Pancreaticoduodenal arterial rupture and hemoabdomen in ACI/SegHsd rats with polyarteritis nodosa

Many lesions associated with aging have been well-characterized in various strains of rats. Although documented in Sprague-Dawley and spontaneously hypertensive rats, polyarteritis nodosa has not previously been reported in ACI/SegHsd rats. ACII SegHsd rats were maintained on high-fat (40.5%), low-fat (11.6%), and high-fat to low-fat dietary protocols to examine the correlation between dietary fat and the regulation of prostate 5alpha-reductase gene expression and prostate cancer. Seven rats died unexpectedly with hemoabdomen and rupture of the pancreaticoduodenal artery secondary to polyarteritis nodosa (PAN). The purpose of this study was to analyze the pathologic findings in these and the remaining ACI/SegHsd rats and to correlate the level of dietary fat with the presence of PAN, arterial rupture, and hemoabdomen. Approximately 65% of the rats had evidence of PAN by histopathology, with a 24% incidence of arterial rupture. Additional lesions noted included an 88% incidence of chronic progressive nephropathy (CPN) and a 32% incidence of cartilaginous foci in the aortic valve. We found no association between the percentage of dietary fat and incidence of PAN, CPN, or cardiac cartilage. Although arterial rupture is a known complication of polyarteritis nodosa in humans, this case series is the first to document arterial rupture and hemoabdomen in rats with PAN.     

Flaxseed alone or in combination with tamoxifen inhibits MCF-7 breast tumor growth in ovariectomized athymic mice with high circulating levels of estrogen

Flaxseed (FS) is rich in mammalian lignan precursors and alpha-linolenic acid, which have been suggested as having anticancer effects. Previous studies have shown that 10% FS inhibits the growth of human estrogen-dependent breast cancer (MCF-7) in athymic mice, and it enhances the inhibitory effect of tamoxifen (TAM). This study determined whether the effect of FS, alone or in combination with TAM, is dose dependent, and it explored the potential mechanism of action. Ovariectomized athymic mice with estradiol (E2) supplementation (1.7 mg/pellet, 60-day release) and established MCF-7 tumors were treated with basal diet control (0FS), 5% FS (5FS), 10% FS (10FS), and TAM (TAM/ 0FS; 5 mg/pellet, 60-day release), alone or in combination (TAM/ 5FS and TAM/10FS) for 8 weeks. Compared with control, 5FS and 10FS significantly inhibited tumor growth by 26% and 38%, respectively. TAM/0FS had an effect similar to the 10FS. TAM/ 5FS and TAM/10FS, respectively, induced significant 48% and 43% reductions in tumor size compared with 0FS, and 18% and 10% reductions compared with TAM/0FS. The relative uterine weight was significantly lower in all TAM groups compared with the control. The reduction of tumor growth resulted from decreased cell proliferation and increased cell apoptosis. TAM/ 5FS caused a significantly higher expression of estrogen receptor-alpha (ERalpha) compared with 5FS and TAM/0FS, whereas TAM/10FS had a higher ERalpha than 10FS and TAM/0FS. Compared with the control, progesterone receptor (PgR) expression was significantly reduced in all treatment groups, but insulin-like growth factor-1 (IGF-1) expression was reduced only by 10FS, TAM/5FS and TAM/10FS. Tumor cell proliferation was significantly positively associated with expression of PgR and IGF-1 and negatively associated with apoptosis and ERalpha. Apoptosis was only associated with ERalpha. In conclusion, FS inhibited MCF-7 tumor growth in a dose-dependent manner and enhanced the inhibitory effect of TAM due to the modulation of ER and growth factor signal transduction pathways.     

Long-term effects on the nitrogen budget of a short-rotation grey alder (Alnus incana (L.) Moench) forest on abandoned agricultural land

Short-rotation energy forestry is one of the potential ways for management of abandoned agricultural areas. It helps sequestrate carbon and mitigate human-induced climate changes. Owing to symbiotic dinitrogen (N₂) fixation by actinomycetes and the soil fertilizing capacity and fast biomass growth of grey alders, the latter can be suitable species for short-rotation forestry. In our study of a young grey alder stand (Alnus incana (L.) Moench) on abandoned arable land in Estonia we tested the following hypotheses: (1) afforestation of abandoned agricultural land by grey alder significantly affects the soil nitrogen (N) status already during the first rotation period; (2) input of symbiotic fixation covers an essential part of the plant annual N demand of the stand; (3) despite a considerable N input into the ecosystem of a young alder stand, there will occur no significant environmental hazards (N leaching or N₂O emissions). The first two hypotheses can be accepted: there was a significant increase in N and C content in the topsoil (from 0.11 to 0.14%, and from 1.4 to 1.7%, respectively), and N fixation (151.5 kg N ha⁻¹ yr⁻¹) covered about 74% of the annual N demand of the stand. The third hypothesis met support as well: N₂O emissions (0.5 kg N ha⁻¹ yr⁻¹) were low, while most of the annual gaseous N losses were in the form of N₂ (73.8 kg N ha⁻¹ yr⁻¹). Annual average NO₃-N leaching was 15 kg N ha⁻¹ yr⁻¹ but the N that leached from topsoil accumulated in deeper soil layers. The soil acidifying effect of alders was clearly evident; during the 14-year period soil acidity increased 1.3 units in the upper 0-10 cm topsoil layer.     

Enhanced denitrification in a bioaugmented horizontal subsurface flow filter

The effect of adding low concentrations of a sediment/microbial community suspension to speed up the development of the denitrification capacity in the restored HSSF of a hybrid CW was studied during a one-year period after the filling of the horizontal filter with new light weight aggregates (LWA). Two HSSF filters with the same LWA substrate but different wastewater flow regimes were used as donor systems for the bioaugmentation. NO₃-N concentrations in the outflows of all variants of studied MCs were significantly influenced by the time factor (p < 0.001, repeated measures ANOVA). Post hoc comparison indicated that MCs bioaugmented with the sediment suspension from a similar HSSF had significantly lower NO₃-N concentrations than the control MCs (p < 0.05, Fisher LSD test), whereas MCs bioaugmented with the sediment suspension from a less similar HSSF did not show significant differences compared to the control MCs. This finding emphasizes the importance of the similarity of flow regime and water parameters in choosing a donor system for bioaugmentation. High variability of the effect of bioaugmentation shows that its importance for full scale operation may be overshadowed by the effect of other factors determining denitrification intensity.     

N5-phosphonoacetyl-L-ornithine (PALO): a convenient synthesis and investigation of influence on regulation of amino acid biosynthetic genes in Saccharomyces cerevisiae

A scalable four-step synthesis of the ornithine transcarbamylase inhibitor N⁵-phosphonoacetyl-l-ornithine (PALO) is achieved through boroxazolidinone protection of ornithine. Investigations in the model organism Saccharomyces cerevisiae found that, in contrast to a previous report, PALO did not influence growth rate or expression of genes involved in arginine metabolism.     

Novel second generation analogs of eribulin. Part II: Orally available and active against resistant tumors in vivo

Eribulin mesylate is a newly approved treatment for locally advanced and metastatic breast cancer. We targeted oral bioavailability and efficacy against multidrug resistant (MDR) tumors for further work. The design, synthesis and evaluation of novel amine-containing analogs of eribulin mesylate are described in this part. Attenuation of basicity of the amino group(s) in the C32 side-chain region led to compounds with low susceptibility to PgP-mediated drug efflux. These compounds were active against MDR tumor cell lines in vitro and in xenograft models in vivo, in addition to being orally bioavailable.     

CCR2 receptor antagonists: optimization of biaryl sulfonamides to increase activity in whole blood

A series of biarylsulfonamides was identified as hCCR2 receptor antagonist but suffered from high plasma protein binding resulting in a >100 fold shift in activity in a functional GTPγS assay run in tandem in the presence and absence of human serum albumin. Introduction of an aryl amide with ethylenediamine linker led to compounds with reduced shifts and improved activity in whole blood.