Highlights • Regional and network functional changes could be seen in the early stage of SCI. • Functional changes were associated with clinical symptom severity in SCI patients. • Functional ...reorganization may reflect a compensatory role in the recovery of SCI.
Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma.
In this phase 3 trial, we ...randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival.
At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients 18.5% in the daratumumab group vs. 116 of 283 41.0% in the control group; hazard ratio, 0.37; 95% confidence interval CI, 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 10
white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2.
The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .).
Over the past few decades, research on Alzheimer’s disease (AD) has focused on pathomechanisms linked to two of the major pathological hallmarks of extracellular deposition of beta-amyloid peptides ...and intra-neuronal formation of neurofibrils. Recently, a third disease component, the neuroinflammatory reaction mediated by cerebral innate immune cells, has entered the spotlight, prompted by findings from genetic, pre-clinical, and clinical studies. Various proteins that arise during neurodegeneration, including beta-amyloid, tau, heat shock proteins, and chromogranin, among others, act as danger-associated molecular patterns, that—upon engagement of pattern recognition receptors—induce inflammatory signaling pathways and ultimately lead to the production and release of immune mediators. These may have beneficial effects but ultimately compromise neuronal function and cause cell death. The current review, assembled by participants of the Chiclana Summer School on Neuroinflammation 2016, provides an overview of our current understanding of AD-related immune processes. We describe the principal cellular and molecular players in inflammation as they pertain to AD, examine modifying factors, and discuss potential future therapeutic targets.
The cancer stem cell hypothesis suggests that neoplastic clones are maintained exclusively by a small subpopulation of cells, which have indefinite proliferation and differentiation potentials and ...give rise to phenotypically diverse cancer cells. Cancer stem cells have been isolated by their ability to efflux Hoechst 33342 dye and are referred to as the 'side population' (SP).
The Hoechst efflux assay was used to isolate and characterize the SP from murine D121 lung carcinoma cells. Here, we demonstrated that D121-SP cells contain cancer stem cell characteristics, that is, upregulation of the transcription factors SOX2 and Oct 4 in D121-SP cells. In addition, the migration of D121-SP was decreased, and apoptosis of D121-SP was upregulated following knocking down of SOX2 in D121 cells. Importantly, downregulation of SOX2 in D121 cells markedly suppressed their metastatic potential in syngeneic mice.
These results suggest that the SP is an enriched source of lung tumour cells with stem cell properties and that SOX2 has an important role in maintaining stem cell properties and functions that may be a potential target for effective lung cancer therapy.
In this paper, we develop a time‐dependent MHD model driven by the daily‐updated synoptic magnetograms (MHD‐DUSM) to study the dynamic evolution of the global corona with the help of the 3D ...Solar‐Interplanetary (SIP) adaptive mesh refinement (AMR) space‐time conservation element and solution element (CESE) MHD model (SIP‐AMR‐CESE MHD Model). To accommodate the observations, the tangential component of the electric field at the lower boundary is specified to allow the flux evolution to match the observed changes of magnetic field. Meanwhile, the time‐dependent solar surface boundary conditions derived from the method of characteristics and the mass flux limit are incorporated to couple the observation and the 3D MHD model. The simulated evolution of the global coronal structure during 2007 is compared with solar observations and solar wind measurements from both Ulysses and spacecrafts near the Earth. The MHD‐DUSM model is also validated by comparisons with the standard potential field source surface (PFSS) model, the newly improved Wang‐Sheeley‐Arge (WSA) empirical formula, and the MHD simulation with a monthly synoptic magnetogram (MHD‐MSM). Comparisons show that the MHD‐DUSM results have good overall agreement with coronal and interplanetary structures, including the sizes and distributions of coronal holes, the positions and shapes of the streamer belts, and the transitions of the solar wind speeds and magnetic field polarities. The MHD‐DUSM results also display many features different from those of the PFSS, the WSA, and the MHD‐MSM models.
Key Points
A time‐dependent model is developed for the dynamic evolution of global corona
The model is driven by the daily‐updated magnetic field synoptic data
MHD results have good agreement with coronal and interplanetary observations
The objective of this paper is to explore the application of a six-component overset grid to solar wind simulation with a three-dimensional (3D) Solar-InterPlanetary Conservation Element/Solution ...Element MHD model. The essential focus of our numerical model is devoted to dealing with: (1) the singularity and mesh convergence near the poles via the use of the six-component grid system, (2) the {nabla} B constraint error via an easy-to-use cleaning procedure by a fast multigrid Poisson solver, (3) the Courant-Friedrichs-Levy number disparity via the Courant-number insensitive method, (4) the time integration by multiple time stepping, and (5) the time-dependent boundary condition at the subsonic region by limiting the mass flux escaping through the solar surface. In order to produce fast and slow plasma streams of the solar wind, we include the volumetric heating source terms and momentum addition by involving the topological effect of the magnetic field expansion factor fS and the minimum angular distance Delta *c b (at the photosphere) between an open field foot point and its nearest coronal hole boundary. These considerations can help us easily code the existing program, conveniently carry out the parallel implementation, efficiently shorten the computation time, greatly enhance the accuracy of the numerical solution, and reasonably produce the structured solar wind. The numerical study for the 3D steady-state background solar wind during Carrington rotation 1911 from the Sun to Earth is chosen to show the above-mentioned merits. Our numerical results have demonstrated overall good agreements in the solar corona with the Large Angle and Spectrometric Coronagraph on board the Solar and Heliospheric Observatory satellite and at 1 AU with WIND observations.
Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and influence disease. Lysine ...acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis, and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in 9 patients with intellectual disability, seizures, autism, dysmorphisms, and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least 2 of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies.
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