Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger-Huet anomaly

The nature of the wild-type gene product at the mouse ichthyosis (ic) locus has been of great interest because mutations at this locus cause marked abnormalities in nuclear heterochromatin, similar to those observed in Pelger-Huët anomaly (PHA). We recently found that human PHA is caused by mutations in the gene (LBR) encoding lamin B receptor, an evolutionarily conserved inner nuclear membrane protein involved in nuclear assembly and chromatin binding. Mice homozygous for deleterious alleles at the ichthyosis (ic) locus present with a blood phenotype similar to PHA, and develop other phenotypic abnormalities, including alopecia, variable expression of syndactyly and hydrocephalus. The ic locus on mouse chromosome 1 shares conserved synteny with the chromosomal location of the human LBR locus on human chromosome 1. In this study, we identified one nonsense (815ins) and two frameshift mutations (1088insCC and 1884insGGAA) within the Lbr gene of mice homozygous for either of three independent mutations (ic, ic(J) and ic(4J), respectively) at the ichthyosis locus. These allelic mutations are predicted to result in truncated or severely impaired LBR protein. Our studies of mice homozygous for the ic(J) mutation revealed a complete loss of LBR protein as shown by immunofluorescence microscopy and immunoblotting. The findings provide the molecular basis for the heterochromatin clumping and other distinct phenotypes caused by ic mutations. These spontaneous Lbr mutations confirm the molecular basis of human PHA and provide a small animal model for determination of the precise function of LBR in normal and pathological states

A scaling relationship for non-thermal radio emission from ordered magnetospheres: From the top of the main sequence to planets

In this paper, we present the analysis of incoherent non-thermal radio emission from a sample of hot magnetic stars, ranging from early-B to early-A spectral type. Spanning a wide range of stellar parameters and wind properties, these stars display a commonality in their radio emission which presents new challenges to the wind scenario as originally conceived. It was thought that relativistic electrons, responsible for the radio emission, originate in current sheets formed, where the wind opens the magnetic field lines. However, the true mass-loss rates from the cooler stars are too small to explain the observed non-thermal broad-band radio spectra. Instead, we suggest the existence of a radiation belt located inside the inner magnetosphere, similar to that of Jupiter. Such a structure explains the overall indifference of the broad-band radio emissions on wind mass-loss rates. Further, correlating the radio luminosities from a larger sample of magnetic stars with their stellar parameters, the combined roles of rotation and magnetic properties have been empirically determined. Finally, our sample of early-type magnetic stars suggests a scaling relationship between the non-thermal radio luminosity and the electric voltage induced by the magnetosphere's co-rotation, which appears to hold for a broader range of stellar types with dipole-dominated magnetospheres (like the cases of the planet Jupiter and the ultracool dwarf stars and brown dwarfs). We conclude that well-ordered and stable rotating magnetospheres share a common physical mechanism for supporting the generation of non-thermal electrons

Stereotactic Ablative Radiotherapy for the Management of Spinal Metastases: A Review

Importance: Rising cancer incidence combined with improvements in systemic and local therapies extending life expectancy are translating into more patients with spinal metastases. This makes the multidisciplinary management of spinal metastases and development of new therapies increasingly important. Spinal metastases may cause significant pain and reduced quality of life and lead to permanent neurological disability if compression of the spinal cord and/or nerve root occurs. Until recently, treatments for spinal metastases were not optimal and provided temporary local control and pain relief. Spinal stereotactic ablative radiotherapy (SABR) is an effective approach associated with an improved therapeutic ratio, with evolving clinical application. Objective: To review the literature of spinal SABR for spinal metastases, discuss a multidisciplinary approach to appropriate patient selection and technical considerations, and summarize current efforts to combine spinal SABR with systemic therapies. Evidence Review: The MEDLINE database was searched to identify articles reporting on spinal SABR to September 30, 2018. Articles including clinical trials, prospective and retrospective studies, systematic reviews, and consensus recommendations were selected for relevance to multidisciplinary management of spinal metastases. Results: Fifty-nine unique publications with 5655 patients who underwent SABR for spinal metastases were included. Four comprehensive frameworks for patient selection were discussed. Spinal SABR was associated with 1-year local control rates of approximately 80% to 90% in the de novo setting, greater than 80% in the postoperative setting, and greater than 65% in the reirradiation setting. The most commonly discussed adverse effect was development of a vertebral compression fracture with variable rates, most commonly reported as approximately 10% to 15%. High-level data on the combination of SABR with modern therapies are still lacking. At present, 19 clinical trials are ongoing, mainly focusing on combined modality therapies, radiotherapy prescription dose, and oligometastic disease. Conclusions and Relevance: These findings suggest that spinal SABR may be an effective treatment option for well-selected patients with spinal metastases, achieving high rates of local tumor control with moderate rates of adverse effects. Optimal management should include review by a multidisciplinary care team