Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with metastatic colorectal cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with metastatic colorectal cancer (mCRC), published in late 2022, were adapted in December 2022, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with mCRC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with mCRC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), co-ordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian countries. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with mCRC across the different countries of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation, coupled with a disparity in the drug approvals and reimbursement strategies, between the different countries.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis treatment and follow-up of patients with localised colon cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of localised colon cancer was published in 2020. It was decided by both the ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special virtual guidelines meeting in March 2021 to adapt the ESMO 2020 guidelines to take into account the ethnic differences associated with the treatment of localised colon cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with localised colon cancer representing the oncological societies of Japan (JSMO), China (CSCO), India (ISMPO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug availability and reimbursement situations in the different Asian countries.

Anterior resection syndrome: a randomized clinical trial of a 5-HT3 receptor antagonist (ramosetron) in male patients with rectal cancer.

BACKGROUND: No effective treatment exists for anterior resection syndrome (ARS) following sphincter-saving surgery for rectal cancer. This RCT assessed the safety and efficacy of a 5-HT3 receptor antagonist, ramosetron, for ARS. METHODS: A single-centre, randomized, controlled, open-label, parallel group trial was conducted. Male patients with ARS 1 month after rectal cancer surgery or ileostomy reversal were enrolled and randomly assigned (1 : 1) to 5 µg of ramosetron (Irribow®) daily or conservative treatment for 4 weeks. Low ARS (LARS) score was calculated after randomization and 4 weeks after treatment. The study was designed as a superiority test with a primary endpoint of the proportion of patients with major LARS between the groups. Primary outcome analysis was based on the modified intention-to-treat population. Safety was assessed by monitoring adverse events during the study. RESULTS: : A total of 100 patients were randomized to the ramosetron (49 patients) or conservative treatment group (51 patients). Two patients were excluded, and 48 and 50 patients were analysed in the ramosetron and control groups, respectively. The proportion of major LARS after 4 weeks was 58 per cent (28 of 48 patients) in the ramosetron group versus 82 per cent (41 of 50 patients) in the control group, with a difference of 23.7 per cent (95 per cent c.i. 5.58 to 39.98, P = 0.011). There were minor adverse events in five patients, which were hard stool, frequent stool or anal pain. These were not different between the two groups. There were no serious adverse events. CONCLUSION: : Ramosetron could be safe and feasible for male patients with ARS. TRIAL REGISTRATION NUMBER: NCT02869984 (http://www.clinicaltrials.gov).

Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, open-label, randomized, phase III, noninferiority trial.

BACKGROUND: Capecitabine plus oxaliplatin (XELOX) has shown modest activity and tolerable toxicity in a phase II trial for biliary tract cancers (BTCs). Meanwhile, gemcitabine plus oxaliplatin (GEMOX) has been the reference arm in recent phase II and III trials for BTCs. We aimed to investigate the efficacy of XELOX versus GEMOX as first-line therapy for advanced BCTs. PATIENTS AND METHODS: In this open-label, randomized, phase III, noninferiority trial, we randomly selected patients with metastatic BCTs to receive GEMOX (gemcitabine 1000 mg/m2 on days 1 and 8, and oxaliplatin 100 mg/m2 on day 1) or XELOX (capecitabine 1000 mg/m2, twice daily, on days 1-14 and oxaliplatin 130 mg/m2 on day 1) as first-line treatment, given every 3 weeks, totaling eight cycles. The primary end point was to prove the noninferiority of XELOX to GEMOX in terms of 6-month progression-free survival (PFS) rate. RESULTS: In total, 114 patients randomly received GEMOX and 108 randomly received XELOX. The median PFS was 5.3 months for the GEMOX group and 5.8 months for the XELOX group. The 6-month PFS rate was 44.5% for the GEMOX group and 46.7% for the XELOX group. The 95% confidence interval of the 6-month PFS rate difference between both groups was -12% to 16%, meeting the criteria for noninferiority of XELOX to GEMOX. There was no difference in objective response (P=0.171) and median overall survival (P=0.131) between both groups. The most common grade three to four adverse events were neutropenia and thrombocytopenia. No patient died of treatment-related causes. The XELOX group had significantly lower frequencies of hospital visits than the GEMOX group (P<0.001). CONCLUSION: XELOX showed significant noninferiority to GEMOX in terms of 6-month PFS rate. Thus, XELOX could be an alternative first-line treatment of BCTs. TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov (number NCT01470443).

Clinical impact of tumor volume reduction in rectal cancer following preoperative chemoradiation.

PURPOSE: The purpose of this study was to correlate tumor volumetric analysis obtained using magnetic resonance (MR) imaging with disease-free survival in patients with advanced rectal cancer who underwent preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS: Institutional review board approval was obtained and patient informed consent was waived. This study included 74 patients (47 men, 27 women; mean age, 64 years±10 [SD] years) who underwent preoperative CRT and subsequent rectal surgery between January 2007 and December 2010. Two radiologists who were blinded to the clinical outcome measured tumor volume separately on two sets of MR images obtained before and after CRT. Patients were classified into two groups according to the episode of recurrence and recorded disease-free survival. To assess factors relevant to disease-free survival, univariate and multivariate Cox regression analysis were performed for tumor volume reduction ratio, circumferential resection margin, tumor regression grade, and pathologic staging. RESULTS: Tumor volume reduction ratio (P=0.009), circumferential resection margin (P=0.008) and tumor regression grade (P=0.002) were significantly associated with disease-free survival. At multivariate analysis, tumor volume reduction ratio was the single variable that was associated with disease-free survival (P=0.003). Tumor volume reduction ratio was also a reliable parameter with an excellent interobserver correlation between two readers for pre-CRT volume (ICC=0.939; 95%CI: 0.885-0.979; P<0.001) and post-CRT volume (ICC=0.889; 95%CI: 0.845-0.934; P<0.001). CONCLUSIONS: MR volumetric measurement of rectal cancer helps predict disease-free survival in patients with rectal cancer who underwent preoperative CRT.

Wnt addiction of genetically defined cancers reversed by PORCN inhibition.

Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Whether these mutations identify a clinical opportunity is an important question. Inhibition of Wnt secretion by blocking an essential post-translational modification, palmitoleation, provides a useful therapeutic intervention. We developed a novel potent, orally available PORCN inhibitor, ETC-1922159 (henceforth called ETC-159) that blocks the secretion and activity of all Wnts. ETC-159 is remarkably effective in treating RSPO-translocation bearing colorectal cancer (CRC) patient-derived xenografts. This is the first example of effective targeted therapy for this subset of CRC. Consistent with a central role of Wnt signaling in regulation of gene expression, inhibition of PORCN in RSPO3-translocated cancers causes a marked remodeling of the transcriptome, with loss of cell cycle, stem cell and proliferation genes, and an increase in differentiation markers. Inhibition of Wnt signaling by PORCN inhibition holds promise as differentiation therapy in genetically defined human cancers.

Genetic analysis and genomic selection of stayability and productive life in New Zealand ewes.

Genetic parameters for ewes were estimated for stayability (STAY) and productive life (Prodlife). Records from 658,871 animals from 241 seed stock or ram breeder flocks and one research flock were used to estimate parameters for ram breeder flock STAY and Prodlife. These flocks would have a culling policy based on criteria typical of a commercial enterprise, but including culls based on knowledge such as estimated breeding values. A subset of 35,688 of these animals from 4 ram breeder and one research flock was used to infer the animals that might be culled based on the perspective of a commercial flock as these flocks recorded reasons for culling. These data were used to estimate parameters for commercial flock STAY and Prodlife. Heritability for ram breeder flock STAY until age 3 to 6 yr ranged from 0.07 to 0.09. The heritability of commercial flock STAY was similar in yr 5 and 6, but lower at 0.05 (age 3) and 0.07 (age 4). Heritability of Prodlife for ram breeder flock and commercial flock was respectively 0.10 and 0.13. The genetic correlations between ram breeder flock STAY and commercial flock STAY ranged from 0.20 to 0.99. Both STAY and Prodlife were most correlated genetically with the trait number of lambs born, at about 0.4, and to a lesser degree, live weight up to the age of 12 mo for the traits analyzed with lower genetic correlations estimated for the commercial flocks. Live weight at 18 mo and fleece weight had little or no correlation with STAY and Prodlife. From the data set used to estimate genetic parameters from a ram breeder flock, 4,330 animals were genotyped with the Illumina OvineSNP50 BeadChip and the genotypes used to develop genomic predictions via genomic best linear unbiased prediction. The animals used in the training data set were multibreed, but were heavily Romney breed based. The genomic prediction accuracy for ram breeder flock STAY, according to breed, was dependent on sample size and ranged from 0.4 to 0.44 for Romney and 0.26 to 0.4 for Coopworth. Accuracies for Perendale and Composites, for which sample sizes were less, were more variable. This study has derived genetic parameters for STAY and Prodlife and investigated genomic predictions for these traits. As these traits are of low heritability, sex limited and expressed late in life genomic selection will be useful.

Inhibition of prolactin with bromocriptine for 28days increases blood-brain barrier permeability in the rat.

The blood-brain barrier (BBB) is necessary for the proper function of the brain. Its maintenance is regulated by endogenous factors. Recent evidences suggest prolactin (PRL) regulates the BBB properties in vitro, nevertheless no evidence of these effects have been reported in vivo. The aim of this study was to evaluate the role of PRL in the maintenance of the BBB in the rat. Male Wistar rats were treated with Bromocriptine (Bromo) to inhibit PRL production for 28days in the absence or presence of lipopolysaccharide (LPS). BBB permeability was evaluated through the Evans Blue dye and fluorescein-dextran extravasation as well as through edema formation. The expression of claudin-5, occludin, glial fibrillary acidic protein (GFAP) and the PRL receptor (PRLR) was evaluated through western blot. Bromo reduced the physiological levels of PRL at 28days. At the same time, Bromo increased BBB permeability and edema formation associated with a decrement in claudin-5 and occludin and potentiated the increase in BBB permeability induced by LPS. However, no neuroinflammation was detected, since the expression of GFAP was unchanged, as well as the expression of the PRLR. These data provide the first evidence that inhibition of PRL with Bromo affects the maintenance of the BBB through modulating the expression of tight junction proteins in vivo.

Single-walled carbon nanotubes (SWCNTs) induce vasodilation in isolated rat aortic rings.

Single-walled carbon nanotubes (SWCNTs) are used in biological systems with impact in biomedicine in order to improve diagnostics and treatment of diseases. However, their effects upon the vascular system, are not fully understood. Endothelium and smooth muscle cells (SMC) communicate through release of vasoactive factors as nitric oxide (NO) to maintain vascular tone. The aim of this study was to evaluate the effect of SWCNTs on vascular tone using isolated rat aortic rings, which were exposed to SWCNTs (0.1, 1 and 10 µg/mL) in presence and absence of endothelium. SWCNTs induced vasodilation in both conditions, indicating that this effect was independent on endothelium; moreover that vasodilation was NO-independent, since its blockage with L-NAME did not modify the observed effect. Together, these results indicate that SWCNTs induce vasodilation in the macrovasculature, may be through a direct interaction with SMC rather than endothelium independent of NO production. Further investigation is required to fully understand the mechanisms of action and mediators involved in the signaling pathway induced by SWCNTs on the vascular system.

Gamma-tocotrienol attenuates high-fat diet-induced obesity and insulin resistance by inhibiting adipose inflammation and M1 macrophage recruitment.

BACKGROUND AND OBJECTIVE: We have previously demonstrated that gamma tocotrienol (γT3) potently inhibits adipocyte hyperplasia in human adipose-derived stem cells (hASCs). In this study, our objective was to investigate the γT3 effects on early-onset obesity, inflammation and insulin resistance in vivo. METHODS: Young C57BL/6J mice were fed a high-fat (HF) diet supplemented with 0.05% γT3 for 4 weeks. The concentrations of γT3 in plasma and adipose tissue were measured using high-performance liquid chromatography. Effects of γT3 on body weight gain, adipose volume, plasma levels of fasting glucose, insulin (enzyme-linked immunosorbent assay (ELISA)), proinflammatory cytokines (mouse cytokine array), insulin signaling (western blotting) and gene expression (quantitative real-time PCR, qPCR) in the liver and adipose tissue were examined. Influences of γT3 on [3H]-2-deoxyglucose uptake and lipopolysaccharide (LPS)-mediated NFκB signaling (western blotting) were assessed in hASCs. Effects of γT3 on macrophage M1/M2 activation were investigated using qPCR in mouse bone marrow-derived macrophages. RESULTS: After a 4-week treatment, γT3 accumulated in adipose tissue and reduced HF diet-induced weight gain in epididymal fat, mesenteric fat and the liver. Compared with HF diet-fed mice, HF+γT3-fed mice were associated with (1) decreased plasma levels of fasting glucose, insulin and proinflammatory cytokines, (2) improved glucose tolerance and (3) enhanced insulin signaling in adipose tissue. There were substantial decreases in macrophage specific markers, and monocyte chemoattractant protein-1, indicating that γT3 reduced the recruitment of adipose tissue macrophages (ATMs). In addition, γT3 treatment in human adipocytes resulted in (1) activation of insulin-stimulated glucose uptake and (2) a significant suppression of MAP kinase and NFκB activation. In parallel, γT3 treatment led to a reduction of LPS-mediated M1 macrophage polarization. CONCLUSION: Our results demonstrated that γT3 ameliorates HF diet-mediated obesity and insulin resistance by inhibiting systemic and adipose inflammation, as well as ATM recruitment.

Towards genomic selection for facial eczema disease tolerance in the New Zealand sheep industry.

Pithomycotoxicosis, more commonly known as facial eczema (FE), is a liver disease that occurs predominantly in New Zealand because of its toxigenic Pithomyces chartarum strains. The first reported case was in sheep in 1887. Since the 1930s, a number of studies have been conducted in an attempt to mitigate the problems FE has on the sheep and dairy industries. The research in these studies included work on fungicide and biological control of the saprophytic fungus, use of different pasture plants to inhibit fungal growth, stock management with respect to pasture fungal spore counts and the use of zinc prophylaxis on animals. The finding that there was a genetic basis in FE sensitivity in sheep prompted research for a genetic approach to mitigation in the form of a diagnostic DNA test for susceptibility to the disease. Recently, we have used the Illumina OvineSNP50 BeadChip to develop a genome-enabled prediction approach to screen for FE-tolerant sheep. Our current best genomic prediction for FE is for the Romney breed and has an accuracy of 0.38. This prediction accuracy is not as high as the individual accuracy gained by an artificial challenge test (0.64). However, it has the advantage of being a non-invasive test and can be provided as part of genomic testing for other traits at minimal cost.

First Report of Clover yellow vein virus on White Clover (Trifolium repens) in South Korea.

White clover (Trifolium repens L.) is a herbaceous, perennial plant that has become one of the most widely distributed legumes in the world. It is extensively used in grass-legume pastures, but also has the potential to invade agricultural lands and natural ecosystems. White clover is a well-known natural host for Alfalfa mosaic virus (AMV), Clover yellow vein virus (ClYVV), Soybean dwarf virus (SbDV), Beet western virus (BWYV), Tomato spotted wilt virus (TSWV), Zucchini yellow mosaic virus (ZYMV), etc (1). In July 2013, during a survey to determine the presence of different viruses infecting weed plants in South Korea, three white clover leaf samples showing yellow mosaic symptoms were collected from Taean County, South Chungcheong Do Province, South Korea. In order to identify the infecting virus, total RNA from three leaf samples was extracted using the Tri-reagent (MRC Reagent, Inc., OH) as described by the manufacturer, and was applied to the large-scale oligonucleotide (LSON) chip (3), wherein probes specific to a ClYVV isolate produced a positive reaction. All three samples tested were positive for ClYVV. To confirm this result, ClYVV-specific primers were designed using the sequences of four ClYVV isolates from NCBI (GenBank Accession Nos. AF185959, AF203536, DQ333346, and NC003536). Total RNA was extracted from symptomatic white clover samples using Easy-Spin Total RNA Extraction Kit (iNtRon, Daejeon, Korea) and used as template for RT-PCR. The positive control RNA was used from ClYVV GM isolate (KF975894) and negative control RNA used symptomless white clover plants. The ClYVV coat protein (CP) gene was amplified by RT-PCR using the specific primer pairs ClYVV-CP-F / ClYVV-CP-R (5'-CAAGAGCAGCACGATGAG-3' and 5'-CTCGCTCTATAAAGATCAGAT-3'). DNA fragments of the expected size (1,042 bp) were obtained from the white clover Korea isolate (AB930132), and the PCR product was cloned into a T&A cloning vector (RBC Bioscience, Taipei, Taiwan) and sequenced directly in both directions. BLAST analyses of the nucleotide sequence CP gene fragments revealed the highest identity with 98% with other ClYVV isolates (AF203536). To determine the experimental host range of the ClYVV Korea isolate, we inoculated five species (Chenopodium amaranticolor, C. quinoa, Nicotiana clevelandii, N. benthamiana, and Trifolium repens) in three families using this isolate. All test plants were mechanically inoculated with 0.1 M phosphate buffered saline (Takara, Tokyo, Japan). Each test plant was inoculated nine times and grown in a greenhouse maintained at 27 to 33°C. Necrotic local lesions were produced on inoculated leaves of C. amaranticolor, C. quinoa, and N. clevelandii 4 to 6 days post-inoculation. After 10 to 14 days, C. amaranticolor and C. quinoa showed systemic chlorotic spot symptoms, and N. clevelandii, N. benthamiana, and T. repens showed chlorotic spot, mild mosaic, and mosaic in the upper leaves, respectively. Up to now, in South Korea, ClYVV has been detected in gladiolus (Gladiolus gandavensis) (3) and soybean (Glycine max) (4). ClYVV can be easily transmitted by insect, aphid, or mechanical inoculation and has a host range including tobacco, soybean, etc. The presence of ClYVV could become an important threat to crop production in South Korea. To our knowledge, this is the first report of a ClYVV infection of the white clover plant in South Korea. References: (1) B. L. Denny and P. L. Guy. Australas. Plant Pathol. 38:270, 2009. (2) M. Nam et al. Plant Pathol. J. 30:51, 2014. (3) I. S. Park et al. Korean J. Plant Pathol. 14:74, 1998. (4) J. C. Shin et al. Plant Dis. 98:1283, 2014.

Evaluation of the antioxidant effect of ganghwayakssuk (Artemisia princeps Pamp.) extract alone and in combination with ascorbic acid in raw chicken patties.

We investigated the inhibition of lipid oxidation of raw chicken patties by the antioxidants ascorbic acid (Aa), ganghwayakssuk extracts (GE), and their combination (Aa + GE). All antioxidant combinations were effective at delaying lipid oxidation compared with the control or Aa. A combination of Aa + GE (0.05% Aa + 0.2% GE) was the most effective for delaying lipid oxidation (TBA reactive substances, conjugated dienes, and peroxide formation). The color values of all samples were significantly affected by adding GE. Additionally, the redness, color difference, and hue values of all treatments, except for Aa, were lower than those of the control as the amount of GE increased. The total viable bacterial counts of samples with GE 0.2 and Aa + GE 0.2 were significantly affected during storage (P < 0.05). The results suggest that adding an antioxidant combination reduced the oxidative stress and microbial growth of raw chicken patties stored for 12 d under normal refrigeration temperature, which may extend the shelf life of chicken patties.

MicroRNA expression profiles in placenta with severe preeclampsia using a PNA-based microarray.

INTRODUCTION: Preeclampsia (PE) is a leading cause of maternal and neonatal mortality and morbidity worldwide. However, the pathophysiology of this disease is not yet fully understood. MiRNA plays an important role in post-transcriptional gene regulation. Recent studies have suggested that dysregulation of miRNAs in placental tissue is involved in the pathogenesis of PE. Therefore, we investigated miRNA profiles in PE placenta to understand the miRNA function in PE pathogenesis. METHODS: MiRNA profiling was performed in 20 formalin-fixed and paraffin-embedded samples (10 placentas from severe PE and 10 from a control group). We used a hybridization-based microarray with a PNA-probe comprised of 158 miRNAs. RESULTS: Thirteen miRNAs (miR-92b, miR-197, miR-342-3p, miR-296-5p, miR-26b, miR-25, miR-296-3p, miR-26a, miR-198, miR-202, miR-191, miR-95, and miR-204) were significantly overexpressed and two miRNAs (miR-21 and miR-223) were underexpressed in PE compared with the control group. Among 15 differentially expressed miRNAs, miR-26b, miR-296-5p, and miR-223 were found to be consistent with results from previous studies. We identified 893 genes that were predicted by at least three of four computational algorithms. Target genes participated in several signaling pathways, adherens junction, focal adhesion, and regulation of the actin cytoskeleton. CONCLUSIONS: Several miRNAs are found to be dysregulated in placentas of PE patients and they seem to be closely associated with the early pathogenesis of PE. Further study is necessary to develop tools for early detection and management.

Different transcriptional responses of heat shock protein 70/90 in the marine diatom Ditylum brightwellii exposed to metal compounds and endocrine-disrupting chemicals.

Environmental hazard assessments using diatoms have been well documented; however, their molecular toxicology has not been sufficiently studied. In this study, we characterized heat shock protein (HSP) 70/90 of the diatom Ditylum brightwellii (Db) and evaluated their transcriptional profiles in response to various environmental stresses (e.g., thermal shocks and metal and non-metal pollutants). Putative DbHSP70 (658aa, 71.7 kDa) and DbHSP90 (707aa, 80.2 kDa) proteins had conserved HSP family motifs but different C-terminus motifs, that is, "EEVD" in DbHSP70 and "MEEVD" in DbHSP90. Phylogenetic analyses of both proteins showed that D. brightwellii was well clustered with other diatoms. Real-time PCR analysis showed that thermal stress considerably upregulated DbHSP70 and DbHSP90. As for chemical pollutants, DbHSP70 greatly responded to CuSO4 and NiSO4 exposure, but not CuCl2 or NiCl2. However, DbHSP90 was significantly upregulated by all the metal compounds tested (CuSO4, NiSO4, CuCl2, and NiCl2). Strikingly, the expression of both genes was not induced by the organic pollutants tested, such as endocrine-disrupting chemicals. These data suggest that DbHSP70 and DbHSP90 are differentially involved in the defense response against various environmental stressors. Moreover, metal toxicity may be specifically affected by the conjugated anion in the metal compounds (e.g., SO4(2-) and Cl(-)).

The heliosphere's interstellar interaction: no bow shock.

As the Sun moves through the local interstellar medium, its supersonic, ionized solar wind carves out a cavity called the heliosphere. Recent observations from the Interstellar Boundary Explorer (IBEX) spacecraft show that the relative motion of the Sun with respect to the interstellar medium is slower and in a somewhat different direction than previously thought. Here, we provide combined consensus values for this velocity vector and show that they have important implications for the global interstellar interaction. In particular, the velocity is almost certainly slower than the fast magnetosonic speed, with no bow shock forming ahead of the heliosphere, as was widely expected in the past.

Efficacy and safety of sitagliptin and the fixed-dose combination of sitagliptin and metformin vs. pioglitazone in drug-naïve patients with type 2 diabetes.

AIM: The efficacy and safety of sitagliptin (SITA) monotherapy and SITA/metformin (MET) vs. pioglitazone (PIO) were assessed in patients with type 2 diabetes and moderate-to-severe hyperglycaemia (A1C = 7.5-12.0%). METHODS: In an initial 12-week phase (Phase A), 492 patients were randomised 1 : 1 in a double-blind fashion to SITA (100 mg qd) or PIO (15 mg qd, up-titrated to 30 mg after 6 weeks). In Phase B (28 additional weeks), the SITA group was switched to SITA/MET (up-titrated to 50/1000 mg bid over 4 weeks) and the PIO group was up-titrated to 45 mg qd RESULTS: At the end of Phase A, mean changes from baseline were -1.0% and -0.9% for A1C; -26.6 mg/dl and -28.0 mg/dl for fasting plasma glucose; and -52.8 mg/dl and -50.1 mg/dl for 2-h post-meal glucose for SITA and PIO, respectively. At the end of Phase B, improvements in glycaemic parameters were greater with SITA/MET vs. PIO: -1.7% vs. -1.4% for A1C (p = 0.002); -45.8 mg/dl vs. -37.6 mg/dl for fasting plasma glucose (p = 0.03); -90.3 mg/dl vs. -69.1 mg/dl for 2-h postmeal glucose (p = 0.001); and 55.0% vs. 40.5% for patients with A1C < 7% (p = 0.004). A numerically higher incidence of gastrointestinal adverse events and a significantly lower incidence of oedema were observed with SITA/MET vs. PIO. The incidence of hypoglycaemia was similarly low in both groups. Body weight decreased with SITA/MET and increased with PIO (-1.1 kg vs. 3.4 kg; p < 0.001). CONCLUSION: Improvements in glycaemic control were greater with SITA/MET vs. PIO, with weight loss vs. weight gain. Both treatments were generally well tolerated.

Direct observations of interstellar H, He, and O by the Interstellar Boundary Explorer.

Neutral gas of the local interstellar medium flows through the inner solar system while being deflected by solar gravity and depleted by ionization. The dominating feature in the energetic neutral atom Interstellar Boundary Explorer (IBEX) all-sky maps at low energies is the hydrogen, helium, and oxygen interstellar gas flow. The He and O flow peaked around 8 February 2009 in accordance with gravitational deflection, whereas H dominated after 26 March 2009, consistent with approximate balance of gravitational attraction by solar radiation pressure. The flow distributions arrive from a few degrees above the ecliptic plane and show the same temperature for He and O. An asymmetric O distribution in ecliptic latitude points to a secondary component from the outer heliosheath.

Welfare myths: the transmission of values and work among TANF families.

Both "welfare culture" arguments and structural explanations of poverty suggest that attitudes may have an effect on work and welfare outcomes. However, most scholars only examine objective behaviors and characteristics despite the fact that values are an underlying mechanism in explanations of the transmission of welfare and work behavior. Using data from a survey of recent welfare recipients in Louisiana and structural equation methods, we analyze causal relationships among family background, socioeconomic characteristics, attitudes, and two outcomes--TANF participation and employment. We find some support for the intergenerational transmission of welfare but not through values; we find no evidence that under the TANF system, values inhibit work.

Epithelioid trophoblastic tumor of paracervix and parametrium.

Epithelioid trophoblastic tumor (ETT) is an unusual variant of gestational trophoblastic tumor that is closely related to choriocarcinoma and placental site trophoblastic tumor but shows different morphologic and immunohistochemical features. We report an ETT discovered in paracervix, parametrium, and periadnexal soft tissue of a 44-year-old woman. She underwent laparoscopic surgery and four courses of chemotherapy with a regimen of etoposide, methotrexate, and dactinomycin. ETT has a distinctive growth pattern and immunohistochemical profile. The difficulties and clues in distinguishing ETT from nontrophoblastic lesions are discussed.