Impact of 5 fluorouracil chemotherapy on gut inflammation, functional parameters, and gut microbiota.

Emerging evidence suggests that gut microbiota may influence the response to chemotherapy. We sought to characterize the effects of 5 fluorouracil (5FU) chemotherapy on colon inflammation and functional measures in colorectal cancer (CRC) and to further determine whether gut microbiota can influence this response. 50 C57BL/6 were randomized into four groups; Control + Vehicle (n = 10), Control + 5FU (n = 10), AOM/DSS + Vehicle (n = 15), and AOM/DSS + 5FU (n = 15). CRC was induced chemically by a single 10 mg/kg injection of azoxymethane (AOM) followed by two cycles (2% and 1%) of dextran sodium sulfate (DSS). Mice were then treated with 3 cycles of vehicle or 5FU (cycle 1: 40 mg/kg, cycle 2 + 3: 20 mg/kg). Functional tests (grip strength and run-to-fatigue) were performed prior to 5FU treatment (baseline) and at the completion of the second cycle of 5FU. Following the third 5FU cycle, mice were euthanized and the colon was evaluated for expression of inflammatory genes using RT-qPCR and stool samples were profiled using 16S rRNA sequencing. A second experiment used fecal microbiota transplantation from 5FU treated mice to control mice (n = 10-15/group) to determine whether 5FU associated changes in the microbiota could influence functional measures and colon inflammation. 5FU reduced grip strength (p < 0.05) and caused a trending decrease in run-to-fatigue performance in cancer mice (p = 0.06). Select intestinal inflammatory genes were significantly elevated with 5FU treatment and this was further exacerbated with cancer (p < 0.05). Microbiota analysis revealed increased dissimilarity and alterations in bacterial taxonomy in 5FU and AOM/DSS-treated mice (p < 0.05). Fecal transplant from 5FU treated mice reduced functional performance (p < 0.05) and altered select colon inflammatory markers (p < 0.05). This study provides evidence of an effect of 5FU on inflammatory responses and functional measures in a mouse model of CRC and suggests that gut microbes may play a role in some, but not all, 5FU related perturbations.

Role of MCP-1 on inflammatory processes and metabolic dysfunction following high-fat feedings in the FVB/N strain.

BACKGROUND: Monocyte chemoattractant protein 1 (MCP-1) is known to be an important chemokine for macrophage recruitment. Thus, targeting MCP-1 may prevent the perturbations associated with macrophage-induced inflammation in adipose tissue. However, inconsistencies in the available animal literature have questioned the role of this chemokine in this process. The purpose of this study was to examine the role of MCP-1 on obesity-related pathologies. METHODS: Wild-type and MCP-1-deficient mice on an friend virus B NIH (FVB/N) background were assigned to either low-fat diet or high-fat diet (HFD) treatment for a period of 16 weeks. Body weight and body composition were measured weekly and monthly, respectively. Fasting blood glucose and insulin, and glucose tolerance were measured at 16 weeks. Macrophages, T-cell markers, inflammatory mediators and markers of fibrosis were examined in the adipose tissue at the time of killing the mice. RESULTS: As expected, HFD increased adiposity (body weight, fat mass, fat percent and adipocyte size), metabolic dysfunction (impaired glucose metabolism and insulin resistance) macrophage number (CD11b(+)F480(+) cells, and gene expression of EMR1 and CD11c), T-cell markers (gene expression of CD4 and CD8), inflammatory mediators (pNFκB and pJNK, and mRNA expression of MCP-1, CCL5, C-X-C motif chemokine-14, tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6)) and fibrosis (expression of IL-10, IL-13, TGF-ß and matrix metalloproteinase-2 (MMP2); P<0.05). However, contrary to our hypothesis, MCP-1 deficiency exacerbated many of these responses resulting in a further increase in adiposity (body weight, fat mass, fat percent and adipocyte size), metabolic dysregulation, macrophage markers (EMR1), inflammatory cell infiltration and fibrosis (formation of type I and III collagens, mRNA expression of IL-10 and MMP2; P<0.05). CONCLUSIONS: These data suggest that MCP-1 may be a necessary component of the inflammatory response required for adipose tissue protection, remodeling and healthy expansion in the FVB/N strain in response to HFD feedings.

Dose equivalence between continuous erythropoietin receptor activator (CERA), Darbepoetin and Epoetin in patients with advanced chronic kidney disease.

BACKGROUND: Anemia is a prevalent situation in patients with chronic kidney disease (CKD) and can be well managed with erythropoiesis-stimulating agents (ESAs). Continuous erythropoietin receptor activator (CERA) has a long half-life that allows to be administered once monthly. The lowest recommended dose for patients with non dialysis CKD is 120 µg per month. The objectives were to assess the efficacy of subcutaneous monthly dosing of CERA in CKD stages 4 and 5 not on dialysis, and to determine the equivalent dose to epoetin ß and darbepoetin α. METHODS: This is a cohort study. A 30-patient group that ESAs was changed to CERA (µg/month) was used as treatment group. We used the following clinically-based equivalent dosing: epoetin ß (IU/week) and darbepoetin α (µg/week): 3000/15= 50; 4000/20=75; 6000/30=100; 8000/40=150. Another group of 30 patients with similar characteristics was used as control group and received the same epoetin ß and darbepoetin α doses. RESULTS: The mean CERA initial dose and at 6 months was 81.9 ± 35.2 and 82.0 ± 37.82 µg/month (p=0.37). The mean erythropoietin resistance index (ERI) and hemoglobin at baseline and at 6 months in the CERA group and in the control group were not statistically significant. CONCLUSION: Monthly dosing treatment with CERA is safe and effective. A dose of 75-100 µg/month is enough to maintain stable levels of hemoglobin. Hippokratia 2014; 18 (4): 315-318.

Monitoring of 35S in ash of incinerated waste.

The National Institute of Environmental Health Sciences incinerates low-level radioactive waste containing 3H, 14C, and 35S as a means of volume reduction. The primary isotope remaining in the ash is 35S. Some effects of the chemical and physical form of the waste on sulfur retention in ash and several methods for determining the activity remaining in the ash have been explored. It was found that the sulfur in sodium sulfate has a higher retention in ash than the sulfur in methionine and that the presence of glass appears to enhance the retention. Liquid scintillation and proportional counting methods were compared. A sulfur extraction procedure using liquid scintillation counting was found to give the lowest minimum detectable activity. However, it was determined that a more practical method for routine monitoring is to suspend a small quantity of ash in a liquid scintillation gel.