CD19-specific CAR T cells were produced centrally for a global study in young people with relapsed B-cell ALL. The overall remission rate was 81%, and patients with a response were negative for ...minimal residual disease. High-grade toxic effects were frequent but treatable.
MicroRNAs (miRNAs) regulate expression of many cancer-related genes through posttranscriptional repression of their mRNAs. In this study we investigate the proto-oncogene MYCN as a target for miRNA ...regulation.
A luciferase reporter assay was used to investigate software-predicted miRNA target sites in the 3'-untranslated region (3'UTR) of MYCN. The miRNAs were overexpressed in cell lines by transfection of miRNA mimics or miRNA-expressing plasmids. Mutation of the target sites was used to validate MYCN 3'UTR as a direct target of several miRNAs. To measure miRNA-mediated suppression of endogenous N-myc protein, inhibition of proliferation and inhibition of clonogenic growth, miRNAs were overexpressed in a MYCN-amplified neuroblastoma cell line.
The results from this study show that MYCN is targeted by several miRNAs. In addition to the previously shown mir-34a/c, we experimentally validate mir-449, mir-19a/b, mir-29a/b/c, mir-101 and let-7e/mir-202 as direct MYCN-targeting miRNAs. These miRNAs were able to suppress endogenous N-myc protein in a MYCN-amplified neuroblastoma cell line. The let-7e and mir-202 were strong negative regulators of MYCN expression. The mir-101 and the let-7 family miRNAs let-7e and mir-202 inhibited proliferation and clonogenic growth when overexpressed in Kelly cells.
The tumour-suppressor miRNAs let-7 and mir-101 target MYCN and inhibit proliferation and clonogenic growth of MYCN-amplified neuroblastoma cells.
•Infections, autoimmunity, and granuloma predispose to organ damage prior HSCT, thereby compromising survival and quality of immune reconstitution.•In patients with hypomorphic ...recombination-activating gene deficiency, HSCT with T-cell depleted grafts shows poor outcome.
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Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio HR = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.
Hypomorphic alleles for the recombination activation genes RAG1 and RAG2 lead to severe immunodeficiency syndromes. Schuetz et al report on a retrospective analysis of transplant outcomes in 60 patients with this rare disorder. Overall survival at 4 years was 67.5%, with poor survival predicted by active infection, organ damage, and T-cell depletion of the graft. Patients diagnosed by newborn screening with early transplant had 100% survival, supporting early transplantation for these patients.
The Lausitz (Lusatia) Volcanic Field is part of the Central European Volcanic Province, and its magmas represent an alkaline trend from olivine nephelinites and basanites to trachytes and phonolites, ...typical for intraplate settings. Neighbouring volcanic fields are the České Středohoří Mountains to the south-west and the Fore-Sudetic Basin in Lower Silesia to the east. More than 1000 volcanic structures associated with approximately 500 vents have been located within this volcanic field. Residuals of scoria cones, lava lakes, lava flows and maar-diatreme in filling occur in situ near the level of the original syn-volcanic terrain. In more deeply eroded structures, volcanic relicts outcrop as plugs or feeders. Evolved rocks occur as monogenetic domes or intrusions in diatremes, while their volcaniclastic equivalents are rare. Twenty-three localities were dated using the
40
Ar/
39
Ar method. The ages range from 35 to 27 Ma, with a focus around 32–29 Ma, indicating Late Eocene and mainly Oligocene volcanism for the LVF. Differentiated rocks appear to be slightly younger than less differentiated. No geographical age clusters are apparent.
The impact of conditioning regimen prior to hematopoietic cell transplant (HCT) in pediatric AML-patients is not well studied. We retrospectively analyzed the impact of Busulfan-Cyclophosphamide ...(BuCy), Busulfan-Cyclophosphamide-Melphalan (BuCyMel) and Clofarabine-Fludarabine-Busulfan (CloFluBu) in pediatric AML-patients, with similar upfront leukemia treatment (NOPHO-DBHconsortium), receiving an HCT between 2010 and 2015. Outcomes of interest were LFS, relapse, TRM and GvHD. 103 patients were included; 30 received BuCy, 37 BuCyMel, and 36 CloFluBu. The 5-years LFS was 43.3% (SE ± 9.0) in the BuCy group, 59.2 % (SE ± 8.1) after BuCyMel, and 66.7 % (SE ± 7.9) after CloFluBu. Multivariable Cox regression analysis showed a trend to lower LFS after BuCy compared to CloFluBu (p = 0.07). BuCy was associated with a higher relapse incidence compared to the other regimens (p = 0.06). Younger age was a predictor for relapse (p = 0.02). A strong correlation between Busulfan Therapeutic Drug Monitoring (TDM) and lower incidence of aGvHD (p < 0.001) was found. In conclusion, LFS after BuCyMel and CloFluBu was comparable, lower LFS was found after BuCy, due to higher relapse incidence. CloFluBu was associated with lower incidence of aGvHD, suggesting lower toxicity with this type of conditioning. This finding is also explained by the impact of Busulfan monitoring.
We present multi spacecraft measurements in the magnetosheath (MSH) and in the solar wind (SW) by Interball, Cluster and Polar, demonstrating that coherent structures with magnetosonic Mach number up ...to 3 - Supermagnetosonic Plasma Streams (SPS) - generate transient and anomalous boundary dynamics, which may cause substantial displacements of the magnetospheric boundaries and the riddling of peripheral boundary layers. In this regard, for the first time, we describe a direct plasma penetration into the flank boundary layers, which is a candidate for being the dominant transport mechanism for disturbed MSH periods. Typically SPS's have a ram pressure exceeding by several times that of the SW and lead to long-range correlations between processes at the bow shock (BS) and at the magnetopause (MP) on one side and between MSH and MP boundary layers on the other side. We demonstrate that SPS's can be observed both near the BS and near the MP and argue that they are often triggered by hot flow anomalies (HFA), which represent local obstacles to the SW flow and can induce the SPS generation as a means for achieving a local flow balance. Finally, we also discuss other causes of SPS's, both SW-induced and intrinsic to the MSH. SPS's appear to be universal means for establishing a new equilibrium between flowing plasmas and may also prove to be important for astrophysical and fusion applications.
The observations of enhanced chromospheric activity on HD 179949 as well as on υ And with the same periods as their close-in planets seem to indicate some kind of magnetic interaction between star ...and planet. A constraint to any possible model are the large phase angles of $60^\circ$ and $169^\circ$, respectively. We present a simple model, which is based on the propagation of Alfvén waves within the stellar wind flow relative to the planet and which can meet this restriction. In the solar system such a model is successfully used to explain the current system between Io and Jupiter.
Issue Title: Advances in Space Environment Research Current sheets are essential for energy dissipation in the solar corona, in particular by enabling magnetic reconnection. Unfortunately, ...sufficiently thin current sheets cannot be resolved observationally and the theory of their formation is an unresolved issue as well. We consider two predictors of coronal current concentrations, both based on geometrical or even topological properties of a force-free coronal magnetic field. First, there are separatrices related to magnetic nulls. Through separatrices the magnetic connectivity changes discontinuously. Coronal magnetic nulls are, however, very rare. Second, inspired by the concept of generalized magnetic reconnection without nulls, quasi-separatrix layers (QSL) were suggested. Through QSL the magnetic connectivity changes continuously, though strongly. The strength of the connectivity change can be quantified by measuring the squashing of the flux tubes which connect the magnetically conjugated photospheres. We verify the QSL and separatrix concepts by comparing the sites of magnetic nulls and enhanced squashing with the location of current concentrations in the corona. Due to the known difficulties of their direct observation, we simulated coronal current sheets by numerically calculating the response of the corona to energy input from the photosphere, heating a simultaneously observed Extreme Ultraviolet Bright Point. We did not find coronal current sheets at separatrices but at several QSL locations. The reason is that, although the geometrical properties of force-free extrapolated magnetic fields can indeed hint at possible current concentrations, a necessary condition for current sheet formation is the local energy input into the corona.PUBLICATION ABSTRACT
We present a newly developed approach to solar coronal magnetic field extrapolation from vector magnetograms, based on the principle of minimum dissipation rate (MDR). The MDR system was derived from ...a variational problem that is more suitable for an open and externally driven system, like the solar corona. The resulting magnetic field equation is more general than force-free. Its solution can be expressed as the superposition of two linear (constant- alpha ) force-free fields (LFFFs) with distinct alpha parameters, and one potential field. Thus, the original extrapolation problem is decomposed into three LFFF extrapolations, utilizing boundary data. The full MDR-based approach requires two layers of vector magnetograph measurements on the solar surface, while a slightly modified practical approach only requires one. We test both approaches against three-dimensional MHD simulation data in a finite volume. Both yield quantitatively good results. The errors in the magnetic energy estimate are within a few percent. In particular, the main features of relatively strong perpendicular current density structures, representative of the non-force-freeness of the solution, are well recovered.
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