Development of a novel apoptosis-based tumor regression grade to assess the efficacy of preoperative chemoradiotherapy for rectal cancer: a retrospective single-center study

International Journal of Clinical Oncology - Preoperative chemoradiotherapy is used preferably for locally advanced rectal cancer, followed by a watch-and-wait strategy for cases showing clinical...     

Combination therapy with telmisartan and spironolactone alleviates L-NAME exacerbated nephrosclerosis with an increase in PPAR-gamma and decrease in TGF-beta(1)

To investigate whether the receptor blockades of angiotensin II type 1 and aldosterone receptors can prevent renal tissue injury in relation to the renal tissue mRNA levels of peroxisome proliferation-activated receptors-gamma (PPAR-gamma) and transforming growth factor-beta (1) (TGF-beta(1)) in spontaneously hypertensive rats (SHR) given N(G)-nitro-L-arginine methyl ester (L-NAME), which is considered a model of malignant hypertension. This study was performed in 5 groups of 17-week-old male SHR treated for 3 weeks as follows: group 1, control; group 2, L-NAME (50 mg/L in drinking); group 3, L-NAME plus aldosterone antagonist, spironolactone (SPRL, 100 mg/kg/day); group 4, L-NAME plus angiotensin II type 1 receptor blocker, telmisartan (TELM, 3 mg/kg/day); group 5, L-NAME plus combination therapy (COMB) with low-dose TELM (1 mg/kg/day) and SPRL (100 mg/kg/day). Urinary protein excretion and the glomerular injury score were significantly reduced in the SPRL, TELM, and COMB groups as compared with the L-NAME group, while significant blood pressure reduction was observed only in the TELM group. In the TELM and COMB groups, the perivascular cell infiltration and fibrosis area were significantly reduced together with the PPAR-gamma mRNA increase and TGF- beta(1) mRNA decrease. The urinary excretion of nitric oxides was significantly recovered and the wall to lumen ratio of the interlobular artery was significantly reduced only in the COMB group compared with the L-NAME group. Combined administration of 1 mg/kg/day telmisartan and 100 mg/kg/day spironolactone is thought to be effective in alleviating hypertensive renal injuries independently of blood pressure changes. The anti-inflammatory and antifibrotic effects due to PPAR-gamma activation and TGF-beta(1) inhibition may participate in the renoprotection of this combination therapy.     

Interferon-alpha and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets

Dendritic cells (DCs) play a crucial role in the immune responses against infections by sensing microbial invasion through toll-like receptors (TLRs). In humans, two distinct DC subsets, CD11c(-) plasmacytoid DCs (PDCs) and CD11c(+) myeloid DCs (MDCs), have been identified and can respond to different TLR ligands, depending on the differential expression of cognate TLRs. In this study, we have examined the effect of TLR-7 ligands on human DC subsets. Both subsets expressed TLR-7 and could respond to TLR-7 ligands, which enhanced the survival of the subsets and upregulated the surface expression of costimulatory molecules such as CD40, CD80, and CD86. However, the cytokine induction pattern was distinct in that PDCs and MDCs produced interferon (IFN)-alpha and interleukin (IL)-12, respectively. In response to TLR-7 ligands, the Th1 cell supporting ability of both DC subsets was enhanced, depending on the cytokines the respective subsets produced. This study demonstrates that TLR-7 exerts its biological effect in a DC subset-specific manner.     

Hypertension promotes phosphorylation of focal adhesion kinase and proline-rich tyrosine kinase 2 in rats: implication for the pathogenesis of hypertensive vascular disease

Atherosclerosis is initiated by adhesion and infiltration of inflammatory leukocytes into the intima, where non-receptor protein tyrosine kinases, such as focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2), play important roles as intracellular messengers of mechanical and biochemical signals. In the present study, we examined whether FAK and PYK2 are up-regulated by elevated blood pressure or circulating humoral factors in hypertension. We used a rat model of abdominal aortic banding that allows separate evaluation of elevated blood pressure (upper body) and circulating humoral factors (lower body). We obtained the proximal and distal aortas of the banding site, 6 hours, 3 days, and 1 and 4 weeks after the banding procedure, for evaluation of phosphorylation of FAK and PYK2 by Western blotting. Arterial pressure was significantly elevated only in the upper body throughout the experimental period. The expression of FAK and the FAK phosphorylation were significantly increased at 1 and 4 weeks only in the proximal aorta. This was also the case for the expression of total PYK2 and the PYK2 phosphorylation. In contrast, there was no significant change in FAK or PYK2 phosphorylation in the distal aorta, whereas plasma levels of angiotensin II were systemically elevated. In sham-operated rats, no change in FAK or PYK2 phoshorylation was noted in the proximal and distal aortas. These results indicate that phosphorylation of FAK and PYK2 is upregulated by elevated blood pressure but not by humoral factors in the rat aorta, demonstrating novel aspects of atherogenesis in hypertension.