Background
The treatment of oligometastatic (≤5 metastases) spinal disease has trended toward ablative therapies, yet to the authors’ knowledge little is known regarding the prognosis of patients ...presenting with oligometastatic spinal disease and the value of this approach. The objective of the current study was to compare the survival and clinical outcomes of patients with cancer with oligometastatic spinal disease with those of patients with polymetastatic (>5 metastases) disease.
Methods
The current study was an international, multicenter, prospective study. Patients who were admitted to a participating spine center with a diagnosis of spinal metastases and who underwent surgical intervention and/or radiotherapy between August 2013 and May 2017 were included. Data collected included demographics, overall survival, local control, and treatment information including surgical, radiotherapy, and systemic therapy details. Health‐related quality of life (HRQOL) measures included the EuroQOL 5 dimensions 3‐level questionnaire (EQ‐5D‐3L), the 36‐Item Short Form Health Survey (SF‐36v2), and the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ).
Results
Of the 393 patients included in the current study, 215 presented with oligometastatic disease and 178 presented with polymetastatic disease. A significant survival advantage of 90.1% versus 77.3% at 3 months and 77.0% versus 65.1% at 6 months from the time of treatment was found for patients presenting with oligometastatic disease compared with those with polymetastatic disease. It is important to note that both groups experienced significant improvements in multiple HRQOL measures at 6 months after treatment, with no differences in these outcome measures noted between the 2 groups.
Conclusions
The treatment of oligometastatic disease appears to offer a significant survival advantage compared with polymetastatic disease, regardless of treatment choice. HRQOL measures were found to improve in both groups, demonstrating a palliative benefit for all treated patients.
There appears to be a significant survival advantage for patients presenting with oligometastatic disease compared with those with polymetastatic disease at the time of the initial treatment of spinal metastases regardless of the treatment method used. In the current study, both groups are reported to experience significant improvements in multiple measures of health‐related quality of life at 6 months.
Successful implantation relies on precisely orchestrated and reciprocal signaling between the implanting blastocyst and the receptive uterus. We have examined the role of the Wnt/β-catenin signaling ...pathway during the process of implantation and demonstrate that this pathway is activated during two distinct stages. Wnt/β-catenin signaling is first transiently activated in circular smooth muscle forming a banding pattern of activity within the uterus on early day 4. Subsequently, activation is restricted to the luminal epithelium at the prospective site of implantation. Activation at both sites requires the presence of the blastocyst. Furthermore, inhibition of Wnt/β-catenin signaling interferes with the process of implantation. Our results demonstrate that the Wnt/β-catenin signaling pathway plays a central role in coordinating uterus-embryo interactions required for implantation.
It is unknown whether statin use among people living with HIV results in a reduction in all-cause mortality. We aimed to evaluate the effect of statin use on all-cause mortality among people living ...with HIV.
We conducted comprehensive literature searches of Medline, Embase, CINAHL, the Cochrane Library, and cross-references up to April 2018. We included randomised, quasi-randomised trials and prospective cohort studies that examined the association between statin use and cardio-protective and mortality outcomes among people living with HIV. Two reviewers independently abstracted the data. Hazard ratios (HRs) were pooled using empirical Bayesian random-effect meta-analysis. A number of sensitivity analyses were conducted.
We included seven studies with a total of 35,708 participants. The percentage of participants on statins across the studies ranged from 8 to 35%. Where reported, the percentage of participants with hypertension ranged from 14 to 35% and 7 to 10% had been diagnosed with diabetes mellitus. Statin use was associated with a 33% reduction in all-cause mortality (pooled HR = 0.67, 95% Credible Interval 0.39 to 0.96). The probability that statin use conferred a moderate mortality benefit (i.e. decreased risk of mortality of at least 25%, HR ≤ 0.75) was 71.5%. Down-weighting and excluding the lower quality studies resulted in a more conservative estimate of the pooled HR.
Statin use appears to confer moderate mortality benefits in people living with HIV.
Insulin sensitivity in skeletal muscle is associated with metabolic flexibility, including a high capacity to increase fatty acid (FA) oxidation in response to increased lipid supply. Lipid overload, ...however, can result in incomplete FA oxidation and accumulation of potentially harmful intermediates where mitochondrial tricarboxylic acid cycle capacity cannot keep pace with rates of β-oxidation. Enhancement of muscle FA oxidation in combination with mitochondrial biogenesis is therefore emerging as a strategy to treat metabolic disease. Dietary inorganic nitrate was recently shown to reverse aspects of the metabolic syndrome in rodents by as yet incompletely defined mechanisms.
Herein, we report that nitrate enhances skeletal muscle FA oxidation in rodents in a dose-dependent manner. We show that nitrate induces FA oxidation through a soluble guanylate cyclase (sGC)/cGMP-mediated PPARβ/δ- and PPARα-dependent mechanism. Enhanced PPARβ/δ and PPARα expression and DNA binding induces expression of FA oxidation enzymes, increasing muscle carnitine and lowering tissue malonyl-CoA concentrations, thereby supporting intra-mitochondrial pathways of FA oxidation and enhancing mitochondrial respiration. At higher doses, nitrate induces mitochondrial biogenesis, further increasing FA oxidation and lowering long-chain FA concentrations. Meanwhile, nitrate did not affect mitochondrial FA oxidation in PPARα(-/-) mice. In C2C12 myotubes, nitrate increased expression of the PPARα targets Cpt1b, Acadl, Hadh and Ucp3, and enhanced oxidative phosphorylation rates with palmitoyl-carnitine; however, these changes in gene expression and respiration were prevented by inhibition of either sGC or protein kinase G. Elevation of cGMP, via the inhibition of phosphodiesterase 5 by sildenafil, also increased expression of Cpt1b, Acadl and Ucp3, as well as CPT1B protein levels, and further enhanced the effect of nitrate supplementation.
Nitrate may therefore be effective in the treatment of metabolic disease by inducing FA oxidation in muscle.
We present the Multifrequency Snapshot Sky Survey (MSSS), the first northern-sky Low Frequency Array (LOFAR) imaging survey. In this introductory paper, we first describe in detail the motivation and ...design of the survey. Compared to previous radio surveys, MSSS is exceptional due to its intrinsic multifrequency nature providing information about the spectral properties of the detected sources over more than two octaves (from 30 to 160 MHz). The broadband frequency coverage, together with the fast survey speed generated by LOFAR's multibeaming capabilities, make MSSS the first survey of the sort anticipated to be carried out with the forthcoming Square Kilometre Array (SKA). Two of the sixteen frequency bands included in the survey were chosen to exactly overlap the frequency coverage of large-area Very Large Array (VLA) and Giant Metrewave Radio Telescope (GMRT) surveys at 74 MHz and 151 MHz respectively. The survey performance is illustrated within the MSSS Verification Field (MVF), a region of 100 square degrees centered at (alpha, delta)J sub(2000) = (15 super(h),69degrees). The MSSS results from the MVF are compared with previous radio survey catalogs. We assess the flux and astrometric uncertainties in the catalog, as well as the completeness and reliability considering our source finding strategy. We determine the 90% completeness levels within the MVF to be 100 mJy at 135 MHz with 108" resolution, and 550 mJy at 50 MHz with 166" resolution. Images and catalogs for the full survey, expected to contain 150000-200000 sources, will be released to a public web server. We outline the plans for the ongoing production of the final survey products, and the ultimate public release of images and source catalogs.
We present LOFAR data from 110–180 MHz of the merging galaxy cluster Abell 1682, alongside archival optical, radio, and X-ray data. Our images of 6 arcsec in resolution at low frequencies reveal new ...structures associated with numerous radio galaxies in the cluster. At a resolution of 20 arcsec we see diffuse emission throughout the cluster over hundreds of kiloparsecs, indicating particle acceleration mechanisms are in play as a result of the cluster merger event and powerful active galactic nuclei. We show that a significant part of the cluster emission is from an old radio galaxy with very steep spectrum emission (having a spectral index of α < −2.5). Furthermore, we identify a new region of diffuse steep-spectrum emission (α < −1.1) as a candidate for a radio halo which is co-spatial with the centre of the cluster merger. We suggest its origin as a population of old and mildly relativistic electrons left over from radio galaxies throughout the cluster which have been re-accelerated to higher energies by shocks and turbulence induced by the cluster merger event. We also note the discovery of six new giant radio galaxies in the vicinity of Abell 1682.
Abstract Background Combined BRAF and MEK inhibition is effective for some BRAFV600E-altered gliomas, a cancer for which there are few effective therapies. While recent clinical trials demonstrate ...objective response rates of 30%–40%, tolerable adverse event rates are 70%–90%, and 12%–15% of patients stop therapy for toxicity. There are no clear guidelines regarding the timing and reinitiation of BRAF-targeted therapies following drug holidays. Here, we describe 4 patients with rapid disease progression during periods of treatment interruption. All patients experienced a response upon resumption of targeted therapy. Methods This is a multi-institutional, retrospective review of 4 patients. Results Three patients were diagnosed with BRAFV600E mutated anaplastic pleomorphic xanthoastrocytoma (aPXA) and 1 with epithelioid glioblastoma. The age range was 32 to 46; 3 patients were female and one patient was male. All patients were initially treated with radiation and were subsequently treated with BRAF/MEK inhibitors after disease progression. All patients with aPXA required the targeted therapy to be held due to toxicity and 1 patient held the therapy prior to transitioning to a novel BRAF-targeted agent. All patients were restarted on BRAF/MEK inhibitors after a drug holiday. Three patients required a dose reduction and all improved clinically following reinitiation. Conclusions Clinical and radiographic progression may occur rapidly upon holding BRAF-targeted therapy, warranting judicious dose reductions and minimization of drug holidays.
The high-mobility group (HMG) proteins 14 and 17 are abundant chromosomal proteins that bind to nucleosomes and enhance transcription. We report that both mRNA species and both proteins are present ...throughout oogenesis and preimplantation development of the mouse. When antisense oligonucleotides targeting each mRNA species are injected into one-cell embryos, the proteins become depleted at the two- and four-cell stages and reaccumulate at the eight-cell stage. One-cell embryos injected with antisense oligonucleotides targeting both HMG-14 and HMG-17 cleave to the two-cell stage. Subsequent cleavages, however, are delayed compared with control-injected embryos. Nevertheless, these embryos ultimately reach the blastocyst stage. Similarly, injection into the nuclei of two-cell embryos of a peptide corresponding to the common nucleosome-binding domain of HMG-14 and HMG-17 delays progression to the four-cell stage. Furthermore, both RNA and protein synthesis is transiently reduced in antisense-injected embryos compared with injected controls. These results identify HMG-14 and HMG-17 as constitutive components of mouse oocyte and embryonic chromatin and establish a link between the structure of embryonic chromatin and the normal progression of embryonic development.
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