The dosimetric effects of limited elective nodal irradiation in volumetric modulated arc therapy treatment planning for locally advanced non-small cell lung cancer

Objective—Contemporary radiotherapy guidelines for locally advanced non-small cell lung carcinoma (LA-NSCLC) recommend omitting elective nodal irradiation, despite the fact that evidence supporting this came primarily from older reports assessing comprehensive nodal coverage using 3D conformal techniques. Herein, we evaluated the dosimetric implications of the addition of limited elective nodal irradiation (LENI) to standard involved field irradiation (IFI) using volumetric modulated arc therapy (VMAT) planning. Method—Target volumes and organs-at-risk (OARs) were delineated on CT simulation images of 20 patients with LA-NSCLC. Two VMAT plans (IFI and LENI) were generated for each patient. Involved sites were treated to 60 Gy in 30 fractions for both IFI and LENI plans. Adjacent uninvolved nodal regions, considered high risk based on the primary tumor site and extent of nodal involvement, were treated to 51 Gy in 30 fractions in LENI plans using a simultaneous integrated boost approach. Results—All planning objectives for PTVs and OARs were achieved for both IFI and LENI plans. LENI resulted in significantly higher esophagus Dmean (15.3 vs. 22.5 Gy, p \u3c 0.01), spinal cord Dmax (34.9 vs. 42.4 Gy, p = 0.02) and lung Dmean (13.5 vs. 15.9 Gy, p = 0.02), V20 (23.0 vs. 27.9%, p = 0.03), and V5 (52.6 vs. 59.4%, p = 0.02). No differences were observed in heart parameters. On average, only 32.2% of the high-risk nodal volume received an incidental dose of 51 Gy when untargeted in IFI plans. Conclusion—The addition of LENI to VMAT plans for LA-NSCLC is feasible, with only modestly increased doses to OARs and marginal expected increase in associated toxicity

Fiber Type Conversion by PGC-1α Activates Lysosomal and Autophagosomal Biogenesis in Both Unaffected and Pompe Skeletal Muscle

PGC-1α is a transcriptional co-activator that plays a central role in the regulation of energy metabolism. Our interest in this protein was driven by its ability to promote muscle remodeling. Conversion from fast glycolytic to slow oxidative fibers seemed a promising therapeutic approach in Pompe disease, a severe myopathy caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) which is responsible for the degradation of glycogen. The recently approved enzyme replacement therapy (ERT) has only a partial effect in skeletal muscle. In our Pompe mouse model (KO), the poor muscle response is seen in fast but not in slow muscle and is associated with massive accumulation of autophagic debris and ineffective autophagy. In an attempt to turn the therapy-resistant fibers into fibers amenable to therapy, we made transgenic KO mice expressing PGC-1α in muscle (tgKO). The successful switch from fast to slow fibers prevented the formation of autophagic buildup in the converted fibers, but PGC-1α failed to improve the clearance of glycogen by ERT. This outcome is likely explained by an unexpected dramatic increase in muscle glycogen load to levels much closer to those observed in patients, in particular infants, with the disease. We have also found a remarkable rise in the number of lysosomes and autophagosomes in the tgKO compared to the KO. These data point to the role of PGC-1α in muscle glucose metabolism and its possible role as a master regulator for organelle biogenesis - not only for mitochondria but also for lysosomes and autophagosomes. These findings may have implications for therapy of lysosomal diseases and other disorders with altered autophagy

A combined AFLP and microsatellite linkage map and pilot comparative genomic analysis of European sea bass Dicentrarchus labrax L

European sea bass (Dicentrarchus labrax L., Moronidae, Teleostei) sustains a regional fishery and is commonly farmed in the Mediterranean basin, but has not undergone much long-term genetic improvement. An updated genetic linkage map of the European sea bass was constructed using 190 microsatellites, 176 amplified fragment length polymorphisms and two single nucleotide polymorphisms. From the 45 new microsatellite markers (including 31 type I markers) reported in this study, 28 were mapped. A total of 368 markers were assembled into 35 linkage groups. Among these markers, 28 represented type I (coding) markers, including those located within the peptide Y, SOX10, PXN1, ERA and TCRB genes (linkage groups 1, 7, 16, 17 and 27 respectively). The sex-averaged map spanned 1373.1 centimorgans (cM) of the genome. The female map measured 1380.0 cM, whereas the male map measured 1046.9 cM, leading to a female-to-male (F:M) recombination rate ratio of 1.32:1. The intermarker spacing of the second-generation linkage map of the European sea bass was 3.67 cM, which is smaller than that of the first-generation linkage map (5.03 cM). Comparative mapping of microsatellite flanking regions was performed with five model teleosts and this revealed a high percentage (33.6%) of evolutionarily conserved regions with the three-spined stickleback.status: publishe

A genetic linkage map of the hermaphrodite teleost fish Sparus aurata L.

The gilthead sea bream (Sparus aurala L.) is a marine fish of great importance for fisheries and aqua-culture. It has also a peculiar sex-determination system, being a protandrous hermaphrodite. Here we report the construction of a first-generation genetic linkage map for S. aurata, based on 204 microsatellite markers. Twenty-six linkage groups (LG) were found. The total map length was 1241.9 cM. The ratio between sex-xpecific map lengths was 1:1:2 (male:female). Comparison with a preliminary radiation hybrid (RH) map reveals a good concordance, as all makers located in a single LG are located in a single RH group, except for Ad-25 and Cld-31. Comparison with the Tetraodon nigroviridis genome revealed a considerable number of evolutionary conserved regions (ECRs) between the two species. The mean size of ECRs was 182 bp (sequence identity 60-90%). Forty-one ECRs have a known chromosomal location in the pufferfish genome. Despite the limited number of anchoring points, significant syntenic relationships were found. The linkage map presented here provides a robust comparative framework for QTL analysis in S. aurata and is a step toward the identification of genetic loci involved both in the determination of economically important traits and in the individual timing of sex reversal