Background: TAS-114 is a first-in-class oral deoxyuridine triphosphatase inhibitor, which acts as a modulator of the pyrimidine nucleotide metabolic pathway. Phase 1 study are conducting a phase 1 ...study of combination treatment with TAS-114 and S-1 to investigate the safety, and to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in patients (pts) with advanced solid tumors refractory to standard therapy. Material and Methods: TAS-114 was administrated orally BID for 14 days followed by 7 days rest at the starting dosage of 5mg/m2 with the fixed dosage of S-1 (30 mg/m2) in a fasting condition. Dose-limiting toxicity (DLT) was assessed using a 3 + 3 design during the first cycle in dose escalation cohort (DEC). Expansion cohort (EC) was conducted in parallel with DEC at the dosage with confirmed tolerability and efficacy in DEC. Results: 76 pts were enrolled with 48 pts in the DEC and 28 pts in the EC. In DEC, dosage of TAS-114 was escalated up to 240 mg/m2. The dosages of S-1 and TAS-114 were then escalated up to 36 mg/m2 and 240 mg/m2, respectively, In 240 mg/m2 of TAS-114. 2 patients of 5 patients enrolled at this dose level had DLTs (Grade 4 platelet count decreased and Grade 3 dermatitis bullous). Therefore 1 lower level was expanded to 6 pts and there were no further DLTs. Based on the above results, the MTD of TAS-114 in combination with S-1 at 36 mg/m2 was estimated to be 200 mg/m2. However, considering other safety data and treatment continuity in DEC and EC, the RD was determined to be TAS-114 at 240 mg/m2 in combination with S-1 at 30 mg/m2, which is the same MTD in the Western study (TAS-114-102). Pharmacokinetics of TAS-114 and S-1 components were dose proportional and consistent with the data in the Western population. The most common treatment related adverse events were anemia, white blood cell count decreased, decreased appetite and rash. Preliminary antitumor efficacy was observed in pts with non-small cell lung cancer (NSCLC). gastric cancer, pancreatic neuroendocrine tumor and gallbladder cancer. Of note, the overall response rate were 31.3% (Including unconfirmed PR) including 2 squamous cancer patients Disease control rate (DCR) was 50% and median progression free survival was 4.2 months in heavily pre-treated patients with NSCLC (Median 3.5 prior regimens). Conclusions: TAS-114 in combination with S-1 was well tolerated in pts with heavily treated advanced solid tumors, resulting in the promising antitumor efficacy. Further safety and efficacy of the global recommended dose of this combination therapy will be investigated in a phase 2 study. Clinical trial information: NCT01610479
The influence of electron energy distribution on helium recombining plasma diagnostics is investigated using a helium collisional‐radiative model. The population densities of excited helium atoms are ...calculated for Maxwellian and non‐Maxwellian distribution plasma cases. In the case of the Maxwellian distribution plasma, the electron temperature and electron density determined by the Boltzmann plot method agree well with the input plasma parameters. On the other hand, it is indicated that the electron temperature and electron density are significantly underestimated in the bi‐Maxwellian distribution plasma case, even though the density of the hot electron components is three orders smaller than that of the bulk electrons. This result indicates that in a non‐Maxwellian helium recombining plasma, evaluation of the particle balance based on line emissions from excited helium atoms would be difficult because the reaction rate of atomic and molecular processes is strongly dependent on the electron temperature and density.
The correlation of oxidative stress on development and DNA damage in bovine embryos was investigated by the comet assay (single-cell microgel electrophoresis), an effective technique for detecting ...single-strand DNA breakage. After in vitro maturation and fertilization, one-cell stage embryos without cumulus cells were cultured for 8 days in SOF medium containing amino acids plus 5 % FCS under low (5%) and atmospheric (20 %) oxygen concentration. After 8 days of culture, the extent of blastocyst formation was significantly decreased (P<0.001) when embryos were cultured under 20 % oxygen concentration (5.8 ± 2.4 %) when compared to embryos cultured under 5 % oxygen concentration (35.1 ± 6.7 %). At the day 3 of development, DNA damage of individual embryos cultured under 5 % or 20 % oxygen concentration was measured by the comet assay, which entails microgel electrophoresis that can readily detect damaged DNA. After measuring the DNA damage in individual embryos by the comet assay, the length (149.9 ± 15.3 μm) of the migrating DNA fragment that is indicative of damaged DNA was significantly increased (P<0.001) in the embryos cultured under 20 % oxygen concentration when compared to embryos cultured in 5 % oxygen concentration (42.3 ± 7 μm). The length of damaged DNA in more than 50 % of embryos was less than 50 μm. when embryos were cultured under 5 % oxygen concentration. In contrast, the distribution of damaged DNA shifted to the more damaged extent when embryos were cultured under 20 % oxygen concentration. These results demonstrate that the retardation in bovine embryo development than in likely due oxidative stress as a consequence of the higher atmospheric oxygen concentration is positively correlated with an increase in the extent of DNA damage. Moreover, these results demonstrate that the comet assay is a useful method to evaluate embryo culture conditions.
Weight gain has been identified as being responsible for increased morbidity and mortality rates of schizophrenia patients. For the management of weight gain, exercise is one of the most acknowledged ...interventions. At the same time, exercise and sports have been recognized for their positive impact on psychiatric symptoms of schizophrenia. However, the neurobiological basis for this remains poorly understood. We aimed to examine the effect of sports participation on weight gain, psychiatric symptoms and brain activation during sports observation in schizophrenia patients. Thirteen schizophrenia patients who participated in a 3-month program, including sports participation and 10 control schizophrenia patients were studied. In both groups, body mass index (BMI), Positive and Negative Syndrome Scale (PANSS), and brain activation during observation of sports-related actions measured by functional magnetic resonance imaging were accessed before and after a 3-month interval. BMI and general psychopathology scale of PANSS were significantly reduced in the program group but not in the control group after a 3-month interval. Compared with baseline, activation of the body-selective extrastriate body area (EBA) in the posterior temporal-occipital cortex during observation of sports-related actions was increased in the program group. In this group, increase in EBA activation was associated with improvement in the general psychopathology scale of PANSS. Sports participation had a positive effect not only on weight gain but also on psychiatric symptoms in schizophrenia. EBA might mediate these beneficial effects of sports participation. Our findings merit further investigation of neurobiological mechanisms underlying the therapeutic effect of sports for schizophrenia.
Epidermal growth factor (EGF) comprises a structurally related family of proteins containing heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor alpha (TGFalpha) that ...regulates the development of dopaminergic neurons as well as monoamine metabolism. We assessed the contribution of EGF to schizophrenia by measuring EGF family protein levels in postmortem brains and in fresh serum of schizophrenic patients and control subjects. EGF protein levels were decreased in the prefrontal cortex and striatum of schizophrenic patients, whereas the levels of HB-EGF and TGFalpha were not significantly different in any of the regions examined. Conversely, EGF receptor expression was elevated in the prefrontal cortex. Serum EGF levels were markedly reduced in schizophrenic patients, even in young, drug-free patients. Chronic treatment of animals with the antipsychotic drug haloperidol had no influence on EGF levels in the brain or serum. These findings suggest that there is abnormal EGF production in various central and peripheral tissues of patients with both acute and chronic schizophrenia. EGF might thus provide a molecular substrate for the pathologic manifestation of the illness, although additional studies are required to determine a potential link between impaired EGF signaling and the pathology/etiology of schizophrenia.
This is the first study on the hemolymph from a spider of the Loxosceles genus. These animals are responsible for a great number of envenomation cases worldwide. Several studies on Loxosceles venoms ...have been published, and the knowledge about the venom and its toxins is considerable, not only regarding the biological and biochemical characterization, but also regarding structural, genetic and phylogenetic approaches. However, the literature on Loxosceles hemolymph is nonexistent. The main goal of the present study was to characterize biochemically the hemolymph content, and especially, to identify its different hemocytes. Moreover, many papers have already shown molecules whose source is the hemolymph and their very interesting activities and biomedical applications, for example, antifungal and antibacterial activities. A 2D-SDS-PAGE of brown spider hemolymph showed approximately 111 spots for pH 3–10 and 150 spots for pH 4–7. A lectin-blotting assay showed that hemolymph carbohydrate residues were similar to those found in venom. Several types of TAG and DAG phospholipids were found in the hemolymph and characterized by HPTLC and mass spectrometry. Four different hemocytes were characterized in Loxosceles intermedia hemolymph: prohemocyte, plasmatocyte, granulocyte and adipohemocyte. This paper opens new possibilities on toxinology, studying an unknown biological material, and it characterizes a source of molecules with putative biotechnological applications.
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•Groundbreaking characterization of Brown spider hemolymph (Loxosceles genus).•Biochemical characterization of protein and lipid molecules from Brown spider hemolymph.•Glycosylation profile of Brown spider hemolymph proteins.•Identification of hemocytes from Brown spider hemolymph.
We implemented a two-step approach to detect potential predictor gene variants for neuroleptic-induced tardive dyskinesia (TD) in schizophrenic subjects. First, we screened associations by using a ...genome-wide (Illumina HumanHapCNV370) SNP array in 61 Japanese schizophrenia patients with treatment-resistant TD and 61 Japanese schizophrenia patients without TD. Next, we performed a replication analysis in 36 treatment-resistant TD and 138 non-TD subjects. An association of an SNP in the DPP6 (dipeptidyl peptidase-like protein-6) gene, rs6977820, the most promising association identified by the screen, was significant in the replication sample (allelic P=0.008 in the replication sample, allelic P=4.6 × 10(-6), odds ratio 2.32 in the combined sample). The SNP is located in intron-1 of the DPP6 gene and the risk allele was associated with decreased DPP6 gene expression in the human postmortem prefrontal cortex. Chronic administration of haloperidol increased Dpp6 expression in mouse brains. DPP6 is an auxiliary subunit of Kv4 and regulates the properties of Kv4, which regulates the activity of dopaminergic neurons. The findings of this study indicate that an altered response of Kv4/DPP6 to long-term neuroleptic administration is involved in neuroleptic-induced TD.
Microstructure and texture evolution in the near-surface layer during friction stir processing (FSP) of AZ31 magnesium alloy was studied. Material flow was found to be a very complex process ...consisting of several stages. The material in front of the friction stir tool was first deformed by the rotating shoulder. Then, approaching the tool, it experienced a secondary deformation caused by the rotating pin, and finally, behind the tool, it again underwent a tertiary deformation induced by the shoulder. The texture evolution was shown to dictate the grain structure development.
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