Comparative Study of Plan Robustness for Breast Radiotherapy: Volumetric Modulated Arc Therapy Plans with Robust Optimization versus Manual Flash Approach.

A previous study investigated robustness of manual flash (MF) and robust optimized (RO) volumetric modulated arc therapy plans for breast radiotherapy based on five patients in 2020 and indicated that the RO was more robust than the MF, although the MF is still current standard practice. The purpose of this study was to compare their plan robustness in terms of dose variation to clinical target volume (CTV) and organs at risk (OARs) based on a larger sample size. This was a retrospective study involving 34 female patients. Their plan robustness was evaluated based on measured volume/dose difference between nominal and worst scenarios (ΔV/ΔD) for each CTV and OARs parameter, with a smaller difference representing greater robustness. Paired sample t-test was used to compare their robustness values. All parameters (except CTV ΔD98%) of the RO approach had smaller ΔV/ΔD values than those of the MF. Also, the RO approach had statistically significantly smaller ΔV/ΔD values (p < 0.001-0.012) for all CTV parameters except the CTV ΔV95% and ΔD98% and heart ΔDmean. This study's results confirm that the RO approach was more robust than the MF in general. Although both techniques were able to generate clinically acceptable plans for breast radiotherapy, the RO could potentially improve workflow efficiency due to its simpler planning process.

A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk.

Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systems-genetics approaches. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein-Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)-a macrophage-associated autoimmune disease-than randomly selected immune response genes (P = 8.85 × 10(-6)). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0 × 10(-10); odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D.

Activation of PPARbeta/delta inhibits leukocyte recruitment, cell adhesion molecule expression, and chemokine release.

The infiltration of PMNs into tissues is a prominent feature in inflammation. The mechanism underlying PMN recruitment depends on the release of chemotactic mediators and CAM expression on endothelial cells. The nuclear receptor PPARbeta/delta is widely expressed in many tissues, including the vascular endothelium; however, its role in acute inflammation remains unclear. Using intravital microscopy in the mouse cremasteric microcirculation, we have shown that activation of PPARbeta/delta by its selective ligand GW501516 inhibits TNF-alpha-induced leukocyte rolling flux, adhesion, and emigration in a dose-dependant manner. Moreover, GW501516 reduced the expression of adhesion molecules such as ICAM-1, VCAM-1, and E-selectin in the cremasteric postcapillary venules. Similarly, rolling and adhesion of hPMNs under physiological flow on TNF-alpha-activated HUVECs were also inhibited markedly by GW501516. These inhibitory responses of GW501516 on activated endothelium were accompanied by a reduction in TNF-alpha-induced endothelial GRO-alpha release and VCAM-1, E-selectin, and ICAM-1 mRNA expression. Taken together, our results show that PPARbeta/delta modulates acute inflammation in vivo and in vitro under flow by targeting the neutrophil-endothelial cell interaction.

Farnesoid x receptor ligands inhibit vascular smooth muscle cell inflammation and migration.

OBJECTIVE: The farnesoid X receptor/bile acid receptor (FXR; NR1H4) is a ligand-activated transcription factor that regulates bile acid and lipid homeostasis, and is highly expressed in enterohepatic tissue. FXR is also expressed in vascular tissue. We have investigated whether FXR regulates inflammation and migration in vascular smooth muscle cells. METHODS AND RESULTS: The FXR target gene, small heterodimer partner (SHP), was induced in vascular smooth muscle cells after treatment with synthetic FXR ligands, GW4064, or 6alpha-ethyl-chenodeoxycholic acid. FXR ligands induced smooth muscle cell death and downregulated interleukin (IL)-1beta-induced inducible nitric oxide synthase and cyclooxygenase-2 expression. In addition, FXR ligands suppressed smooth muscle cell migration stimulated by platelet-derived growth factor-BB. Reporter gene assays showed that FXR ligands activated an FXR reporter gene and suppressed IL-1beta-induced nuclear factor (NF)-kappaB activation and iNOS in a manner that required functional FXR and SHP. CONCLUSIONS: Our observations suggest that a FXR-SHP pathway may be a novel therapeutic target for vascular inflammation, remodeling, and atherosclerotic plaque stability.