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A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with acute myeloid leukemia (AML). However, comprehensive studies regarding the impact of genetic alterations in this group of patients are limited. In this study, we compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Compared with the younger patients, the elderly had significantly higher incidences of PTPN11 , NPM1 , RUNX1 , ASXL1 , TET2 , DNMT3A and TP53 mutations but a lower frequency of WT1 mutations. The older patients more frequently harbored one or more adverse genetic alterations. Multivariate analysis showed that DNMT3A and TP53 mutations were independent poor prognostic factors among the elderly, while NPM1 mutation in the absence of FLT3 /ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetics into three risk groups. In conclusion, older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetics and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment modalities.

Purpose The function of B cells in papillary thyroid cancer (PTC) is controversial. The role of B-cell-related tertiary lymphoid structures (TLSs) is still unclear. Whether B cells exert their anti-tumor effect through forming TLS in PTC needs further investigation. Methods We detected the percentage of B cells in PTC tissues by multi-parameter flow cytometry. Paraffin-embedded tumor tissues of 125 PTC patients were collected and stained with Haematoxylin–Eosin (H&E) for inflammatory infiltration analysis in combination with clinical features. Multiplexed immunohistochemistry (mIHC) was performed to verify the TLSs in above inflammatory infiltration. Correlation of B cells and TLSs with prognosis was analyzed using the TCGA database. Results We observed that PTC patients with higher expression of B lineage cell genes had improved survival and the percentage of B cells in the PTC tumor tissues was variable. Moreover, PTC tumor tissues with more B cells were surrounded by immune cell aggregates of varying sizes. We furtherly confirmed the immune cell aggregates as TLSs with different maturation stages. By analyzing PTC data from TCGA database, we found the maturation stages of TLSs were associated with genders and clinical stages among PTC patients. Moreover, patients with high TLSs survived longer and had a better prognosis. Conclusion B cells are associated with the existence of TLSs which have different maturation stages in PTC. Both B cells and TLSs are associated with the survival rate of PTC. These observations indicate that the anti-tumor effects of B cells in PTC are associated with TLSs formation.

Conventionally, acute myeloid leukemia (AML) patients are categorized into good-, intermediate- and poor-risk groups according to cytogenetic changes. However, patients with intermediate-risk cytogenetics represent a largely heterogeneous population regarding treatment response and clinical outcome. In this study, we integrated cytogenetics and molecular mutations in the analysis of 318 patients with de novo non-M3 AML who received standard chemotherapy. According to the mutation status of eight genes, including NPM1 , CEBPA , IDH2 , RUNX1 , WT1 , ASXL1 , DNMT3A and FLT3 , that had prognostic significance, 229 patients with intermediate-risk cytogenetics could be refinedly stratified into three groups with distinct prognosis ( P <0.001); patients with good-risk genotypes had a favorable outcome (overall survival, OS, not reached) similar to those with good-risk cytogenetics, whereas those with poor-risk genotypes had an unfavorable prognosis (OS, 10 months) similar to those with poor-risk cytogenetics (OS, 13.5 months), and the remaining patients with other genotypes had an intermediate outcome (OS, 25 months). Integration of cytogenetic and molecular profiling could thus reduce the number of intermediate-risk AML patients from around three-fourth to one-fourth. In conclusion, integration of cytogenetic and molecular changes improves the prognostic stratification of AML patients, especially those with intermediate-risk cytogenetics, and may lead to better decision on therapeutic strategy.

The generation of cosmic ray particles with ultra‐relativistic energies is a crucial issue in astrophysical and space physics. Shocks have been acknowledged as efficient accelerators in the universe which can produce energetic particles through a variety of mechanisms, such as diffusive shock acceleration (DSA), shock surfing acceleration (SSA) and shock drift acceleration (SDA). Using the data set obtained by the Magnetospheric Multiscale mission, we report an unusually sharp enhancement of energetic electron flux in the upstream region of Earth's bow shock, associated with a bipolar variation of the interplanetary magnetic field. To explain these observations, we propose a two‐step acceleration scenario where electrons trapped in a flux rope (FR) first undergo head‐on collisions and are further accelerated by FR contraction as the FR crosses the shock. Such a scenario can well explain the spacecraft observations. This work can improve our understanding of particle acceleration processes at shocks. Plain Language Summary The cosmic ray comprises ions and electrons with energies up to 1,020 eV and thus its generation mechanism is an important issue. A conventional theory known as diffusive shock acceleration is a promising candidate but it needs seed electrons with sufficient initial energies. How these electrons are generated is still unclear. In this study, we report an unusually sharp enhancement of energetic electron flux with a large variation of magnetic field direction in the upstream region of Earth's bow shock, and propose a two‐step acceleration scenario to explain the spacecraft measurements. Electrons first gain energies from the head‐on collisions with the bow shock, and then bounce between the two ends of a circular magnetic field of shrinkage, analogous to a ball reflecting between two converging walls. This scenario has been mathematically confirmed and shows good agreement with the spacecraft measurements. Key Points Efficient electron acceleration is observed when a flux rope collides with the Earth's bow shock Electrons trapped in the flux rope are successively accelerated by the head‐on reflection at shock front and the flux rope contraction This two‐step acceleration scenario is mathematically reproduced and fit the spacecraft observations well

Electron rolling‐pin distribution (RPDs), characterized by triple peaks at pitch angles 0°, 90°, and 180°, have recently been discovered in the terrestrial magnetosphere. Since the RPDs' formation is typically attributed to local betatron acceleration, RPDs have been believed to appear primarily inside strong magnetic regions, such as flux pileup regions (FPRs) behind dipolarization fronts (DFs). Different from such expectation, in this study we present unique observations of RPDs made by Cluster spacecraft in the terrestrial magnetotail, showing that RPDs are present inside weak magnetic field regions ahead of the DFs but absent in the strong magnetic field region behind them. The presence of RPD prior to the fronts may be atttributed to the combined effect of global betatron acceleration, global Fermi acceleration, and frontward transport driven by magnetic gradient drift. The atypical features of RPDs are important for fully understanding electron acceleration and transport in the magnetosphere. Plain Language Summary Electrons usually experience efficient acceleration and transport in space, and account for many explosive phenomena, such as magnetospheric substorms. The accelerated electrons typically exhibit certain velocity distributions, such as rolling‐pin distributions (RPDs), which are key to understanding the underlying acceleration mechanisms. Electron RPD has been traditionally believed to develop inside strong magnetic field regions, such as inside FPRs behind dipolarization fronts (DFs) in the terrestrial magnetotail. Different from the conventional knowledge, we present in this study the first observation of electron RPD inside weak magnetic field regions preceding DFs inside plasma jets, by using data collected by ESA’ Cluster spacecraft. Taking advantage of multipoint measurements provided by Cluster, we have investigated in detail the underlying acceleration and transport processes responsible for such unique feature of RPDs. Key Points We report unique observations showing that rolling‐pin distribution (RPDs) is present before dipolarization fronts (DFs) but absent behind them Presence of RPD before the fronts may be attributed to combined effect of global betatron and Fermi acceleration Absence of RPD behind the fronts may be explained by electron loss due to three‐dimensional gradient drift

Dipolarization fronts (DFs), characterized by sharp increases in the northward magnetic field and usually preceded by magnetic dips, are suggested to play an important role in energy conversion and transport in the magnetotail. It has been documented that strong energy conversion typically develops right at the fronts. Here we present spacecraft observations of electron‐scale energy conversion (EEC) developed inside the dip region ahead of a DF, by using high‐cadence data from the Magnetospheric Multiscale Mission. The EEC, with magnitude comparable to that at the front, is primarily driven by ion current and electron‐scale electric field. The electric field inside the dip is provided by electrostatic waves fed by lower hybrid drift instability, which experiences temporal decaying. Such decaying leads to nonhomogeneity of EEC along the dawn‐dusk direction. These results, uncovering a new channel for DF‐driven energy conversion, can provide important insights into understanding energy transport in the magnetotail. Plain Language Summary Space weather is determined by earthward transport of energy and mass in the magnetosphere. In the magnetotail, such transport is usually associated with dipolarization fronts embedded inside high‐speed plasma jets, which are characterized by a sharp enhancement of the northward component of the magnetic field and serve as the leading boundaries of plasma jets. Statistical studies reveal that a small decrease in the magnetic field often occurs ahead of the fronts, which is dubbed as a magnetic dip. Dipolarization fronts have been suggested to play a key role in the energy conversion chain in the magnetotail, and the energy conversion typically happens right in the front region where strong currents and electric fields usually develop. In this research, we find that in addition to the front region, the dip preceding the fronts can also host strong energy conversion. Our results help further understand energy conversion in the terrestrial magnetotail. Key Points Electron‐scale energy conversion (EEC) is observed for the first time in the magnetic dip ahead of a dipolarization front The EEC, with magnitude comparable to that at the front, is primarily driven by ion current and electron‐scale motional electric field The EEC electric field is induced by a decaying lower hybrid drift instability which may cause temporal damping of the EEC

Although the clinical features of the Isocitrate dehydrogenase 2 ( IDH2 ) mutation in acute myeloid leukemia (AML) have been characterized, its prognostic significance remains controversial and its stability has not been investigated. We analyzed 446 adults with primary non-M3 AML and found IDH2 R172, R140 and IDH1 R132 mutations occurred at a frequency of 2.9, 9.2 and 6.1%, respectively. Compared with wild-type IDH2 , mutation of IDH2 was associated with higher platelet counts, intermediate-risk or normal karyotype and isolated +8, but was inversely correlated with expression of HLA-DR, CD34, CD15, CD7 and CD56, and was mutually exclusive with WT1 mutation and chromosomal translocations involving core-binding factors. All these correlations became stronger when IDH1 and IDH2 mutations were considered together. Multivariate analysis revealed IDH2 mutation as an independent favorable prognostic factor. IDH2 − / FLT3 -ITD + genotype conferred especially negative impact on survival. Compared with IDH2 R140 mutation, IDH2 R172 mutation was associated with younger age, lower white blood cell count and lactate dehydrogenase level, and was mutually exclusive with NPM1 mutation. Serial analyses of IDH2 mutations at both diagnosis and relapse in 121 patients confirmed high stability of IDH2 mutations. In conclusion, IDH2 mutation is a stable marker during disease evolution and confers favorable prognosis.

Magnetic flux ropes (MFRs) are significant regions for the production of energetic electrons in space and astrophysical plasmas. However, the research on electron heating and acceleration driven by turbulence in MFRs is still quite rare. Utilizing in‐situ measurements from MMS satellite, we study electron heating and associated electrostatic waves in an ion‐scale MFR within terrestrial super‐Alfvén plasma flow. Lower‐hybrid drift waves, generated locally in this MFR, can contribute to the perpendicular heating through their electrostatic potential accelerating electrons. The parallel heating is attributed to antiparallel propagating electron beams. These beams excite the broadband electrostatic waves that can interact with electrons and thermalize electrons. Our study promotes understanding of electron energization driven by plasma waves and wave‐particle interaction in MFRs. Plain Language Summary Magnetic flux ropes (MFRs) are ubiquitous magnetic structures existing in space and astrophysical plasmas. They are produced by magnetic reconnection, and can in turn trigger small‐scale reconnection and modulate reconnection process. In addition, they are widely used to explain electron heating and acceleration, which is a long‐standing problem in space and astrophysical plasmas. Thus, they receive significant attention nowadays. However, there has been still lack of research on electron heating and acceleration driven by turbulence in MFRs. In our study, we find perpendicular electron heating is partly attributed to lower‐hybrid drift waves and parallel electron heating is closely related to antiparallel propagating electron beams, which excites strong broadband electrostatic waves that can result in thermalization of electrons. Key Points Electron heating is detected inside an ion‐scale magnetic flux rope Lower‐hybrid drift waves can contribute to the perpendicular heating through their electrostatic potential accelerating electrons The parallel heating is caused by electron beams, which excite the broadband electrostatic waves that can thermalize electrons

Dipolarization fronts (DFs), ion‐scale magnetic transients characterized by dramatic enhancement of northward magnetic field, have been documented as crucial energy transfer regions in the magnetosphere. DF‐driven energy transfer has hitherto been studied mainly in the laminar regime. Energy transfer driven by turbulent processes, however, remains unclear. Here we perform a comprehensive investigation of turbulent energy transfer (TET) developed at DFs, via using high‐cadence data from Magnetospheric Multiscale mission. We find that: (a) TET is equally governed by energy loads and generators, different from laminar energy transfer which is typically dominated by energy loads; (b) ion and electron currents play comparable roles in driving TET; (c) TET is positively correlated with local magnetic field strength and ion speed; (d) TET shows asymmetric global distributions along the dawn‐dusk direction. These features implicate that TET is primarily related to electromagnetic turbulence at electron‐ion hybrid scales. These new results, uncovering unique characteristics of DF‐driven TET, can deeply advance our understanding of energy budgets in the magnetosphere. Plain Language Summary The sun constantly emits outward‐propagating plasma flows called solar wind. When arriving close to Earth, the solar wind interacts with Earth's internal, dipolar magnetic field, leading to formation of long, stretched magnetic field lines in the Earth's nightside, dubbed as magnetotail. The magnetotail hosts a variety of plasma structures which contribute to energy transport therein. Dipolarization fronts (DFs), characterized by sharp enhancement of northward component of magnetic field at ion scale, have been suggested as the leading boundaries of plasma jets (bursty bulk flows) in the magnetotail. They usually host the interaction between the jets and the ambient plasma. Hence, DFs have been suggested as the crucial regions in which intense energy transfer occurs. So far, it has been well documented that the DF‐driven energy transfer is closely related to large‐scale electric fields and ion currents, which are essentially laminar (i.e., direct‐current). Contributions from turbulent (i.e., alternating ‐current) fields and currents remain not well understood. In this study, we use high‐cadence data from NASA's Magnetospheric Multiscale mission to perform a comprehensive investigation of turbulent energy transfer (TET) developed at DFs, uncovering some important features. These results help better understand energy transport in the terrestrial magnetotail. Key Points Turbulent energy transfer (TET) is equally governed by energy loads and generators, with comparable contributions from electron and ion currents TET is positively correlated with local magnetic field strength and ion speed TET may be related to electromagnetic turbulence at electron‐ion hybrid scales

The hippocampus and the medial prefrontal cortex (mPFC) are traditionally associated with regulating memory and executive function, respectively. The contribution of these brain regions to food intake control, however, is poorly understood. The present study identifies a novel neural pathway through which monosynaptic glutamatergic ventral hippocampal field CA1 (vCA1) to mPFC connectivity inhibits food-motivated behaviors through vCA1 glucagon-like peptide-1 receptor (GLP-1R). Results demonstrate that vCA1-targeted RNA interference-mediated GLP-1R knockdown increases motivated operant responding for palatable food. Chemogenetic disconnection of monosynaptic glutamatergic vCA1 to mPFC projections using designer receptors exclusively activated by designer drugs (DREADDs)-mediated synaptic silencing ablates the food intake and body weight reduction following vCA1 GLP-1R activation. Neuropharmacological experiments further reveal that vCA1 GLP-1R activation reduces food intake and inhibits impulsive operant responding for palatable food via downstream communication to mPFC NMDA receptors. Overall these findings identify a novel neural pathway regulating higher-order cognitive aspects of feeding behavior.