.

Conclusions

PRS-050, a novel Anticalin with high affinity for VEGF-A, was well-tolerated when administered at the highest dose tested, 10 mg/kg. Based on target engagement and PK/PD data, the recommended phase II dose is 5 mg/kg every 2 weeks administered as a 120-minute infusion.

Trial Registration

ClinicalTrials.gov NCT01141257 http://clinicaltrials.gov/ct2/show/NCT01141257     

A garlic derivative, S-allylcysteine (SAC), suppresses proliferation and metastasis of hepatocellular carcinoma

Background

Hepatocellular carcinoma (HCC) is highly malignant and metastatic. Currently, there is no effective chemotherapy for patients with advanced HCC leading to an urgent need to seek for novel therapeutic options. We aimed to investigate the effect of a garlic derivative, S-allylcysteine (SAC), on the proliferation and metastasis of HCC.

Methodology/Principal Findings

A series of in vitro experiments including MTT, colony-forming, wound-healing, invasion, apoptosis and cell cycle assays were performed to examine the anti-proliferative and anti-metastatic effects of SAC on a metastatic HCC cell line MHCC97L. The therapeutic values of SAC single and combined with cisplatin treatments were examined in an in vivo orthotopic xenograft liver tumor model. The result showed that the proliferation rate and colony-forming abilities of MHCC97L cells were suppressed by SAC together with significant suppression of the expressions of proliferation markers, Ki-67 and proliferating cell nuclear antigen (PCNA). Moreover, SAC hindered the migration and invasion of MHCC97L cells corresponding with up-regulation of E-cadherin and down-regulation of VEGF. Furthermore, SAC significantly induced apoptosis and necrosis of MHCC97L cells through suppressing Bcl-xL and Bcl-2 as well as activating caspase-3 and caspase-9. In addition, SAC could significantly induce the S phase arrest of MHCC97L cells together with down-regulation of cdc25c, cdc2 and cyclin B1. In vivo xenograft liver tumor model demonstrated that SAC single or combined with cisplatin treatment inhibited the progression and metastasis of HCC tumor.

Conclusions/Significance

Our data demonstrate the anti-proliferative and anti-metastatic effects of SAC on HCC cells and suggest that SAC may be a potential therapeutic agent for the treatment of HCC patients.     

An outbreak of dengue fever in St. Croix (US Virgin Islands), 2005

Background

Periodic outbreaks of dengue fever occur in the United States Virgin Islands. In June 2005, an outbreak of dengue virus (DENV) serotype-2 with cases of dengue hemorrhagic fever (DHF) was detected in St. Croix, US Virgin Islands. The objective of this report is to describe this outbreak of DENV-2 and the findings of a case-control study examining risk factors for DHF.

Methodology/Principal Findings

This is the largest dengue outbreak ever recorded in St. Croix, with 331 suspected dengue cases reported island-wide during 2005 (62.2 cases/10,000 population); 54% were hospitalized, 21% had at least one hemorrhagic manifestation, 28% had thrombocytopenia, 5% had DHF and 1 patient died. Eighty-nine laboratory-positive hospitalized patients were identified. Of these, there were 15 (17%) who met the WHO criteria for DHF (cases) and 74 (83%) who did not (controls). The only variable significantly associated with DHF on bivariate or multivariable analysis was age, with an adjusted odds ratio (95% confidence interval) of 1.033 (1.003,1.064).

Conclusions/Significance

During this outbreak of DENV-2, a high proportion of cases developed DHF and increasing age was significantly associated with DHF.     

Silent coronary artery disease in type 2 diabetes mellitus: the role of Lipoprotein(a), homocysteine and apo(a) polymorphism

Background  

There is little data on the relationship between novel cardiovascular risk factors and silent coronary artery disease (CAD) in diabetic patients. We investigated whether Lipoprotein(a), homocysteine and apolipoprotein(a) polymorphism are associated with angiographically assessed asymptomatic coronary artery disease (CAD) in diabetic patients.