Control of inflammation by stromal Hedgehog pathway activation restrains colitis

Inflammation disrupts tissue architecture and function, thereby contributing to the pathogenesis of diverse diseases; the signals that promote or restrict tissue inflammation thus represent potential targets for therapeutic intervention. Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. Conversely, genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. Within the colon, the Hedgehog protein signal does not act directly on the epithelium itself, but on underlying stromal cells to induce expression of IL-10, an immune-modulatory cytokine long known to suppress inflammatory intestinal damage. IL-10 function is required for the full protective effect of small-molecule Hedgehog pathway activation in colitis; this pharmacologic augmentation of Hedgehog pathway activity and stromal IL-10 expression are associated with increased presence of CD4(+) Foxp3(+) regulatory T cells. We thus identify stromal cells as cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a potential means to treat colitis.11138Ysciescopu

Pressure/temperature/substitution-induced melting of A-site charge disproportionation in Bi_(1-x)La_(x)NiO_3 (0 =< x =< 0.5)

Metal-insulator transitions strongly coupled with lattice were found in Bi1-xLaxNiO3. Synchrotron X-ray powder diffraction revealed that pressure (P ~ 3 GPa, T = 300 K), temperature (T ~ 340 K, x = 0.05), and La-substitution (x ~ 0.075, T = 300 K) caused the similar structural change from a triclinic (insulating) to an orthorhombic (metallic) symmetry, suggesting melting of the A-site charge disproportionation. Comparing crystal structure and physical properties with the other ANiO3 series, an electronic state of the metallic phase can be described as [A3+Ld, Ni2+L1-d], where a ligand-hole L contributes to a conductivity. We depicted a schematic P-T phase diagram of BiNiO3 including a critical point (3 GPa, 300 K) and an inhomogeneous region, which implies universality of ligand-hole dynamics in ANiO3 (A = Bi, Pr, Nd,...).Comment: 24 pages, 8 figures, Phys. Rev. B in pres

Phase II trial of oral S-1 combined with gemcitabine in metastatic pancreatic cancer

We conducted a phase II trial of gemcitabine with S-1, oral fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2, 4-dihydroxypyridine and potassium oxonate, to evaluate the activity and toxicity of such a combination in metastatic pancreatic cancer (MPC) patients. Patients who had pathologically proven pancreatic cancer with metastatic lesions were eligible candidates for entry into the study. S-1 was given orally (30 mg m−2) b.i.d. for 14 consecutive days and gemcitabine (1000 mg m−2) was given on days 8 and 15. The cycle was repeated every 21 days. We enrolled 33 MPC patients. The median number of cycles was eight (range 1–20). Grade 3–4 toxicities were leucopenia (33%), neutropenia (55%), anaemia (9%), thrombocytopenia (15%), anorexia (6%), fever (9%), and interstitial pneumonia (6%). Objective responses were obtained in 16 patients (one complete response and 15 partial responses; response rate, 48%; 95% confidence interval (CI), 33–65). Median survival and 1-year survival rate were 12.5 months (95% CI, 5.9–19.1) and 54% (95% CI, 36–72), respectively. Combination chemotherapy with GEM and S-1 was well tolerated and yielded a significantly high response rate