Cancers result from the accumulation of somatic mutations, and their properties are thought to reflect the sum of these mutations. However, little is known about the effect of the order in which ...mutations are acquired.
We determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells.
The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 mutation was acquired first (hereafter referred to as "TET2-first patients"), patients in whom the Janus kinase 2 (JAK2) mutation was acquired first ("JAK2-first patients") had a greater likelihood of presenting with polycythemia vera than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2-TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from up-regulating genes associated with proliferation.
The order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. (Funded by Leukemia and Lymphoma Research and others.).
The Hawaiian‐Emperor chain is the ∼6,000 km long surface expression of the deeply sourced Hawaiian mantle plume active over the past ∼81 Myr. The Hawaiian Islands (<∼6.5 Ma) present two ...geographically and geochemically distinct trends, Kea and Loa, while the Emperor Seamounts (>81–47 Ma) show only Kea compositions. New Sr‐Nd‐Hf isotope, trace and major element data of 23 Northwest Hawaiian Ridge (∼47–6.5 Ma) shield‐stage tholeiitic basalts analyzed in this study fill a critical gap and show both Kea and Loa compositions. A logistic regression model fit to a high‐quality isotopic database of Hawaiian Island basalts is used to predict Loa‐type or Kea‐type affinity of new NWHR isotope analyses. Daikakuji, Mokumanamana, West Nīhoa, Nīhoa, and Middle Bank erupt Loa‐type compositions, a finding corroborated by their geochemical characteristics (e.g., low Th/La, CaO/Al2O3, and high Sr/Nb, Zr/Nb, SiO2). Participation of the Loa composition gradually increases toward the Hawaiian Islands with time and there is no evidence for the presence of the Lō‘ihi component along the NWHR or before ∼1 Myr. A new Hf‐Nd Hawaiian array is calculated based on an up‐to‐date extended Hawaiian Island basalt database (n = 403). The NWHR array is slightly steeper than the Hawaiian array, suggesting minimal participation of the high Hf isotopic source component present in Hawaiian Island volcanoes before ∼6.5 Ma. This study fills a significant geochemical data gap in the Hawaiian‐Emperor seamount chain, and shows that Hawaiian plume chemistry evolves significantly with time as the plume samples different deep mantle reservoirs.
Plain Language Summary
Mantle plumes transport deep mantle material to the surface, where it melts to create volcanoes such as the Hawaiian‐Emperor seamount chain. Analyzing the elemental and isotopic compositions, and how they vary between volcanoes of different ages, allows for reconstruction of the composition and structure of the deep mantle over time. In this study, the chemistry of Northwest Hawaiian Ridge volcanoes (∼47–6.5 Ma) is analyzed and compared to volcanoes from the Hawaiian Islands (6.5 Ma–present). We find that the previously defined geochemical components that explain the observed isotopic variation on the Hawaiian Islands actually change significantly back in time. A new scale of mantle heterogeneity is resolved, showing that mantle components are finite and can reoccur periodically over time. The potential reservoir for these compositional components may be lower mantle seismically imaged structures, whose periodic entrainment supplies distinctive geochemical compositions.
Key Points
First high‐precision Sr, Nd, and Hf isotopes are reported on basalts from a ∼40 million year span of the Northwest Hawaiian Ridge
A new value for the Kea end‐member and a new Hawaiian array are defined
The Loa geochemical trend is composed of multiple geochemical components that are restricted in size and limited to specific locations
We consider the reconstruction expected for the Fermi surface of underdoped YBa(2)Cu(3)O(6+x) in the case of a collinear spin-density wave with a characteristic vector Q = (pi1 +/- 2delta,pi), ...assuming an incommensurability delta approximately 0.06 similar to that found in recent neutron scattering experiments. A Fermi surface possibly consistent with the multiple observed quantum oscillation frequencies is obtained. From the low band masses expected using this model as compared with experiment, a uniform enhancement of the quasiparticle effective mass over the Fermi surface by a factor of approximately 7 is indicated. Further predictions of the Fermi surface topology are made, which may potentially be tested by experiment to indicate the relevance of this model to underdoped YBa(2)Cu(3)O(6+x).
Thirty years on, and the mechanism of superconductivity in copper-oxide superconductors remains a mystery. Knowledge of their normal nonsuperconducting state is also incomplete; however, we do know ...that the more robust the superconductivity, the higher the magnetic fields required to suppress it. Ramshaw et al. studied samples of three different compositions of the copper-oxide YBa2Cu3O6+δ in magnetic fields exceeding 90 T. They found that as the oxygen content increased toward the point of the maximum transition temperature, the conducting electrons became heavier and heavier. This mass enhancement reflected an increase in electronic correlations, which in turn may be a signature of a quantum critical point. Science, this issue p. 317 In the quest for superconductors with higher transition temperatures (Tc), one emerging motif is that electronic interactions favorable for superconductivity can be enhanced by fluctuations of a broken-symmetry phase. Recent experiments have suggested the existence of the requisite broken-symmetry phase in the high-Tc cuprates, but the impact of such a phase on the ground-state electronic interactions has remained unclear. We used magnetic fields exceeding 90 tesla to access the underlying metallic state of the cuprate YBa2Cu3O6+δ over a wide range of doping, and observed magnetic quantum oscillations that reveal a strong enhancement of the quasiparticle effective mass toward optimal doping. This mass enhancement results from increasing electronic interactions approaching optimal doping, and suggests a quantum critical point at a hole doping of pcrit approximate 0.18.
Advances in understanding the pathogenesis and molecular landscape of myelofibrosis have occurred over the last decade. Treating physicians now have access to an ever-evolving armamentarium of novel ...agents to treat patients, although allogeneic hematopoietic stem cell transplantation remains the only curative approach. Improvements in donor selection, conditioning regimens, disease monitoring and supportive care have led to augmented survival after transplantation. Nowadays, there are comprehensive guidelines concerning allogeneic hematopoietic stem cell transplantation for patients with myelofibrosis. However, it commonly remains difficult for both physicians and patients alike to weigh up the risk-benefit ratio of transplantation given the inherent heterogeneity regarding both clinical course and therapeutic response. In this timely review, we provide an up-to-date synopsis of current transplantation recommendations, discuss usage of JAK inhibitors before and after transplantation, examine donor selection and compare conditioning platforms. Moreover, we discuss emerging data concerning the impact of the myelofibrosis mutational landscape on transplantation outcome, peritransplant management of splenomegaly, poor graft function and prevention/management of relapse.
Myelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ...ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF.
This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. Overall survival (OS; a secondary endpoint in both trials) was evaluated using pooled intent-to-treat data from patients randomized to ruxolitinib or the control groups. OS was also evaluated in subgroups stratified by baseline anemia and transfusion status at week 24.
A total of 528 patients were included in this analysis; 301 were originally randomized to ruxolitinib (COMFORT-I, n = 155; COMFORT-II, n = 146) and 227 to control (n = 154 and n = 73, respectively). The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio HR, 0.70 95% CI, 0.54-0.91; P = 0.0065). After correcting for crossover using a rank-preserving structural failure time (RPSFT) method, the OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS, 5.3 vs 2.3 years; HR ruxolitinib vs RPSFT, 0.35 95% CI, 0.23-0.59). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged OS compared with control (median OS, 5.3 vs 2.4 years; HR ruxolitinib vs censored at crossover, 0.53 95% CI, 0.36-0.78; P = 0.0013). The survival benefit with ruxolitinib was observed irrespective of baseline anemia status or transfusion requirements at week 24.
These findings support ruxolitinib treatment for patients with int-2 or high-risk MF, regardless of anemia or transfusion status. Further analyses will be important for exploring ruxolitinib earlier in the disease course to assess the effect on the natural history of MF.
ClinicalTrials.gov identifiers, NCT00952289 and NCT00934544 .
Extensive phylogenetic analyses were performed based on sequences of the 16S rRNA gene and two ribosomal protein (rp) genes, rplV (rpl22) and rpsC (rps3), from 46 phytoplasma strains representing 12 ...phytoplasma 16Sr groups, 16 other mollicutes and 28 Gram-positive walled bacteria. The phylogenetic tree inferred from rp genes had a similar overall topology to that inferred from the 16S rRNA gene. However, the rp gene-based tree gave a more defined phylogenetic interrelationship among mollicutes and Gram-positive walled bacteria. Both phylogenies indicated that mollicutes formed a monophyletic group. Phytoplasmas clustered with Acholeplasma species and formed one clade paraphyletic with a clade consisting of the remaining mollicutes. The closest relatives of mollicutes were low-G+C-content Gram-positive bacteria. Comparative phylogenetic analyses using the 16S rRNA gene and rp genes were performed to evaluate their efficacy in resolving distinct phytoplasma strains. A phylogenetic tree was constructed based on analysis of rp gene sequences from 87 phytoplasma strains belonging to 12 16Sr phytoplasma groups. The phylogenetic relationships among phytoplasmas were generally in agreement with those obtained on the basis of the 16S rRNA gene in the present and previous works. However, the rp gene-based phylogeny allowed for finer resolution of distinct lineages within the phytoplasma 16Sr groups. RFLP analysis of rp gene sequences permitted finer differentiation of phytoplasma strains in a given 16Sr group. In this study, we also designed several semi-universal and 16Sr group-specific rp gene-based primers that allow for the amplification of 11 16Sr group phytoplasmas.
Evidence suggests some overlap between the pathological use of food and drugs, yet how impulsivity compares across these different clinical disorders remains unclear. Substance use disorders are ...commonly characterized by elevated impulsivity, and impulsivity subtypes may show commonalities and differences in various conditions. We hypothesized that obese subjects with binge-eating disorder (BED) and abstinent alcohol-dependent cohorts would have relatively more impulsive profiles compared to obese subjects without BED. We also predicted decision impulsivity impairment in obesity with and without BED.
Thirty obese subjects with BED, 30 without BED and 30 abstinent alcohol-dependent subjects and age- and gender-matched controls were tested on delay discounting (preference for a smaller immediate reward over a larger delayed reward), reflection impulsivity (rapid decision making prior to evidence accumulation) and motor response inhibition (action cancellation of a prepotent response).
All three groups had greater delay discounting relative to healthy volunteers. Both obese subjects without BED and alcohol-dependent subjects had impaired motor response inhibition. Only obese subjects without BED had impaired integration of available information to optimize outcomes over later trials with a cost condition.
Delay discounting appears to be a common core impairment across disorders of food and drug intake. Unexpectedly, obese subjects without BED showed greater impulsivity than obese subjects with BED. We highlight the dissociability and heterogeneity of impulsivity subtypes and add to the understanding of neurocognitive profiles across disorders involving food and drugs. Our results have therapeutic implications suggesting that disorder-specific patterns of impulsivity could be targeted.
•Respiratory failure is a primary cause of mortality in individuals with VCP multisystem.•Respiratory resistance training strengthens inspiratory muscles.•Maximum inspiratory pressure increased ...significantly by a mean of 0.392cm. H2O/week.•Remote respiratory resistance treatments are feasible and successful.
Valosin-containing protein (VCP) disease is an autosomal dominant multisystem proteinopathy associated with hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Myopathy frequently results in respiratory muscle weakness, leading to early mortality due to respiratory failure. We investigated the effects of a remotely administered inspiratory muscle training program in individuals with VCP disease. Nine adults with VCP mutation-positive familial myopathy without evidence of dementia were recruited for a 40-week remotely administered study. Baseline performance was established during the first 8 weeks, followed by 32 weeks of inspiratory muscle training. The primary outcome was maximum inspiratory pressure (MIP). The secondary and exploratory endpoints included spirometry, grip strength, Inclusion Body Myopathy Functional Rating Scale (IBMFRS), Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS), timed up and go, and six-minute walk test (6MWT). During the treatment phase, MIP increased significantly by a weekly mean of 0.392cm. H2O (p=0.023). In contrast, grip strength and ALSFRS significantly decreased by 0.088 lbs. (p=0.031) and 0.043 points (p=0.004) per week, respectively, as expected from the natural progression of this disease. A remotely administered inspiratory muscle training program is therefore feasible, safe, and well-tolerated in individuals with VCP disease and results in improved inspiratory muscle strength.
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