Photobiomodulation enhances M2 macrophage polarization properties of tonsil-derived mesenchymal stem cells.

In this study, the effect of photobiomodulation (PBM) treatment using 630 nm light emitting diode (LED) array (continuous wave type, 10 mW power) on tonsil-derived mesenchymal stem cells (TMSCs) and its interaction with RAW 264.7 macrophage cells via co-culture in vitro were investigated. PBM treatment was used as a priming method for TMSCs to improve therapeutic efficacy. TMSCs were subjected to multi-dose PBM treatments before co-culture with M1 activated (1 µg/mL lipopolysaccharide, LPS) macrophage cells with total energy doses of 0, 15, 30, and 60 J. Irradiation set at 15 J (1500 s treatment time) was performed once, twice for 30 J, and four times for 60 J in an incubator kept at 37 °C and 5% CO2. No significant anti-inflammatory response was observed for TMSCs co-cultured with macrophage cells without PBM. But PBM treatment of TMSCs with 630 nm LED array at 30 J reduced expression of inducible nitric oxide synthase, iNOS (M1) and increased expression of Arginase-1, Arg-1 (M2) phenotype macrophage markers. Anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1RA) gene expression also increased significantly. Based on the results, PBM priming of TMSCs supports M2 macrophage polarization. PBM can be used to improve the therapeutic efficacy of TMSCs for potential applications in oral mucositis and wound healing.

Maraviroc Prevents HCC Development by Suppressing Macrophages and the Liver Progenitor Cell Response in a Murine Chronic Liver Disease Model.

Maraviroc (MVC), a CCR5 antagonist, reduces liver fibrosis, injury and tumour burden in mice fed a hepatocarcinogenic diet, suggesting it has potential as a cancer therapeutic. We investigated the effect of MVC on liver progenitor cells (LPCs) and macrophages as both have a role in hepatocarcinogenesis. Mice were fed the hepatocarcinogenic choline-deficient, ethionine-supplemented diet (CDE) ± MVC, and immunohistochemistry, RNA and protein expression were used to determine LPC and macrophage abundance, migration and related molecular mechanisms. MVC reduced LPC numbers in CDE mice by 54%, with a smaller reduction seen in macrophages. Transcript and protein abundance of LPC-associated markers correlated with this reduction. The CDE diet activated phosphorylation of AKT and STAT3 and was inhibited by MVC. LPCs did not express Ccr5 in our model; in contrast, macrophages expressed high levels of this receptor, suggesting the effect of MVC is mediated by targeting macrophages. MVC reduced CD45+ cells and macrophage migration in liver and blocked the CDE-induced transition of liver macrophages from an M1- to M2-tumour-associated macrophage (TAM) phenotype. These findings suggest MVC has potential as a re-purposed therapeutic agent for treating chronic liver diseases where M2-TAM and LPC numbers are increased, and the incidence of HCC is enhanced.

Time of day and outcomes of nonurgent percutaneous coronary intervention performed during working hours.

BACKGROUND: During daytime working hours, outcomes may be worse when percutaneous coronary intervention (PCI) is performed later in the day because of operator fatigue and differences in process of care. METHODS: Using the APPROACH database, we analyzed 2,492 consecutive nonurgent PCI procedures performed during working hours. Patients undergoing PCI for acute coronary syndromes were excluded. Patients were separated into 2 groups based on whether PCI was started in the morning (7:00 am-12:00 pm, n = 1,446) or after noon (12:01 pm-6:00 pm, n = 1,037). Outcomes included procedural complications; target vessel revascularization (TVR); and death at 7 days, 30 days, and 1 year. RESULTS: Patients undergoing PCI in the afternoon were more likely to have heart failure, reduced ejection fraction, and Canadian Cardiovascular Society class IV or atypical angina symptoms; more likely to be inpatients; less likely to have stable angina; and less likely to receive glycoprotein IIb/IIIa inhibitors. Patients undergoing PCI in the afternoon had significantly higher unadjusted rates of the composite of death and TVR at 7 days (0.9% vs 0.3%, P = .04) and 30 days (2.0% vs 1.0%, P = .04) and death at 1 year (2.2% vs 1.1%, P = .03) compared with PCI performed in the morning. After multivariate adjustment, the differences in the composite of death and TVR at 30 days and at 1 year were not statistically significant. CONCLUSION: Patients undergoing nonurgent PCI during working hours after noon had higher rates of TVR in the first 30 days and death at 1 year. Further study is required to determine whether patient characteristics, operator fatigue, differences in process of care, or a combination of these factors accounts for the difference in outcomes.

Identification of a thalidomide derivative that selectively targets tumorigenic liver progenitor cells and comparing its effects with lenalidomide and sorafenib.

BACKGROUND & AIMS: The availability of non-tumorigenic and tumorigenic liver progenitor cell (LPC) lines affords a method to screen putative anti-liver cancer agents to identify those that are selectively effective. To prove this principle we tested thalidomide and a range of its derivatives and compared them to lenalidomide and sorafenib, to assess their growth-inhibitory effects. METHODS: Cell growth, the mitotic and apoptotic index of cell cultures were measured using the Cellavista instrument (SynenTec) using commercially available reagents. RESULTS: Neither lenalidomide nor thalidomide (100 µM) affected tumorigenic LPCs but killed their non-tumorigenic counterparts. Sorafenib arrested growth in both cell types. All but two derivatives of thalidomide were ineffective; of the two effective derivatives, one (thalidomide C1) specifically affected the tumorigenic cell line (10 µM). Mitotic and apoptotic analyses revealed that thalidomide C1 induced apoptotic cell death and not mitotic arrest. CONCLUSIONS: This study shows that screens incorporating non-tumorigenic and tumorigenic liver cell lines are a sound approach to identify agents that are effective and selective. A high throughput instrument such as the Cellavista affords robust and reproducible objective measurements with a large number of replicates that are reliable. These experiments show that neither lenalidomide nor thalidomide are potentially useful for anti-liver cancer therapy as they kill non-tumorigenic liver cells and not their tumorigenic counterparts. Sorafenib in contrast, is highly effective, but not selective. One tested thalidomide derivative has potential as an anti-tumor drug since it induced growth arrest; and importantly, it selectively induced apoptotic cell death only in tumorigenic liver progenitor cells.

A modified choline-deficient, ethionine-supplemented diet reduces morbidity and retains a liver progenitor cell response in mice.

The choline-deficient, ethionine-supplemented (CDE) dietary model induces chronic liver damage, and stimulates liver progenitor cell (LPC)-mediated repair. Long-term CDE administration leads to hepatocellular carcinoma in rodents and lineage-tracing studies show that LPCs differentiate into functional hepatocytes in this model. The CDE diet was first modified for mice by our laboratory by separately administering choline-deficient chow and ethionine in the drinking water (CD+E diet). Although this CD+E diet is widely used, concerns with variability in weight loss, morbidity, mortality and LPC response have been raised by researchers who have adopted this model. We propose that these inconsistencies are due to differential consumption of chow and ethionine in the drinking water, and that incorporating ethionine in the choline-deficient chow, and altering the strength, will achieve better outcomes. Therefore, C57Bl/6 mice, 5 and 6 weeks of age, were fed an all-inclusive CDE diet of various strengths (67% to 100%) for 3 weeks. The LPC response was quantitated and cell lines were derived. We found that animal survival, LPC response and liver damage are correlated with CDE diet strength. The 67% and 75% CDE diet administered to mice older than 5 weeks and greater than 18 g provides a consistent and acceptable level of animal welfare and induces a substantial LPC response, permitting their isolation and establishment of cell lines. This study shows that an all-inclusive CDE diet for mice reproducibly induces an LPC response conducive to in vivo studies and isolation, whilst minimizing morbidity and mortality.

Feasibility of determining myocardial infarction type from medical record review.

BACKGROUND: Hospital discharge data are used extensively in health research. Given the clinical differences between ST segment elevation myocardial infarction (STEMI) and non-ST segment elevation myocardial infarction (NSTEMI), it is important that these entities be distinguishable in a medical record. The authors sought to determine the extent to which the type of MI is recorded in medical records, as well as the consistency of this designation within individual records. METHODS: Records of all MI patients admitted to a tertiary care centre in Canada from April 1, 2000, to March 31, 2001, were reviewed. Documentation and consistency of the use of the terms STEMI (Q wave, ST elevation or transmural MI) or NSTEMI (non-Q wave, subendocardial or nontransmural MI) were assessed in the admission history, progress notes, coronary care unit summary and discharge summary sections of each record. RESULTS: Missing data were common; each chart section mentioned MI type in fewer than one-half of charts. When information was combined, it was possible to determine the type of MI in 81.1% of cases. MI type was consistently described as STEMI in 48.7% of cases, and as NSTEMI in 32.4%. Of concern, MI type was discrepant across sections in 10.5% of cases and missing entirely in 8.4% of cases. CONCLUSIONS: The designation of MI cases as STEMI or NSTEMI is both incomplete and inconsistent in hospital records. This has implications for health services research conducted retrospectively using medical record data, because it is difficult to comprehensively study processes and outcomes of MI care if the type cannot be retrospectively determined.