Osteosarcoma (OS) is the most frequent pediatric malignant bone tumor that has a high propensity for metastases. Through osteoblast-specific alteration of p53 status, we developed a genetically ...engineered mouse model of localized and metastatic OS to gain an understanding into the molecular pathogenesis of OS. Microarray analysis of both localized tumors and metastatic tumors identified the downregulation of the naked cuticle homolog 2 (NKD2) gene, a negative regulator of Wnt signaling. Overexpression of NKD2 in metastatic human and mouse OS cells significantly decreases cell proliferation, migration and invasion ability in vitro and drastically diminishes OS tumor growth and metastasis in vivo, whereas downregulation enhances migratory and invasive potential. Evaluation of NKD2-overexpressing tumors revealed upregulation of tumor-suppressor genes and downregulation of molecules involved in blood vessel formation and cell migration. Furthermore, assessment of primary human OS revealed downregulation of NKD2 in metastatic and recurrent OS. Finally, we provide biological evidence that use of small-molecule inhibitors targeting the Wnt pathway can have therapeutic efficacy in decreasing metastatic properties in OS. Our studies provide compelling evidence that downregulation of NKD2 expression and alterations in associated regulated pathways have a significant role in driving OS tumor growth and metastasis.
Leflunomide has been reported as an alternative therapy in sarcoidosis. However, the published data are limited. We performed a retrospective chart review of the tolerance and effects of leflunomide ...therapy in patients with sarcoidosis. 76 patients were included. The most common reasons for initiation were progression of disease or failure of other immunomodulator therapy. Side-effects attributable to leflunomide were noted in 34% of subjects, prompting discontinuation in 17%. The lungs were a target of therapy in 33 (44%) and extrapulmonary organs were a target in 45 (59%). The mean ± sd change in forced vital capacity in the 6 months prior to leflunomide was -0.1 ± 0.3 L, and it was +0.09 ± 0.3 L in the following 6 months (p=0.01). For extrapulmonary target organ response, 51% had a good response and 32% a partial response. The median corticosteroid dose at initiation was 10 mg (interquartile range 5-20) mg at baseline, and 0 (0-10) mg at the 6-month follow-up (p<0.001). Leflunomide is a viable alternative agent for pulmonary and extrapulmonary sarcoidosis. Leflunomide appears to facilitate reduction of steroid dose and can be considered as monotherapy or as add-on therapy in cases of progressive disease.
In this study, we present experimental results of the second-order nonlinear optical response of a series of pyrazoline derivatives. The main aim of this study was to determine the correlation ...between the chemical structure of the pyrazoline derivatives family and their nonlinear optical properties. The investigated group of materials consists of pairs or triplets of derivatives and structural isomers, which are characterized by the same electron-donor unit, whereas differ in their electron-accepting part. Moreover, some of them possess different moieties, which can change the electron cloud distribution in the molecule. Their efficient nonlinear optical responses and possibility of tuning in this group of materials promote them for various optoelectronic applications where optical nonlinearity plays a crucial role. Since material engineering enables the control of molecular structure, the nonlinear optical features of the created systems can be consequently optimized.
In this study, we present experimental results of the second-order nonlinear optical response of a series of pyrazoline derivatives.
The signature of positron annihilation, namely the 511 keV γ-ray line, was first detected coming from the direction of the Galactic center in the 1970s, but the source of Galactic positrons still ...remains a puzzle. The measured flux of the annihilation corresponds to an intense steady source of positron production, with an annihilation rate on the order of ∼1043 . The 511 keV emission is the strongest persistent Galactic γ-ray line signal, and it shows a concentration toward the Galactic center region. An additional low-surface brightness component is aligned with the Galactic disk; however, the morphology of the latter is not well constrained. The Compton Spectrometer and Imager (COSI) is a balloon-borne soft γ-ray (0.2-5 MeV) telescope designed to perform wide-field imaging and high-resolution spectroscopy. One of its major goals is to further our understanding of Galactic positrons. COSI had a 46-day balloon flight in 2016 May-July from Wanaka, New Zealand, and here we report on the detection and spectral and spatial analyses of the 511 keV emission from those observations. To isolate the Galactic positron annihilation emission from instrumental background, we have developed a technique to separate celestial signals using the COMPTEL Data Space. With this method, we find a 7.2 detection of the 511 keV line. We find that the spatial distribution is not consistent with a single point source, and it appears to be broader than what has previously been reported.
Marine wildlife faces a growing number of threats across the globe, and the survival of many species and populations will be dependent on conservation action. One threat in particular that has ...emerged over the last 4 decades is the pollution of oceanic and coastal habitats with plastic debris. The increased occurrence of plastics in marine ecosystems mirrors the increased prevalence of plastics in society, and reflects the high durability and persistence of plastics in the environment. In an effort to guide future research and assist mitigation approaches to marine conservation, we have generated a list of 16 priority research questions based on the expert opinions of 26 researchers from around the world, whose research expertise spans several disciplines, and covers each of the world's oceans and the taxa most at risk from plastic pollution. This paper highlights a growing concern related to threats posed to marine wildlife from microplastics and fragmented debris, the need for data at scales relevant to management, and the urgent need to develop interdisciplinary research and management partnerships to limit the release of plastics into the environment and curb the future impacts of plastic pollution.
Amyotrophic lateral sclerosis (ALS) is an incurable neuromuscular disease that leads to a profound loss of life quality and premature death. Around 10% of the cases are inherited and ALS8 is an ...autosomal dominant form of familial ALS caused by mutations in the vamp-associated protein B/C (VAPB) gene. The VAPB protein is involved in many cellular processes and it likely contributes to the pathogenesis of other forms of ALS besides ALS8. A number of successful drug tests in ALS animal models could not be translated to humans underscoring the need for novel approaches. The induced pluripotent stem cells (iPSC) technology brings new hope, since it can be used to model and investigate diseases in vitro. Here we present an additional tool to study ALS based on ALS8-iPSC. Fibroblasts from ALS8 patients and their non-carrier siblings were successfully reprogrammed to a pluripotent state and differentiated into motor neurons. We show for the first time that VAPB protein levels are reduced in ALS8-derived motor neurons but, in contrast to over-expression systems, cytoplasmic aggregates could not be identified. Our results suggest that optimal levels of VAPB may play a central role in the pathogenesis of ALS8, in agreement with the observed reduction of VAPB in sporadic ALS.
Heart failure is a prevalent disorder whose prognosis remains poor despite advances in treatment. Women with or at risk for HIV may be particularly susceptible, yet the metabolic pathways that ...promote myocardial disease and heart failure in this context remain incompletely characterized.
To evaluate the metabolomic signatures of cardiac magnetic resonance measured phenotypes, we used available plasma metabolomic measures from participants in the Women's Interagency HIV Study who underwent cardiac magnetic resonance imaging. Our primary outcomes were myocardial extracellular volume fraction (MECV) and intramyocardial triglyceride content (IMTG). We applied partial least squares and identified the top 10 lipid and polar metabolites associated with MECV and IMTG. We used multivariable linear regression to evaluate these metabolites' individual associations with each phenotype.
The mean age of participants (n = 153) was 53 ± 7, 93% were Black or Hispanic, and 74% were HIV positive. Phenylacetylglutamine, a microbial metabolite, was positively associated with MECV after full adjustment and false discovery rate correction. Three phosphatidylcholine species, N-acetylaspartic acid, and a lysophosphatidylcholine species were inversely associated with IMTG, while prolylglycine, methionine sulfoxide, sphingosine, taurine, and phosphorylcholine were positively associated with this phenotype. We found no evidence of interaction by HIV for the observed associations, but there was effect modification by hepatitis C virus of taurine's and phosphorylcholine's associations with IMTG.
Among women with or at risk for HIV, we related various lipid and polar metabolites to cardiac fibrosis or steatosis, of which phenylacetylglutamine, N-acetylaspartic acid, and prolylglycine are novel. These findings implicate plausible mechanisms that could be targetable for therapeutics.
Abstract Background People with human immunodeficiency virus (HIV) (PWH) have an increased risk of cardiovascular disease (CVD). Cardiac magnetic resonance (CMR) has documented higher myocardial ...fibrosis, inflammation, and steatosis in PWH, but studies have mostly relied on healthy volunteers as comparators and focused on men. Methods We investigated the associations of HIV and HIV-specific factors with CMR phenotypes in female participants enrolled in the Women's Interagency HIV Study's New York and San Francisco sites. Primary phenotypes included myocardial native (n) T1 (fibro-inflammation), extracellular volume fraction (fibrosis), and triglyceride content (steatosis). Associations were evaluated with multivariable linear regression, and results pooled or meta-analyzed across centers. Results Among 261 women with HIV (WWH, N = 362), 76.2% had undetectable viremia at CMR. For the 82.8% receiving continuous antiretroviral therapy (ART) in the preceding 5 years, adherence was 51.7%, and 69.4% failed to achieve persistent viral suppression (40.7% with peak viral load <200 cp/mL). Overall, WWH showed higher nT1 than women without HIV after full adjustment. This higher nT1 was more pronounced in those with antecedent or current viremia or nadir CD4+ count <200 cells/μL, with the latter also associated with higher extracellular volume fraction. WWH and current CD4+ count <200 cells/μL had less cardiomyocyte steatosis. Cumulative exposure to specific ART showed no associations. Conclusions Compared with sociodemographically similar women without HIV, WWH on ART exhibit higher myocardial fibro-inflammation, which is more prominent with unsuppressed viremia or CD4+ lymphopenia. These findings support the importance of improved ART adherence strategies, along with better understanding of latent infection, to mitigate cardiac end-organ damage in this population.
HIV and HCV have each been linked with cardiac dysfunction. Studies of HIV have often lacked appropriate controls and primarily involved men, whereas data for HCV are sparse.
We performed repeat ...echocardiography over a median interval of 12 years in participants from the Women's Interagency HIV Study in order to evaluate the relationships of HIV and HCV with incident left ventricular (LV) dysfunction (systolic or diastolic).
Of the 311 women included (age 39 ± 9), 70% were HIV-positive and 20% HCV-positive. Forty three participants (13.8%) developed LV dysfunction, of which 79.1% was diastolic. Compared with participants with neither infection, the group with HIV--HCV coinfection showed a significantly increased risk of incident LV dysfunction after adjustment for risk factors RR = 2.96 (95% CI = 1.05-8.31), but associations for the HCV monoinfected and HIV monoinfected groups were not statistically significant RR = 2.54 (0.83-7.73) and RR = 1.66 (0.65-4.25), respectively. Comparison of HCV-positive and HCV-negative women showed a significantly increased risk independent of covariates RR = 1.96 (1.02-3.77) but this was not the case for HIV-positive vs. HIV-negative women RR = 1.43 (0.76-2.69). There was no evidence of HCV-by-HIV interaction. A more restrictive definition of LV diastolic dysfunction led to fewer incident cases, but a similar, though nonsignificant, risk estimate for HCV.
Among mostly middle-aged women, HCV but not HIV infection was associated with a pronounced risk of incident LV dysfunction. Although the influence of residual confounding cannot be excluded, these findings bolster the potential benefits that could be realized by adopting recent recommendations for expanding HCV screening and treatment.
ABSTRACT
Tidal features in the outskirts of galaxies yield unique information about their past interactions and are a key prediction of the hierarchical structure formation paradigm. The Vera C. ...Rubin Observatory is poised to deliver deep observations for potentially millions of objects with visible tidal features, but the inference of galaxy interaction histories from such features is not straightforward. Utilizing automated techniques and human visual classification in conjunction with realistic mock images produced using the NewHorizon cosmological simulation, we investigate the nature, frequency, and visibility of tidal features and debris across a range of environments and stellar masses. In our simulated sample, around 80 per cent of the flux in the tidal features around Milky Way or greater mass galaxies is detected at the 10-yr depth of the Legacy Survey of Space and Time (30–31 mag arcsec−2), falling to 60 per cent assuming a shallower final depth of 29.5 mag arcsec−2. The fraction of total flux found in tidal features increases towards higher masses, rising to 10 per cent for the most massive objects in our sample (M⋆ ∼ 1011.5 M⊙). When observed at sufficient depth, such objects frequently exhibit many distinct tidal features with complex shapes. The interpretation and characterization of such features varies significantly with image depth and object orientation, introducing significant biases in their classification. Assuming the data reduction pipeline is properly optimized, we expect the Rubin Observatory to be capable of recovering much of the flux found in the outskirts of Milky Way mass galaxies, even at intermediate redshifts (z < 0.2).
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