Numerical Study of TAP Metastable States in 3-body Ising Spin Glasses

The distribution of solutions of the Thouless-Anderson-Palmer equation is studied by extensive numerical experiments for fully connected 3-body interaction Ising spin glass models in a level of annealed calculation. A recent study predicted that when the equilibrium state of the system is characterized by one-step replica symmetry breaking, the distribution is described by a Becchi-Rouet-Stora-Tyutin (BRST) supersymmetric solution in the relatively low free energy region, whereas the BRST supersymmetry is broken for higher values of free energy (Crisanti et al., Phys. Rev. B 71 (2005) 094202). Our experiments qualitatively reproduce the discriminative behavior of macroscopic variables predicted by the theoretical assessment.Comment: 13 pages, 4 figure

Severe thrombocytopenia and maculopapular erythema-induced by regorafenib in a patient with advanced gastrointestinal stromal tumor

　A 28-year-old Japanese male was diagnosed with a gastrointestinal stromal tumor and multiple liver metastases at 23 years of age underwent gastrectomy and partial hepatectomy. At 27 year of age, multiple liver metastases and peritoneal dissemination were observed and the patient was switched to sunitinib. Approximately, one year later, the liver metastases worsened, and the patient was switched to regorafenib. Fatigue and palmar-plantar erythrodysesthesia syndrome occurred seven days after starting regorafenib, and thrombocytopenia occurred nine days later. Eleven days later, small erythema with fever and erythematous papules appeared throughout the body; therefore regorafenib was discontinued, and oral administration of steroids was initiated accordingly. After 17 days, platelets count decreased to 14,000/μL, prompting platelet transfusion. Maculopapular erythema was diagnosed based on the skin findings and histopathological examination. Oral and topical steroids were initiated and the maculopapular eruption gradually improved. A drug hypersensitivity reaction to regorafenib was diagnosed and treatment was discontinued, after which the patient entered a clinical trial for a new drug. We encountered a case of marked thrombocytopenia and maculopapular erythema during the early stages of regorafenib treatment. Regorafenib occasionally causes serious adverse events; therefore, careful observation and prompt treatment are necessary

PRDM14 Drives OCT3/4 Recruitment via Active Demethylation in the Transition from Primed to Naive Pluripotency

Primordial germ cells (PGCs) are specified from epiblast cells in mice. Genes associated with naive pluripotency are repressed in the transition from inner cell mass to epiblast cells, followed by upregulation after PGC specification. However, the molecular mechanisms underlying the reactivation of pluripotency genes are poorly characterized. Here, we exploited the in vitro differentiation of epiblast-like cells (EpiLCs) from embryonic stem cells (ESCs) to elucidate the molecular and epigenetic functions of PR domain-containing 14 (PRDM14). We found that Prdm14 overexpression in EpiLCs induced their conversion to ESC-like cells even in the absence of leukemia inhibitory factor in adherent culture. This was impaired by the loss of Kruppel-like factor 2 and ten-eleven translocation (TET) proteins. Furthermore, PRDM14 recruited OCT3/4 to the enhancer regions of naive pluripotency genes via TET-base excision repair-mediated demethylation. Our results provide evidence that PRDM14 establishes a transcriptional network for naive pluripotency via active DNA demethylation

Erosion Between Two Curved Surface Oscillating at Close Proximity in Liquid

In the previous paper，the erosion damages have been discussed by using on two parallel surfaces oscillating at close proximity in liquid. In the present paper，further erosion tests are carried out on the curved surfaces which are frequent1y found in machine elements. In this test conditions，the shearing force of squeezed film becomes very small，and the damages are mainly caused by the collapse pressure of cavitation bubbles. The cavitation bubble moves due to the flow of liquid film in the radial direction and no fixed-type cavitation appears at the small film thickness. Accordingly，t he distribution of damage in the radial direction of the spherical disc depends on the minimum fi1m thickness and also on the curvature of disc

Species difference in intestinal absorption mechanism of etoposide and digoxin between cynomolgus monkey and rat

金沢大学医薬保健研究域薬学系 金沢大学医薬保健研究域医学系Purpose. The oral bioavailability of some therapeutic agents is markedly lower in cynomolgus monkeys than in humans. We investigated small-intestinal absorption of the P-glycoprotein (P-gp) substrates etoposide and digoxin in monkeys to clarify the influence of efflux transport on their intestinal permeability. Methods. The pharmacokinetics of etoposide and digoxin was examined in monkeys and rats after oral and intravenous administration. Intestinal permeability and segmental differences in permeability were investigated with an Ussing-type chamber. Results. The bioavailability of etoposide was 12.9 and 13.9% in monkeys and rats, respectively. Total body clearance of etoposide in monkeys was much less than hepatic blood flow, suggesting that the bioavailability would be limited at intestinal absorption. Marked vectorial transport of etoposide in the secretory direction was observed in rats, especially in the lower small intestine, and segmental differences were consistent with the distribution of P-gp expression. Vectorial transport was minimal in monkey small intestine. Our kinetic analysis indicated that P-gp contributes little to the intestinal permeability of etoposide and digoxin in monkeys, and apical uptake is rate-limiting. Conclusion. Low bioavailability of etoposide in monkeys is due to poor intestinal uptake resulting from low influx from the apical side, rather than secretion via P-gp. © 2008 Springer Science+Business Media, LLC

Inhibition of oligopeptide transporter suppress growth of human pancreatic cancer cells

金沢大学医薬保健研究域薬学系Oligopeptide transporters are abundantly expressed in various types of cancer cells. We here synthesized two novel dipeptides, l-phenylalanyl sarcosine (Phe-Sar) and 4-(4-methoxyphenyl)-l-phenylalanyl sarcosine (Bip(OMe)-Sar), and examined their effect on the growth of human pancreatic cancer AsPC-1 cells, which are known to highly express oligopeptide transporter PEPT1/SLC15A1. Growth of AsPC-1 cells was inhibited by these two peptides and a typical PEPT1/SLC15A1 substrate Gly-Sar. Growth inhibition by Gly-Sar, Phe-Sar and Bip(OMe)-Sar was concentration-dependent with half-maximal inhibitory concentration of 50, 0.91 and 0.55mM, respectively. These peptides also inhibited PEPT1-mediated [3H]Gly-Sar uptake with half-maximal inhibitory concentration of 2.6, 0.81 and 0.27mM, respectively. Thus, the rank order of the tumor cell growth inhibition by these three peptides was the same as that of PEPT1-inhibitory activity. Growth of AsPC-1 cells was also inhibited by 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid (BCH), which is a typical inhibitor of amino acid transporter system L. The growth inhibition by BCH and Gly-Sar was additive, suggesting that these compounds act at distinct loci. Oligopeptide transporters thus appear to be a promising target for inhibition of pancreatic cancer progression. These results also proposed the idea that oligopeptide transporter is required for growth of AsPC-1 cells. © 2010 Elsevier B.V

Prognostic Significance of C-reactive Protein-to-prealbumin Ratio in Patients with Esophageal Cancer

Background: The prognostic value of combination of C-reactive protein and prealbumin (CRP/PAlb) in esophageal cancer remains unclear. Methods: We enrolled 167 esophageal cancer patients who underwent curative esophagectomy. Univariate and multivariate analyses were performed to determine the prognostic significance of various markers, including CRP-to-albumin (CRP/Alb) ratio, modified Glasgow prognostic score, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index. Results: Receiver operating characteristic analysis revealed the optimal cut-off value of each inflammatory factor, and CRP/PAlb ratio had the greatest discriminative power in predicting recurrence-free survival (RFS) among the examined measures (AUC 0.668). The 5-year overall survival and RFS rates were significantly lower in patients with high CRP/PAlb ratio than in those with low CRP/PAlb ratio (P < 0.001, P = 0.001, respectively). In the univariate analysis, RFS was significantly worse in patients with low BMI, T2 or deeper tumor invasion, positive lymph node metastasis, positive venous invasion, high CRP/PAlb ratio, high CRP/Alb ratio, high NLR, and high LMR. Multivariate analysis revealed that CRP/PAlb, but not CRP/Alb, was an independent prognostic factor along with lymph node metastasis. Conclusion: CRP/PAlb ratio was useful for predicting the prognosis of esophageal cancer patients

Safety analysis of two different regimens of uracil–tegafur plus leucovorin as adjuvant chemotherapy for high-risk stage II and III colon cancer in a phase III trial comparing 6 with 18 months of treatment: JFMC33-0502 trial

PURPOSE: The JFMC33-0502 trial is a phase III clinical study designed to determine the most appropriate duration of postoperative adjuvant chemotherapy with uracil–tegafur (UFT) plus leucovorin in patients with stage IIB or III colon cancer. We report the interim results of preplanned safety analyses. METHODS: Patients with stage IIB or III colon cancer who had undergone curative resection were randomly assigned to receive UFT (300 mg/m(2)) plus leucovorin (75 mg/day) for 6 months (control group, 4 weeks of treatment followed by a 1-week rest, five courses) or for 18 months (study group, 5 days of treatment followed by a 2-day rest, 15 courses). Treatment status and safety were evaluated. RESULTS: A total of 1,071 patients were enrolled, and 1,063 were included in safety analyses. Treatment completion rate at 6 months was 74.0 % in the control group and 76.7 % in the study group. Treatment completion rate in the study group at 18 months was 56.0 %. The overall incidence of adverse events (AEs) was 75.3 % in the control group and 77.6 % in the study group. The incidences of grade 3 or higher AEs were low in both groups. During the first 6 months, the incidences of the subjective AEs were significantly lower in the study group. CONCLUSIONS: Oral UFT plus leucovorin given by either dosage schedule is a very safe regimen for adjuvant chemotherapy. In particular, 5 days of treatment followed by a 2-day rest was a useful treatment option from the viewpoint of toxicity even when given for longer than 6 months. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-014-2461-5) contains supplementary material, which is available to authorized users

Discovery of Self‐Assembling Small Molecules as Vaccine Adjuvants

自己集合性ワクチンアジュバントの発見. 京都大学プレスリリース. 2020-10-07.Vaccine ingredients could be hiding in small molecule libraries. 京都大学プレスリリース. 2020-10-07.Immune potentiators, termed adjuvant, trigger early innate immune responses to ensure the generation of robust and long‐lasting adaptive immune responses of vaccines. Here we present study that takes advantage of a self‐assembling small molecule library for the development of a novel vaccine adjuvant. Cell‐based screening of the library and subsequent structural optimization led to the discovery of a simple, chemically tractable deoxycholate derivative (molecule 6 , also named cholicamide) whose well‐defined nano‐assembly potently elicits innate immune responses in macrophages and dendritic cells. Functional and mechanistic analyses indicate that the virus‐like assembly is engulfed inside cells and stimulates the innate immune response through toll‐like receptor 7 (TLR7), an endosomal TLR that detects single‐stranded viral RNA. As an influenza vaccine adjuvant in mice, molecule 6 was as potent as Alum, a clinically used adjuvant. The studies described here paves the way for a new approach to discovering and designing self‐assembling small‐molecule adjuvants against pathogens, including emerging viruses