Purpose
Evolocumab reduced low-density lipoprotein cholesterol (LDL-C) in 12-week trials in statin-intolerant patients (GAUSS-1 and GAUSS-2); however, the persistence of efficacy during longer-term ...treatment is unknown. This subset analysis of the open-label extension studies (OSLER-1 and OSLER-2) aimed to evaluate the safety and efficacy of evolocumab up to 2 years in statin-intolerant patients.
Methods
Patients who completed GAUSS-1 and GAUSS-2 were enrolled in the OSLER studies and rerandomized 2:1 to evolocumab (140 mg biweekly or 420 mg monthly) plus standard of care (SOC) or SOC during year 1, and thereafter, evolocumab plus SOC.
Results
A total of 382 statin-intolerant patients who completed the GAUSS-1 and GAUSS-2 parent studies were enrolled and rerandomized into the OSLER studies. After year 1, 246 (98%) patients randomized to evolocumab plus SOC and 124 (95%) on SOC during year 1 remained in the OSLER studies; after year 2, 364 (95%) remained on study. Mean parent study baseline LDL-C concentration was 4.97–5.02 mmol/L (192–194 mg/dL). The median percentage reduction from baseline in LDL-C was 13% for SOC and 57% for evolocumab plus SOC at year 1, and 59% for evolocumab plus SOC at year 2. The patient incidence of muscle-related adverse events during year 1 in the SOC and evolocumab plus SOC groups was 16% and 14%, respectively, and 11% for evolocumab plus SOC at year 2. No patient discontinued the study due to adverse events.
Conclusion
Evolocumab plus SOC was persistently safe, tolerable, and efficacious for up to 2 years in statin-intolerant patients.
In eukaryotes, chromosomal rearrangements, such as inversions, translocations and duplications, are common and range from part of a gene to hundreds of genes. Lineage-specific patterns are also seen: ...translocations are rare in dipteran flies, and angiosperm genomes seem prone to polyploidization. In most eukaryotes, there is a strong association between rearrangement breakpoints and repeat sequences. Current data suggest that some repeats promoted rearrangements via non-allelic homologous recombination, for others the association might not be causal but reflects the instability of particular genomic regions. Rearrangement polymorphisms in eukaryotes are correlated with phenotypic differences, so are thought to confer varying fitness in different habitats. Some seem to be under positive selection because they either trap favorable allele combinations together or alter the expression of nearby genes. There is little evidence that chromosomal rearrangements cause speciation, but they probably intensify reproductive isolation between species that have formed by another route.
Background Primary mediastinal large B-cell lymphoma is a rare lymphoma accounting for no more than 3% of all B-cell lymphomas in children and adolescents. However, patients in this young age group ...with this lymphoma have the shortest event-free survival of patients with any B-cell lymphoma under current standard chemotherapy protocols. Lymphomas with features intermediate between primary mediastinal large B-cell lymphoma and classical Hodgkin's lymphoma (mediastinal gray zone lymphomas) have been acknowledged in the latest World Health Organization classification. Recent studies suggest that mediastinal gray zone lymphomas have an aggressive clinical course whereas patients, at least adult ones, with primary mediastinal large B-cell lymphoma might respond very well to chemotherapy in combination with anti-CD20 antibody.
We aimed to evaluate whether biological differences or so far unrecognized admixed mediastinal gray zone lymphomas might explain the relatively poor outcome of pediatric patients with apparent primary mediastinal large B-cell lymphoma. We, therefore, performed a retrospective histopathological, immunohistochemical and interphase cytogenetic analysis of 52 pediatric lymphomas.
The childhood primary mediastinal large B-cell lymphomas (n=44) showed a similar pattern of histology, immunophenotype and gains at 9p (59%) and 2p (41%) as adult cases, as determined from published data. We identified only four so far unrecognized cases of mediastinal gray zone lymphoma among 52 lymphomas registered in previous trials. Conclusions Mediastinal gray zone lymphoma is very rare in children and adolescents. It does, therefore, seem unlikely that these lymphomas account for the unsatisfactory clinical results with current therapy protocols in pediatric patients. These data have major implications for the design of future treatment protocols for mediastinal lymphomas in children and adolescents.
We have previously shown that hypoxia selects for more invasive, apoptosis-resistant LNCaP prostate cancer cells, with upregulation of the osteogenic transcription factor RUNX2 and the anti-apoptotic ...factor Bcl-2 detected in the hypoxia-selected cells. Following this observation, we questioned through what biological mechanism this occurs.
We examined the effect of hypoxia on RUNX2 expression and the role of RUNX2 in the regulation of Bcl-2 and apoptosis resistance in prostate cancer.
Hypoxia increased RUNX2 expression in vitro, and bicalutamide-treated LNCaP tumours in mice (previously shown to have increased tumour hypoxia) exhibited increased RUNX2 expression. In addition, RUNX2-overexpressing LNCaP cells showed increased cell viability, following bicalutamide and docetaxel treatment, which was inhibited by RUNX2 siRNA; a range of assays demonstrated that this was due to resistance to apoptosis. RUNX2 expression was associated with increased Bcl-2 levels, and regulation of Bcl-2 by RUNX2 was confirmed through chromatin immunoprecipitation (ChIP) binding and reporter assays. Moreover, a Q-PCR array identified other apoptosis-associated genes upregulated in the RUNX2-overexpressing LNCaP cells.
This study establishes a contributing mechanism for progression of prostate cancer cells to a more apoptosis-resistant and thus malignant phenotype, whereby increased expression of RUNX2 modulates the expression of apoptosis-associated factors, specifically Bcl-2.
CCAAT/enhancer-binding proteins (C/EBP) are critical determinants for cellular differentiation and cell type-specific gene expression. Their functional roles in osteoblast development have not been ...determined. We addressed a key component of the mechanisms by which C/EBP factors regulate transcription of a tissue-specific gene during osteoblast differentiation. Expression of both C/EBPbeta and C/EBPdelta increases from the growth to maturation developmental stages and, like the bone-specific osteocalcin (OC) gene, is also stimulated 3-6-fold by vitamin D(3), a regulator of osteoblast differentiation. We characterized a C/EBP enhancer element in the proximal promoter of the rat osteocalcin gene, which resides in close proximity to a Runx2 (Cbfa1) element, essential for tissue-specific activation. We find that C/EBP and Runx2 factors interact together in a synergistic manner to enhance OC transcription (35-40-fold) in cell culture systems. We show by mutational analysis that this synergism is mediated through the C/EBP-responsive element in the OC promoter and by a direct interaction between Runx2 and C/EBPbeta. Furthermore, we have mapped a domain in Runx2 necessary for this interaction by immunoprecipitation. A Runx2 mutant lacking this interaction domain does not exhibit functional synergism. We conclude that, in addition to Runx2 DNA binding functions, Runx2 can also form a protein complex at C/EBP sites to regulate transcription. Taken together, our findings indicate that C/EBP is a principal transactivator of the OC gene and the synergism with Runx2 suggests that a combinatorial interaction of these factors is a principal mechanism for regulating tissue-specific expression during osteoblast differentiation.
Although interventions exist to reduce violent crime, optimal implementation requires accurate targeting. We report the results of an attempt to develop an actuarial model using machine learning ...methods to predict future violent crimes among US Army soldiers.
A consolidated administrative database for all 975 057 soldiers in the US Army in 2004-2009 was created in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). Of these soldiers, 5771 committed a first founded major physical violent crime (murder-manslaughter, kidnapping, aggravated arson, aggravated assault, robbery) over that time period. Temporally prior administrative records measuring socio-demographic, Army career, criminal justice, medical/pharmacy, and contextual variables were used to build an actuarial model for these crimes separately among men and women using machine learning methods (cross-validated stepwise regression, random forests, penalized regressions). The model was then validated in an independent 2011-2013 sample.
Key predictors were indicators of disadvantaged social/socioeconomic status, early career stage, prior crime, and mental disorder treatment. Area under the receiver-operating characteristic curve was 0.80-0.82 in 2004-2009 and 0.77 in the 2011-2013 validation sample. Of all administratively recorded crimes, 36.2-33.1% (male-female) were committed by the 5% of soldiers having the highest predicted risk in 2004-2009 and an even higher proportion (50.5%) in the 2011-2013 validation sample.
Although these results suggest that the models could be used to target soldiers at high risk of violent crime perpetration for preventive interventions, final implementation decisions would require further validation and weighing of predicted effectiveness against intervention costs and competing risks.
As physical activity may modify the effect of the apolipoprotein E (APOE) ε4 allele on the risk of dementia and Alzheimer's disease (AD) dementia, we tested for such a gene-environment interaction in ...a sample of general practice patients aged ⩾75 years.
Data were derived from follow-up waves I-IV of the longitudinal German study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe). The Kaplan-Meier survival method was used to estimate dementia- and AD-free survival times. Multivariable Cox regression was used to assess individual associations of APOE ε4 and physical activity with risk for dementia and AD, controlling for covariates. We tested for gene-environment interaction by calculating three indices of additive interaction.
Among the randomly selected sample of 6619 patients, 3327 (50.3%) individuals participated in the study at baseline and 2810 (42.5%) at follow-up I. Of the 2492 patients without dementia included at follow-up I, 278 developed dementia (184 AD) over the subsequent follow-up interval of 4.5 years. The presence of the APOE ε4 allele significantly increased and higher physical activity significantly decreased risk for dementia and AD. The co-presence of APOE ε4 with low physical activity was associated with higher risk for dementia and AD and shorter dementia- and AD-free survival time than the presence of APOE ε4 or low physical activity alone. Indices of interaction indicated no significant interaction between low physical activity and the APOE ε4 allele for general dementia risk, but a possible additive interaction for AD risk.
Physical activity even in late life may be effective in reducing conversion to dementia and AD or in delaying the onset of clinical manifestations. APOE ε4 carriers may particularly benefit from increasing physical activity with regard to their risk for AD.
•Grief is an important risk factor for depression in old people.•With increasing age and grief burden depression severity increases.•Loneliness is the mechanism by which grief intensifies depressive ...symptoms.•People living alone were the most vulnerable group.
The proportion of older adults is increasing due to demographic changes. Depression belongs to the most common mental disorders in late life. The loss of an emotionally significant person is a risk factor for the development of depression. The aim of this study is to analyze the association between depression and grief burden resulting from loss. Based on prior evidence, we examined loneliness as a possible mediator and social support as possible moderator of this association.
The cross-sectional analyses are based on a sample (N = 863) of study participants aged 75+ (M = 81.4 years, SD = 4.4, 62.2% female) with loss experience deriving from the multicenter prospective German cohort study AgeMooDe. Regression analyses (moderated mediation) were performed.
With increasing age (β = 0.10, p = .005) and grief burden (β = 0.33, p <. 001) depression severity increased. There was an indirect mediating effect of loneliness on the correlation of grief burden and depression (b = 0.04, CI 0.03, 0.05), but no moderating effect of social support on the correlation of grief burden and loneliness. People living alone had a significantly higher risk of depression, increased loneliness and lack of social support.
Assessments were based on self-reporting and recorded dimensionally. The cross-sectional design limits conclusions about directions and causality of associations. Sampling bias cannot be completely excluded.
The study provides empirical evidence and a better understanding of the association between grief and depression among the very old and the mediating role of loneliness.
This paper provides an overview of the Curiosity rover's exploration at Vera Rubin ridge (VRR) and summarizes the science results. VRR is a distinct geomorphic feature on lower Aeolis Mons ...(informally known as Mount Sharp) that was identified in orbital data based on its distinct texture, topographic expression, and association with a hematite spectral signature. Curiosity conducted extensive remote sensing observations, acquired data on dozens of contact science targets, and drilled three outcrop samples from the ridge, as well as one outcrop sample immediately below the ridge. Our observations indicate that strata composing VRR were deposited in a predominantly lacustrine setting and are part of the Murray formation. The rocks within the ridge are chemically in family with underlying Murray formation strata. Red hematite is dispersed throughout much of the VRR bedrock, and this is the source of the orbital spectral detection. Gray hematite is also present in isolated, gray‐colored patches concentrated toward the upper elevations of VRR, and these gray patches also contain small, dark Fe‐rich nodules. We propose that VRR formed when diagenetic event(s) preferentially hardened rocks, which were subsequently eroded into a ridge by wind. Diagenesis also led to enhanced crystallization and/or cementation that deepened the ferric‐related spectral absorptions on the ridge, which helped make them readily distinguishable from orbit. Results add to existing evidence of protracted aqueous environments at Gale crater and give new insight into how diagenesis shaped Mars' rock record.
Plain Language Summary
Vera Rubin ridge is a feature at the base of Mount Sharp with a distinct texture and topography. Orbiter observations showed hematite, a mineral that sometimes forms by chemical reactions in water environments, was present atop the ridge. The presence of both water and chemical activity suggested the area preserved a past habitable environment. In this paper, we detail how the Curiosity science team tested this and other orbital‐based hypotheses. Curiosity data suggested that most ridge rocks were lain down in an ancient lake and had similar compositions to other Mount Sharp rocks. Curiosity confirmed that hematite was present in the ridge but no more abundantly than elsewhere. Larger grain size or higher crystallinity probably account for the ridge's hematite being more visible from orbit. We conclude Vera Rubin ridge formed because groundwater recrystallized and hardened the rocks that now make up the ridge. Wind subsequently sculpted and eroded Mount Sharp, leaving the harder ridge rocks standing because they resisted erosion compared with surrounding rocks. The implication of these results is that liquid water was present at Mount Sharp for a very long time, not only when the crater held a lake but also much later, likely as groundwater.
Key Points
We summarize Curiosity's campaign at Vera Rubin ridge (Sols 1726–2302) and the high‐level results from articles in this special issue
Vera Rubin ridge formed when diagenesis hardened rocks along the base of Aeolis Mons; wind subsequently etched the feature into a ridge
Results add evidence for protracted aqueous environments at Gale crater and give new insight into how diagenesis shaped Mars' rock record
For ~500 Martian solar days (sols), the Mars Science Laboratory team explored Vera Rubin ridge (VRR), a topographic feature on the northwest slope of Aeolis Mons. Here we review the sedimentary ...facies and stratigraphy observed during sols 1,800–2,300, covering more than 100 m of stratigraphic thickness. Curiosity's traverse includes two transects across the ridge, which enables investigation of lateral variability over a distance of ~300 m. Three informally named stratigraphic members of the Murray formation are described: Blunts Point, Pettegrove Point, and Jura, with the latter two exposed on VRR. The Blunts Point member, exposed just below the ridge, is characterized by a recessive, fine‐grained facies that exhibits extensive planar lamination and is crosscut by abundant curvi‐planar veins. The Pettegrove Point member is more resistant, fine‐grained, thinly planar laminated, and contains a higher abundance of diagenetic concretions. Conformable above the Pettegrove Point member is the Jura member, which is also fine‐grained and parallel stratified, but is marked by a distinct step in topography, which coincides with localized meter‐scale inclined strata, a thinly and thickly laminated facies, and occasional crystal molds. All members record low‐energy lacustrine deposition, consistent with prior observations of the Murray formation. Uncommon outcrops of low‐angle stratification suggest possible subaqueous currents, and steeply inclined beds may be the result of slumping. Collectively, the rocks exposed at VRR provide additional evidence for a long‐lived lacustrine environment (in excess of 106 years via comparison to terrestrial records of sedimentation), which extends our understanding of the duration of habitable conditions in Gale crater.
Plain language summary
The primary goal of the Mars Science Laboratory Curiosity rover mission is to explore and assess ancient habitable environments on Mars. This requires a detailed understanding of the environments recorded by sedimentary rocks exposed at the present‐day surface in Gale crater. Here we review the types of sedimentary rocks exposed at a location known as Vera Rubin ridge. We find that the rocks at Vera Rubin ridge record an ancient lake environment and are a continuation of underlying lake deposits. Ancient lake deposits are highly desirable targets in the search for habitable environments, due to their ability to concentrate and preserve organic matter. This study significantly expands the duration of habitable conditions that can be confirmed through ground truth of sedimentary rocks and provides a framework for interpreting strata that lie ahead as Curiosity continues to explore Aeolis Mons.
Key Points
Six sedimentary facies were identified at and just below Vera Rubin ridge and comprise three members of the Murray formation
Vera Rubin ridge records deposition in a lacustrine environment, which expands the duration of habitable conditions observed in Gale
The facies and stratigraphy identified here serve as a framework for interpreting strata within the Glen Torridon region and beyond
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