Oceanic redox conditions through the late Pliensbachian to early Toarcian on the northwestern Panthalassa margin : Insights from pyrite and geochemical data

Part of this work was financially supported by JSPS grants 15J08821 to KI. DBK acknowledges receipt of NERC Fellowship NE/I02089X/1, and grants from the Great Britain Sasakawa Foundation: grant number 4883 and Daiwa Anglo-Japanese Foundation: grant number 10960/12369. This study contributes to IGCP 655. We thank M. Ikeda, T. Ohta, K. Suzuki, S. Itamiya, and K. Kawano for assistance in the field and/or helpful discussion. Fieldwork was carried out with full permission and support from its landowners. Technical staff at Geo-Science Laboratory (Chikyu Kagaku Kenkyusho) are thanked for performance of TOC and carbon-isotope analysis.Peer reviewedPostprin

Two-Directional Arthrographic Assessment for Treating Bilateral Development Dislocation of the Hips in Children after Walking Age

We reviewed the treatment outcome in 14 hips of 7 patients who were diagnosed as having bilateral developmental dislocation of the hip (DDH) after walking age and could be followed up until they were at least 14 years of age. Based on the results of two-directional arthrography of the hip, closed reduction was performed in 2 hips, and open reduction was performed without osteotomy in 12 hips. The final radiographic evaluations were made according to the Kalamchi and MacEwen classification and Severin classification. The mean age at the initial visit was 1 year and 9 months (range, 1 year and 5 months to 3 years). The outcome was satisfactory for one hip in Group Ⅰ and 2 hips in Group Ⅱ according to the Kalamchi and MacEwen classification, and in 83% of the Severin Class Ⅰ and Ⅱ hips. Arthrography was useful for identifying asymmetry, demonstrating the usefulness of a treatment strategy based on arthrography of the hip

Patient-derived orthotopic xenograft models for cancer of unknown primary precisely distinguish chemotherapy, and tumor-targeting S. typhimurium A1-R is superior to first-line chemotherapy.

Cancer of unknown primary (CUP) is a recalcitrant disease with poor prognosis because it lacks standard first-line therapy. CUP consists of diverse malignancy groups, making personalized precision therapy essential. The present study aimed to identify an effective therapy for a CUP patient using a patient-derived orthotopic xenograft (PDOX) model. This paper reports the usefulness of the PDOX model to precisely identify effective and ineffective chemotherapy and to compare the efficacy of S. typhimurium A1-R with first-line chemotherapy using the CUP PDOX model. The present study is the first to use a CUP PDOX model, which was able to precisely distinguish the chemotherapeutic course. We found that a carboplatinum (CAR)-based regimen was effective for this CUP patient. We also demonstrated that S. typhimurium A1-R was more effective against the CUP tumor than first-line chemotherapy. Our results indicate that S. typhimurium A1-R has clinical potential for CUP, a resistant disease that requires effective therapy

The combination of temozolomide-irinotecan regresses a doxorubicin-resistant patient-derived orthotopic xenograft (PDOX) nude-mouse model of recurrent Ewing's sarcoma with a FUS-ERG fusion and CDKN2A deletion: Direction for third-line patient therapy.

The aim of the present study was to determine the usefulness of a patient-derived orthotopic xenograft (PDOX) nude-mouse model of a doxorubicin-resistant metastatic Ewing's sarcoma, with a unique combination of a FUS-ERG fusion and CDKN2A deletion, to identify effective drugs for third-line chemotherapy of the patient. Our previous study showed that cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors were effective on the Ewing's sarcoma PDOX, but not doxorubicin, similar to the patient's resistance to doxorubicin. The results of the previous PDOX study were successfully used for second-line therapy of the patiend. In the present study, the PDOX mice established with the Ewing's sarcoma in the right chest wall were randomized into 5 groups when the tumor volume reached 60 mm3: untreated control; gemcitabine combined with docetaxel (intraperitoneal [i.p.] injection, weekly, for 2 weeks); irinotecan combined with temozolomide (irinotecan: i.p. injection; temozolomide: oral administration, daily, for 2 weeks); pazopanib (oral administration, daily, for 2 weeks); yondelis (intravenous injection, weekly, for 2 weeks). All mice were sacrificed on day 15. Body weight and tumor volume were assessed 2 times per week. Tumor weight was measured after sacrifice. Irinotecan combined with temozolomide was the most effective regimen compared to the untreated control group (p=0.022). Gemcitabine combined with docetaxel was also effective (p=0.026). Pazopanib and yondelis did not have significant efficacy compared to the untreated control (p=0.130, p=0.818). These results could be obtained within two months after the physician's request and were used for third-line therapy of the patient

Recombinant methioninase effectively targets a Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.

Methionine dependence is due to the overuse of methionine for aberrant transmethylation reactions in cancer. Methionine dependence may be the only general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine α-deamino-γ-mercaptomethane lyase [EC 4.4.1.11]). The cloned methioninase, termed recombinant methioninase, or rMETase, has been tested in mouse models of human cancer cell lines. Ewing's sarcoma is recalcitrant disease even though development of multimodal therapy has improved patients'outcome. Here we report efficacy of rMETase against Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) model. The Ewing's sarcoma was implanted in the right chest wall of nude mice to establish a PDOX model. Eight Ewing's sarcoma PDOX mice were randomized into untreated control group (n = 4) and rMETase treatment group (n = 4). rMETase (100 units) was injected intraperitoneally (i.p.) every 24 hours for 14 consecutive days. All mice were sacrificed on day-15, 24 hours after the last rMETase administration. rMETase effectively reduced tumor growth compared to untreated control. The methionine level both of plasma and supernatants derived from sonicated tumors was lower in the rMETase group. Body weight did not significantly differ at any time points between the 2 groups. The present study is the first demonstrating rMETase efficacy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as Ewing's sarcoma

Host range and receptor utilization of canine distemper virus analyzed by recombinant viruses: Involvement of heparin-like molecule in CDV infection

AbstractWe constructed recombinant viruses expressing enhanced green fluorescent protein (EGFP) or firefly luciferase from cDNA clones of the canine distemper virus (CDV) (a Japanese field isolate, Yanaka strain). Using these viruses, we examined susceptibilities of different cell lines to CDV infection. The results revealed that the recombinant CDVs can infect a broad range of cell lines. Infectivity inhibition assay using a monoclonal antibody specific to the human SLAM molecule indicated that the infection of B95a cells with these recombinant CDVs is mainly mediated by SLAM but the infection of 293 cell lines with CDV is not, implying the presence of one or more alternative receptors for CDV in non-lymphoid tissue. Infection of 293 cells with the recombinant CDV was inhibited by soluble heparin, and the recombinant virus bound to immobilized heparin. Both F and H proteins of CDV could bind to immobilized heparin. These results suggest that heparin-like molecules are involved in CDV infection

Tumor-targeting Salmonella typhimurium A1-R regresses an osteosarcoma in a patient-derived xenograft model resistant to a molecular-targeting drug.

Osteosarcoma occurs mostly in children and young adults, who are treated with multiple agents in combination with limb-salvage surgery. However, the overall 5-year survival rate for patients with recurrent or metastatic osteosarcoma is 20-30% which has not improved significantly over 30 years. Refractory patients would benefit from precise individualized therapy. We report here that a patient-derived osteosarcoma growing in a subcutaneous nude-mouse model was regressed by tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R, p<0.001 compared to untreated control). The osteosarcoma was only partially sensitive to the molecular-targeting drug sorafenib, which did not arrest its growth. S. typhimurium A1-R was significantly more effective than sorafenib (P <0.001). S. typhimurium grew in the treated tumors and caused extensive necrosis of the tumor tissue. These data show that S. typhimurium A1-R is powerful therapy for an osteosarcoma patient-derived xenograft model

Low-energy Variety of Asymmetric SUSY Flavor Structure

In this letter we study the low-energy phenomenology and cosmological implications of supersymmetric grand unified theory with asymmetric flavor structure, which is suggested by the recent observation of fermion masses and mixing angles. The predictions of the scenario are rather dependent on a Yukawa parameter fixed by group-theoretical argument. A reduced value of the parameter gives a resolution to the sign problem of supersymmetric Higgs mass \mu, with which the theory becomes simultaneously consistent with the experimental data of bottom/tau mass ratio, flavor-changing rare decay of bottom quark, and the muon anomalous magnetic moment. The relic abundance of the lightest superparticle as cold dark matter of the universe is also investigated in light of the three-years WMAP result. A new source of flavor violation is found in the D-term induced scalar masses, that is a distinctive signature of the generation asymmetry.Comment: 15 pages, 4 figures, minor comments and references adde