Extreme, abrupt Northern Hemisphere climate oscillations during the last glacial cycle (140,000 years ago to present) were modulated by changes in ocean circulation and atmospheric forcing. However, ...the variability of the Atlantic meridional overturning circulation (AMOC), which has a role in controlling heat transport from low to high latitudes and in ocean CO2 storage, is still poorly constrained beyond the Last Glacial Maximum. Here we show that a deep and vigorous overturning circulation mode has persisted for most of the last glacial cycle, dominating ocean circulation in the Atlantic, whereas a shallower glacial mode with southern-sourced waters filling the deep western North Atlantic prevailed during glacial maxima. Our results are based on a reconstruction of both the strength and the direction of the AMOC during the last glacial cycle from a highly resolved marine sedimentary record in the deep western North Atlantic. Parallel measurements of two independent chemical water tracers (the isotope ratios of (231)Pa/(230)Th and (143)Nd/(144)Nd), which are not directly affected by changes in the global cycle, reveal consistent responses of the AMOC during the last two glacial terminations. Any significant deviations from this configuration, resulting in slowdowns of the AMOC, were restricted to centennial-scale excursions during catastrophic iceberg discharges of the Heinrich stadials. Severe and multicentennial weakening of North Atlantic Deep Water formation occurred only during Heinrich stadials close to glacial maxima with increased ice coverage, probably as a result of increased fresh-water input. In contrast, the AMOC was relatively insensitive to submillennial meltwater pulses during warmer climate states, and an active AMOC prevailed during Dansgaard-Oeschger interstadials (Greenland warm periods).
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is ...achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.
For most cell culture experiments, it is indispensable that the cells are firmly anchored to culture plates, withstanding rinsing steps that can create shear forces and tolerating temperature changes ...without detaching. For semi-adherent cells such as the common HEK 293 or PC-12 cells, this could so far be obtained by time-consuming plate pre-coating with cationic polymer solutions. We report here, that i) pre-coating with the cheaper poly-ethylenimine (PEI) works as well as the commonly used poly-D-lysine (PDL), but more importantly and novel ii) that simple direct addition of either PEI (1.5 μg/ml) or PDL (2 μg/ml) to the cell culture medium results in strongly anchored HEK 293 cells, indistinguishable from ones seeded on pre-coated plates. Therefore, the replacement of plate pre-coating by direct addition of either PEI or PDL gives comparable excellent results, but is highly labour-, time-, and cost-efficient. Moreover, we could show that addition of PDL or PEI also works similarly well in animal-free culture using human platelet lysate instead of fetal bovine serum. Interestingly, additional experiments showed that strong cell attachment requires only cationic polymers but not fetal bovine serum or human platelet lysate added to the medium.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Several tyrosine kinase inhibitors have activity in Ph-positive chronic and acute leukemia, but resistant disease and unacceptable side effects may limit efficacy. Ponatinib showed a high level of ...activity in a phase 2 study of tyrosine kinase inhibitor–resistant disease but was associated with arterial thrombosis.
Patients with newly diagnosed chronic myeloid leukemia (CML) frequently receive imatinib. Although initial response rates are high, imatinib fails in up to 40% of patients because of disease resistance, frequently because of BCR-ABL kinase domain mutations or unacceptable side effects.
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Patients who discontinue imatinib may have a response to second-generation tyrosine kinase inhibitors. However, 37 to 52% of patients do not have a response,
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and 23 to 26% of patients have an initial major cytogenetic response that is lost by 2 years.
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The prognosis for these patients is very poor. With the exception of the small number . . .
Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML ...have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing followed by gene-targeted validation. Genes mutated in ⩾10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2 and CSMD1. Most CMML patients (71%) had mutations in ⩾2 ARCH genes and 52% had ⩾7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage-biased aged hematopoietic system.
Mastocytosis is a myeloproliferative neoplasm characterized by expansion of abnormal mast cells (MCs) in various tissues, including skin, bone marrow, gastrointestinal tract, liver, spleen, or lymph ...nodes. Subtypes include indolent systemic mastocytosis, smoldering systemic mastocytosis and advanced systemic mastocytosis (AdvSM), a term collectively used for the three most aggressive forms of the disease: aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with an associated clonal hematological non-mast cell disease (SM-AHNMD). MC activation and proliferation is physiologically controlled in part through stem cell factor (SCF) binding to its cognate receptor, KIT. Gain-of-function KIT mutations that lead to ligand-independent kinase activation are found in most SM subtypes, and the overwhelming majority of AdvSM patients harbor the KIT
mutation. Several approved tyrosine kinase inhibitors (TKIs), such as imatinib and nilotinib, have activity against wild-type KIT but lack activity against KIT
. Midostaurin, a broad spectrum TKI with activity against KIT
, has a 60% clinical response rate, and is currently the only drug specifically approved for AdvSM. While this agent improves the prognosis of AdvSM patients and provides proof of principle for targeting KIT
as a driver mutation, most responses are partial and/or not sustained, indicating that more potent and/or specific inhibitors are required. Avapritinib, a KIT and PDGFRα inhibitor, was specifically designed to inhibit KIT
. Early results from a Phase 1 trial suggest that avapritinib has potent antineoplastic activity in AdvSM, extending to patients who failed midostaurin. Patients exhibited a rapid reduction in both symptoms as well as reductions of bone marrow MCs, serum tryptase, and KIT
mutant allele burden. Adverse effects include expected toxicities such as myelosuppression and periorbital edema, but also cognitive impairment in some patients. Although considerable excitement about avapritinib exists, more data are needed to assess long-term responses and adverse effects of this novel TKI.
In this study, we present a Holocene rainfall index based on three high‐resolution speleothem records from the Western Mediterranean, a region under the influence of the westerly winds belt modulated ...by the North Atlantic Oscillation (NAO). On centennial to millennial timescales, we show that the North Atlantic ice‐rafting events were likely associated with negative NAO‐like conditions during the Early Holocene and the Late Holocene. However, our data reveal that this is not clearly the case for the mid‐Holocene ice‐rafting events, during which we also show evidence of positive NAO‐like patterns from other paleo‐oceanographic and paleo‐atmospheric data. Hence, contradictory mechanisms involving prolonged periods of both north and south shifts of the westerly winds belt (resembling positive and negative NAO‐like patterns) might at least partially trigger or amplify the ice‐rafting events and the slowdown of the Atlantic Meridional Overturning Circulation.
Plain Language Summary
During the Holocene, periods of enhanced ice‐rafting, associated with cooling and sea ice expansion in the North Atlantic high latitudes, have been recognized over distant regions. While the causes of these events are still a matter of debate, changes in the atmospheric circulation have been proposed as a potential trigger or amplifier. Here, we use speleothems to establish a precisely dated record of rainfall variability in the Western Mediterranean, a highly sensitive region to the westerly winds belt modulated by the North Atlantic Oscillation. Our results reveal new insights about the dynamics of NAO‐like patterns during the Holocene. On centennial to millennial timescales, prolonged periods of both north and south shifts of the westerly winds belt might trigger or amplify the slowdown of the Atlantic Meridional Overturning Circulation and the North Atlantic ice‐rafting. However, not all ice‐rafting events are associated with either positive or negative NAO‐like conditions.
Key Points
A high‐resolution multi‐speleothem rainfall index describes the Holocene rainfall variability in the Western Mediterranean
On centennial to millennial scales, negative NAO‐like conditions were likely associated with the Early and Late Holocene ice‐rafting events
Different mechanisms involving north and south shifts of the westerly winds belt might contribute to ice‐rafting and the AMOC slowdown
Chronic myeloid leukemia (CML) patients who relapse on imatinib due to acquired ABL1 kinase domain mutations are successfully treated with second-generation ABL1-tyrosine kinase inhibitors (ABL-TKIs) ...such as dasatinib, nilotinib or ponatinib. However, ~40% of relapsed patients have uncharacterized BCR-ABL1 kinase-independent mechanisms of resistance. To identify these mechanisms of resistance and potential treatment options, we generated ABL-TKI-resistant K562 cells through prolonged sequential exposure to imatinib and dasatinib. Dual-resistant K562 cells lacked BCR-ABL1 kinase domain mutations, but acquired other genomic aberrations that were characterized by next-generation sequencing and copy number analyses. Proteomics showed that dual-resistant cells had elevated levels of FOXO1, phospho-ERK and BCL-2, and that dasatinib no longer inhibited substrates of the PI3K/AKT pathway. In contrast to parental cells, resistant cells were sensitive to growth inhibition and apoptosis induced by the class I PI3K inhibitor, GDC-0941 (pictilisib), which also induced FOXO1 nuclear translocation. FOXO1 was elevated in a subset of primary specimens from relapsed CML patients lacking BCR-ABL1 kinase domain mutations, and these samples were responsive to GDC-0941 treatment ex vivo. We conclude that elevated FOXO1 contributes to BCR-ABL1 kinase-independent resistance experienced by these CML patients and that PI3K inhibition coupled with BCR-ABL1 inhibition may represent a novel therapeutic approach.
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