We evaluated the impact of clinical and molecular characteristics on overall survival (OS) in 108 patients with indolent (n=41) and advanced systemic mastocytosis (SM) (advSM, n=67). Organomegaly was ...measured by magnetic resonance imaging-based volumetry of the liver and spleen. In multivariate analysis of all patients, an increased spleen volume ⩾450 ml (hazard ratio (HR), 5.2; 95% confidence interval (CI), (2.1-13.0); P=0.003) and an elevated alkaline phosphatase (AP; HR 5.0 (1.1-22.2); P=0.02) were associated with adverse OS. The 3-year OS was 100, 77, and 39%, respectively (P<0.0001), for patients with 0 (low risk, n=37), 1 (intermediate risk, n=32) or 2 (high risk, n=39) parameters. For advSM patients with fully available clinical and molecular data (n=60), univariate analysis identified splenomegaly ⩾1200 ml, elevated AP and mutations in the SRSF2/ASXL1/RUNX1 (S/A/R) gene panel as significant prognostic markers. In multivariate analysis, mutations in S/A/R (HR 3.2 (1.1-9.6); P=0.01) and elevated AP (HR 2.6 (1.0-7.1); P=0.03) remained predictive adverse prognostic markers for OS. The 3-year OS was 76 and 38%, respectively (P=0.0003), for patients with 0-1 (intermediate risk, n=28) or 2 (high risk, n=32) parameters. We conclude that splenomegaly, elevated AP and mutations in the S/A/R gene panel are independent of the World Health Organization classification and provide the most relevant prognostic information in SM patients.
Aberrant aggregation of the RNA-binding protein TDP-43 in neurons is a hallmark of frontotemporal lobar degeneration caused by haploinsufficiency in the gene encoding progranulin
. However, the ...mechanism leading to TDP-43 proteinopathy remains unclear. Here we use single-nucleus RNA sequencing to show that progranulin deficiency promotes microglial transition from a homeostatic to a disease-specific state that causes endolysosomal dysfunction and neurodegeneration in mice. These defects persist even when Grn
microglia are cultured ex vivo. In addition, single-nucleus RNA sequencing reveals selective loss of excitatory neurons at disease end-stage, which is characterized by prominent nuclear and cytoplasmic TDP-43 granules and nuclear pore defects. Remarkably, conditioned media from Grn
microglia are sufficient to promote TDP-43 granule formation, nuclear pore defects and cell death in excitatory neurons via the complement activation pathway. Consistent with these results, deletion of the genes encoding C1qa and C3 mitigates microglial toxicity and rescues TDP-43 proteinopathy and neurodegeneration. These results uncover previously unappreciated contributions of chronic microglial toxicity to TDP-43 proteinopathy during neurodegeneration.
Basaltic volcanism "samples" the Earth's mantle to great depths, because solid-state convection transports deep material into the (shallow) melting region. The isotopic and trace-element chemistry of ...these basalts is discussed.
The precise molecular pathogenesis of splenic marginal zone lymphoma (SMZL) is still unknown. Clinical and epidemiological data suggest that chronic hepatitis C virus (HCV) infection may have an ...etiological role in a subset of cases.We performed a large-scale microRNA (miRNA) expression profiling analysis of 381 miRNAs by quantitative reverse transcription PCR (Q-RT-PCR) of 26 microdissected splenic tissue samples (7 HCV(+) SMZL; 8 HCV(-) SMZL and 11 non-neoplastic splenic controls). Single assay Q-RT-PCR and miRNA in situ hybridization (miRNA-ISH) were used to confirm the results in an independent cohort. Unsupervised hierarchical clustering of miRNA expression profiles demonstrated a distinct signature of SMZL compared with the normal splenic marginal zone. Supervised analysis revealed differentially expressed miRNAs, including miRNAs with previously recognized tumor suppressive or oncogenic potential. Five miRNAs were found significantly overexpressed in SMZL, including miR-21, miR-155 and miR-146a, whereas seven miRNAs showed significantly reduced expression, including miR-139, miR-345, miR-125a and miR-126. Furthermore, we identified miR-26b, a miRNA known to have tumor suppressive properties, as significantly downregulated in SMZL arising in HCV-positive patients (P=0.0016). In conclusion, there is a characteristic dysregulation of miRNA expression in SMZL with a possible implication in its molecular tumorigenesis.
The North China Craton is a classic case for the destruction of an ancient craton, in that it records the loss of more than 100km of ancient refractory lithospheric mantle during the late Mesozoic ...and early Cenozoic. However, the mechanisms for this lithospheric thinning remain controversial in large part due to the lack of any systematic investigations of the Mesozoic asthenospheric mantle via its derived mafic rocks, which are key to understand the thinning processes. In this paper, we present detailed zircon U–Pb geochronology, elemental geochemistry, and Sr–Nd–Hf isotopic data for lamprophyres and diabase-porphyries of the Jiaodong Peninsula, in the eastern North China Craton in order to place constraints on models for lithospheric thinning. Our results show that the lamprophyres and diabase-porphyries are derived from the convective asthenospheric mantle via different degrees of partial melting, and that this mantle source was previously modified by carbonatitic liquids. Zircon LA-ICP-MS U–Pb dating suggests an emplacement age for these rocks of 123–121Ma, the earliest evidence for asthenospherically-derived melts in the Jiaodong Peninsula so far. This emplacement age indicates that the thickness of the lithosphere in the Jiaodong Peninsula was relatively thin at that time. Co-occurrence of the asthenospheric and lithospheric mantle-derived mafic rocks as well as high-Mg adakites record a rapid transition from lithospheric to asthenospheric mantle sources, indicating that the lithosphere beneath the Jiaodong Peninsula was rapidly detached just prior to ca. 120Ma. Lithospheric thinning of the North China Craton may have been initiated from the Jiaodong Peninsula and Bohai Sea and then propagated towards the interior of the craton.
•The studied Cretaceous mafic dikes from Jiaodong were derived from an asthenospheric mantle.•The mantle source was previously modified by carbonatitic liquids.•Both the lamprophyres and diabase-porphyries were emplaced at 123–121Ma.•Lithosphere was suddenly detached just prior to ca. 120Ma.•Jiaodong and Bohai area may be the center of the lithospheric thinning of the NCC.
Frontotemporal dementia is a group of early onset dementia syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology that can be classified based on the formation of abnormal ...protein aggregates involving tau and two RNA binding proteins, TDP-43 and FUS. Although elucidation of the mechanisms leading to FTLD pathology is in progress, recent advances in genetics and neuropathology indicate that a majority of FTLD cases with proteinopathy involving RNA binding proteins show highly congruent genotype-phenotype correlations. Specifically, recent studies have uncovered the unique properties of the low-complexity domains in RNA binding proteins that can facilitate liquid-liquid phase separation in the formation of membraneless organelles. Furthermore, there is compelling evidence that mutations in FTLD genes lead to dysfunction in diverse cellular pathways that converge on the endolysosomal pathway, autophagy, and neuroinflammation. Together, these results provide key mechanistic insights into the pathogenesis and potential therapeutic targets of FTLD.
More than 50 per cent of the Earth's upper mantle consists of olivine and it is generally thought that mantle-derived melts are generated in equilibrium with this mineral. Here, however, we show that ...the unusually high nickel and silicon contents of most parental Hawaiian magmas are inconsistent with a deep olivine-bearing source, because this mineral together with pyroxene buffers both nickel and silicon at lower levels. This can be resolved if the olivine of the mantle peridotite is consumed by reaction with melts derived from recycled oceanic crust, to form a secondary pyroxenitic source. Our modelling shows that more than half of Hawaiian magmas formed during the past 1 Myr came from this source. In addition, we estimate that the proportion of recycled (oceanic) crust varies from 30 per cent near the plume centre to insignificant levels at the plume edge. These results are also consistent with volcano volumes, magma volume flux and seismological observations.
Size and Composition of the MORB+OIB Mantle Reservoir Hofmann, A. W.; Class, C.; Goldstein, S. L.
Geochemistry, geophysics, geosystems : G3,
August 2022, 2022-08-00, 20220801, 2022-08-01, Letnik:
23, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Most efforts to characterize the size and composition of the mantle that complements the continental crust have assumed that the mid‐ocean ridge basalt (MORB) source is the incompatible‐element ...depleted residue of continental crust extraction. The use of Nd isotopes to model this process led to the conclusion that the “depleted MORB reservoir” is confined to the upper ∼30% of the mantle, leaving the lower mantle in a more “primitive” state. Here, we use Nb/U and Ta/U to evaluate mass and composition of the mantle reservoir residual to continent extraction and find that it exceeds 60% of the total mantle. Thus, the (Nb, Ta)/U‐based mass balance conflicts with the ε(Nd)‐based mass balance, and this invalidates the classical 3‐reservoir silicate Earth model (continental crust, depleted mantle, and primitive mantle). Including the combined MORB + ocean island basalt (OIB) sources in the ε(Nd)‐based mass balance does not reconcile the conflict as it would require their average ε(Nd) to be ≤3.0, much lower than observed MORB + OIB ε(Nd) averages. We resolve this conflict by invoking an additional, “early enriched reservoir” (EER), formed prior to extraction of significant continental crust, but now hidden or lost. This EER differs from EERs previously invoked by having no Nb‐Ta anomaly. We suggest that it originated as an early mafic crust, which had unfractionated (Nb, Ta)/U but fractionated Sm/Nd ratios. The corresponding “early depleted” reservoir generated the present‐day continental crust and the “residual mantle” MORB‐OIB reservoir, which occupies at least 63% of the present‐day mantle and is only moderately depleted in incompatible trace elements.
Plain Language Summary
The Earth's continental crust makes up only about half a percent of Earth's mass, but it contains a large portion of its total budget of uranium and thorium, which produce much of Earth's interior heat. In making the crust, these elements have been extracted via melts and volcanism from Earth's mantle. But what portion of the mantle was involved in making the continents? Previously, geochemists concluded that only its uppermost 30% was involved, leaving the lower two‐thirds of the mantle essentially untouched. The measure used for this estimate has been the difference in the isotope ratios of neodymium, 143Nd/144Nd, between crust and mantle. However, when we use an alternative measure for the same calculation, namely the ratio of niobium to uranium, Nb/U, we find the depleted mantle fraction to be greater than 60%. We therefore need an Earth model that involves an additional “reservoir” with crust‐like Nd isotopes but mantle‐like Nb/U. We model this as an early Earth basaltic crust, which may have been lost to space, or may now be hidden at the base of the mantle. A buried ancient crust might well explain the large density/temperature anomalies recently discovered at the base of the mantle by seismologists.
Key Points
A new assessment of the depleted mantle (DM) mass (>63%) based on (Nb, Ta)/U conflicts with conventional estimates using Nd isotopes (<50%)
This invalidates the classic 3‐reservoir silicate Earth (continental crust, DM, and primitive mantle)
The observable, present‐day mantle was permanently depleted by segregation or loss of an early enriched reservoir
Circulating endothelial progenitor cells (EPC) are incorporated into newly formed capillaries, enhance neovascularization after hind limb ischemia and improve cardiac function after ischemic injury. ...Incorporated progenitor cells may also promote neovascularization and cardiac regeneration by releasing factors, which act in a paracrine manner to support local angiogenesis and mobilize tissue residing progenitor cells. Therefore, we analyzed the expression profile of cytokines in human peripheral blood-derived EPC as opposed to human umbilical vein endothelial cells (HUVEC), human microvascular endothelial cells (HMVEC), and CD14
+ monocytes by microarray technology. A gene tree analysis revealed a distinct expression pattern of angiogenic growth factors in EPC, mature endothelial cells, and CD14
+ monocytes. VEGF-A, VEGF-B, SDF-1, and IGF-1 mRNA levels were higher in EPC as compared to HUVEC or HMVEC. The enhanced mRNA expression was paralleled by a significant release of VEGF, SDF-1, and IGF-1 protein into the cell culture supernatant of EPC. Moreover, immunohistological analysis of ischemic limbs from nude rats revealed that VEGF is also released from recruited human EPC in vivo. As a functional consequence, conditioned medium of EPC induced a strong migratory response of mature endothelial cells, which was significantly inhibited by VEGF and SDF-1 neutralizing antibodies. Finally, conditioned medium of EPC significantly stimulated the migration of cardiac resident c-kit
+ progenitor cells in vitro. Taken together, EPC exhibit a high expression of angiogenic growth factors, which enhanced migration of mature endothelial cells and tissue resident cardiac progenitor cells. In addition to the physical contribution of EPC to newly formed vessels, the enhanced expression of cytokines may be a supportive mechanism to improve blood vessel formation and cardiac regeneration after cell therapy.
Multidrug-resistant organisms (MDRO) have been developing as an emerging problem in allogeneic hematopoietic cell transplantation (HCT). Since no data are available on the course of MDRO colonization ...after HCT, we investigated in this retrospective, single-center study, persistence and clearance of MDRO after HCT. From June 2010 to December 2015, 121 consecutive HCT patients were included. Patients received a MDRO screening before conditioning as well as surveillance cultures after HCT. In MDRO-colonized patients, surveillance specimens were taken until MDRO were no longer detectable. Thirty-three patients (27%) were found to be colonized by at least one MDRO at any time point until day 100 post HCT. Day 100 (2-year) non-relapse mortality (NRM) and overall survival (OS) of MDRO-colonized (MDRO
+
) versus non-colonized (MDRO
−
) patients were essentially the same. NRM is 15% (21%) versus 15% (24%). Two-year OS is 60 versus 55% for MDRO
+
versus MDRO
−
patients. Out of the 33 MDRO
+
patients, 21 cleared the MDRO. Median time to non-detectability of MDRO was 6 months. In 12 patients, the MDRO persisted. There was a significant (
p
< 0.0001) survival difference between patients who cleared the MDRO versus those with MDRO persistence (2-year OS 80 vs 40%). Except for the length of antibiotic therapy as a potential risk factor for MDRO persistence after HCT, no other conventional factors could be identified. (a) colonization by MDRO per se had no negative impact on the outcome, (b) MDRO can be cleared by the majority of patients after allogeneic HCT, and (c) to increase the probability to clear MDRO, the use of antibiotics in MDRO
+
patients should be reviewed critically.
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