A novel Arabidopsis pathosystem reveals cooperation of multiple hormonal response-pathways in host resistance against the global crop destroyer Macrophomina phaseolina.

Dubbed as a "global destroyer of crops", the soil-borne fungus Macrophomina phaseolina (Mp) infects more than 500 plant species including many economically important cash crops. Host defenses against infection by this pathogen are poorly understood. We established interactions between Mp and Arabidopsis thaliana (Arabidopsis) as a model system to quantitatively assess host factors affecting the outcome of Mp infections. Using agar plate-based infection assays with different Arabidopsis genotypes, we found signaling mechanisms dependent on the plant hormones ethylene, jasmonic acid and salicylic acid to control host defense against this pathogen. By profiling host transcripts in Mp-infected roots of the wild-type Arabidopsis accession Col-0 and ein2/jar1, an ethylene/jasmonic acid-signaling deficient mutant that exhibits enhanced susceptibility to this pathogen, we identified hundreds of genes potentially contributing to a diverse array of defense responses, which seem coordinated by complex interplay between multiple hormonal response-pathways. Our results establish Mp/Arabidopsis interactions as a useful model pathosystem, allowing for application of the vast genomics-related resources of this versatile model plant to the systematic investigation of previously understudied host defenses against a major crop plant pathogen

Boundary ABF Models

We diagonalise the transfer matrix of boundary ABF models using bosonized vertex operators. We compute the boundary S-matrix and check the scaling limit against known results for perturbed boundary conformal field theories.Comment: 26 pages, Latex, uses amssymbols.sty and pb-diagram.sty, 3 ps figure

Intraperitoneal administration of tumor-targeting Salmonella typhimurium A1-R inhibits disseminated human ovarian cancer and extends survival in nude mice.

UnlabelledPeritoneal disseminated cancer is highly treatment resistant. We here report the efficacy of intraperitoneal (i.p.) administration of tumor-targeting Salmonella typhimurium A1-R in a nude mouse model of disseminated human ovarian cancer. The mouse model was established by intraperitoneal injection of the human ovarian cancer cell line SKOV3-GFP. Seven days after implantation, mice were treated with S. typhimurium A1-R via intravenous (i.v.) or i.p. administration at the same dose, 5 × 10(7) CFU, once per week. Both i.v. and i.p. treatments effected prolonged survival compared with the untreated control group (P=0.025 and P<0.001, respectively). However, i.p. treatment was less toxic than i.v.TreatmentTumor-specific targeting of S. typhimurium A1-R was confirmed with bacterial culture from tumors and various organs and tumor or organ colony formation after i.v. or i.p. injection. Selective tumor targeting was most effective with i.p. administration. The results of the present study show S. typhimurium A1-R has promising clinical potential for disseminated ovarian cancer, especially via i.p. administration

Tumor-targeting Salmonella typhimurium A1-R prevents experimental human breast cancer bone metastasis in nude mice.

Bone metastasis is a lethal and morbid late stage of breast cancer that is currently treatment resistant. More effective mouse models and treatment are necessary. High bone-metastatic variants of human breast cancer cells were selected in nude mice by cardiac injection. After cardiac injection of a high bone-metastatic variant of breast cancer, all untreated mice had bone metastases compared to only 20% with parental cells. Treatment with tumor-targeting Salmonella typhimurium A1-R completely prevented the appearance of bone metastasis of the high metastatic variant in nude mice (P < 0.001). After injection of the highly bone-metastatic breast cancer variant to the tibia of nude mice, S. typhimurium A1-R treatment significantly reduced tumor growth in the bone (P < 0.001). These data indicated that S. typhimurium A1-R is useful to prevent and inhibit breast cancer bone metastasis and should be of future clinical use for breast cancer in the adjuvant setting

Protein kinase A and Epac activation by cAMP regulateS the expression of glial fibrillary acidic protein in glial cells

Cyclic adenosine monophosphate (cAMP) controls differentiation in several types of cells during brain development. However, the molecular mechanism of cAMP-controlled differentiation is not fully understood. We investigated the role of protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac) on cAMP-induced glial fibrillary acidic protein (GFAP), an astrocyte marker, in cultured glial cells. B92 glial cells were treated with cAMP-elevating drugs, an activator of adenylate cyclase, phosphodiesterase inhibitor and a β adrenal receptor agonist. These cAMP-elevating agents induced dramatic morphological changes and expression of GFAP. A cAMP analog, 8-Br-cAMP, which activates Epac as well as PKA, induced GFAP expression and morphological changes, while another cAMP analog, 8-CPT-cAMP, which activates Epac with greater efficacy when compared to PKA, induced GFAP expression but very weak morphological changes. Most importantly, the treatment with a PKA inhibitor partially reduced cAMP-induced GFAP expression. Taken together, these results indicate that cAMP-elevating drugs lead to the induction of GFAP via PKA and/or Epac activation in B92 glial cells. © 2016 by the Serbian Biological Society

Inhibition of spontaneous and experimental lung metastasis of soft-tissue sarcoma by tumor-targeting Salmonella typhimurium A1-R.

Prognosis of patients with lung metastases of soft-tissue sarcoma is still poor. Therefore, novel systemic therapy is needed to improve the survival of soft-tissue sarcoma. In the present study, tumor-targeting therapy with a genetically-modified auxotrophic strain of Salmonella typhimurium, termed A1-R, was evaluated. Mouse models of primary soft tissue sarcoma and spontaneous lung metastasis were obtained by orthotopic intra-muscular injection of HT1080-RFP human fibrosarcoma cells. S. typhimurium A1-R was administered from day 14, once a week for two weeks. On day 28, lung samples were excised and observed with a fluorescence imaging system. The number of lung metastasis was 8.8 ± 3.4 in the untreated group and 0.8 ± 0.8 in the treated group (P = 0.024). A mouse model of experimental lung metastasis was obtained by tail vein injection of HT1080-RFP cells. The mice were treated with S. typhimurium A1-R (i.v.) on day 7, once a week for three weeks. S. typhimurium A1-R significantly reduced lung metastases and improved overall survival (P = 0.004). S. typhimurium A1-R bacterial therapy has future potential for treating advanced soft tissue sarcoma and improving prognosis of patients with lung metastasis

Temozolomide combined with irinotecan caused regression in an adult pleomorphic rhabdomyosarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model.

Adult pleomorphic rhabdomyosarcoma (RMS) is a rare and recalcitrant, highly-malignant mesenchymal tumor in need of improved therapeutic strategies. Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI). We previously described the development of a PDOX model of adult pleomorphic RMS where the tumor behaved similar to the patient donor. A high-grade pleomorphic rhabdomyosarcoma from a striated muscle was previously grown orthotopically in the right biceps-femoris muscle of nude mice to establish the PDOX model. In the present study, the PDOX models were randomized into the following treatment groups when tumor volume reached 100 mm3: G1, control without treatment; G2, cyclophosphamide (CPA) 140 mg/kg, intraperitoneal (i.p.) injection, weekly, for 3 weeks; G3, temozolomide (TEM), 25 mg/kg, per oral (p.o.), daily, for 21 days; G4, temozolomide (TEM) 25 mg/kg, p.o., daily, for 21 days combined with irinotecan (IRN), 4 mg/kg, i.p., daily for 21 days. After 3 weeks, treatment of PDOX with TEM combined with IRN was so powerful that it resulted in tumor regression and the smallest tumor volume compared to other groups. The RMS PDOX model should be of use to design the treatment program for the patient and for drug discovery and evaluation for this recalcitrant tumor type

Exquisite Tumor Targeting by Salmonella A1-R in Combination with Caffeine and Valproic Acid Regresses an Adult Pleomorphic Rhabdomyosarcoma Patient-Derived Orthotopic Xenograft Mouse Model.

Adult pleomorphic rhabdomyosarcoma (RMS) is a rare and malignant mesenchymal tumor. Recently, we developed a patient-derived orthotopic xenograft (PDOX) model of adult pleomorphic RMS. In the present study, we evaluated the efficacy of tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R combined with caffeine (CAF) and valproic acid (VPA) on the adult RMS PDOX. An adult pleomorphic RMS cell line was established from the PDOX model. Cell survival after exposure to CAF and VPA was assessed, and the IC50 value was calculated for each drug. The RMS PDOX models were randomized into five groups: untreated control; tumor treated with cyclophosphamide (CPA); tumor treated with CAF + VPA; tumor treated with S. typhimurium A1-R; and tumor treated with S. typhimurium A1-R + CAF + VPA. Tumor size and body weight was measured twice a week. VPA caused a concentration-dependent cytocidal effect. A synergistic effect of combination treatment with CAF was observed against the RMS cell line. For the in vivo study, all treatments significantly inhibited tumor growth compared with the untreated control. S. typhimurium A1-R combined with VPA and CAF was significantly more effective than CPA, VPA combined with CAF, or S. typhimurium A1-R alone and significantly regressed the tumor volume compared with day 0. These results suggest that S. typhimurium A1-R together with VPA and CAF could regresses an adult pleomorphic RMS in a PDOX model and therefore has important future clinical potential

Effectiveness of two novel anionic and cationic platinum complexes in the treatment of osteosarcoma

Aim: This study aimed to characterize the cellular basis of the platinum cytotoxicity of two novel platinum complexes, 3Pt and 1Pt, in comparison with that of cisplatin. 3Pt comprises anionic phosphate moieties, while 1Pt comprises neutral aromatic ligands. Methods: We compared the cytotoxic potency of 3Pt and 1Pt with that of cisplatin in osteosarcoma cell lines and an orthotopic mouse model. Results: The cytotoxic potency of 3Pt was markedly higher than that of cisplatin in all cell lines. Both novel platinum complexes showed a complete lack of cross resistance in cisplatin-resistant cells. Caffeine enhanced the cytotoxic potency of these novel platinum complexes, as observed for cisplatin. Apoptosis after drug administration was observed by DNA ladder formation and an annexin V/PI assay. DNA double-strand breaks were confirmed by phosphorylation of histone H2AX. In vivo, the antitumor activity of 3Pt and 1Pt was superior and similar, respectively, to that of cisplatin. Both novel platinum complexes exerted strong antitumor effects on osteosarcoma in vitro and in vivo. Conclusions: 3Pt may be an effective drug for the treatment of bone cancer because the PO3 moiety has a high affinity to bone, as exhibited by bisphosphonates, and is expected to decrease the incidence of side effects at extraskeletal sites and overcome drug resistance. Cationic 1Pt may also be an effective antitumor drug because of its unique chemical structure and properties. Further investigations to detail the antitumor effects of these ionic Pt complexes on osteosarcoma are warranted. © 2015 Bentham Science Publishers

Risk factors of recurrent lumbar disk herniation: A single center study and review of the literature

Background: The recurrence of lumbar disk herniation (LDH) is a major problem in the treatment of LDH. The purpose of this study was to investigate the risk factors for recurrent LDH. Methods: Between April 2005 and March 2008, 298 patients with LDH, who underwent surgical treatment, were enrolled in this study. The patients were divided into a nonrecurrent group (N group) and a recurrent group (R group). We compared their clinical parameters including age, sex, body mass index, smoking, alcohol, sports activity, occupational lifting, and occupational driving. The relationships between the variables and recurrent LDH were evaluated by univariate analysis and multiple logistic regression analysis. Results: The N group had 266 patients (89.3%) and the R group had 32 patients (10.7%). Univariate analysis showed that current smoking (P<0.001) and occupational lifting (P=0.02) significantly correlated with recurrent LDH. Multivariate analysis showed that current smoking significantly related with recurrent LDH (OR, 3.47; 95% CI, 1.55-7.80; P=0.003). Conclusions: Our study suggests that smoking cessation and restraining from lifting may significantly decrease the incidence of recurrent LDH. © 2013 Wolters Kluwer Health, Inc. All rights reserved