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Risk stratified treatment for childhood acute lymphoblastic leukaemia: a multicentre observational study from India
No full textBackground
Overall survival rates of children with acute lymphoblastic leukaemia (ALL) in high-income countries approach 90%. Treated on the same protocols, outcomes in India, were ∼65%.
Methods
The Indian Childhood Collaborative Leukaemia (ICiCLe) group used genetics and measurable residual disease (MRD) to categorise B-cell precursor (BCP) ALL as standard (SR), intermediate (IR) and high-risk (HR) to receive increasing intensity of therapy. T-ALL were treated uniformly. Data on risk stratification, deaths and relapses were collected annually.
Findings
2695 patients aged 1–18 years were enrolled between January 2013 and May 2018. Induction deaths were significantly lower in SR patients (p = 0·002) compared to others. At a median 61 (59–62) months, the 4-year event free and overall survival was 76% (72–79%) and 88% (85–90%) in SR; 70% (66–74%) and 80% (77–83%) in IR; 61% (51–64%) and 73% (70–76%) in HR; and 69% (62–75%) and 77% (70–83%) in T-ALL patients (p < 0·0001). For BCP-ALL, regression analyses showed age, white cell count, bulky disease, high risk genetics and treating centre as independent prognostic variables. The cumulative incidence of treatment deaths (TRD) and relapses at centres varied from 2% (1–5) to 13% (10–17) (p ≤ 0·0001); and 21% (17–26) to 45% (39–51) (p ≤ 0·0001) respectively with significant differences in proportion of BCP-ALL patients with MRD ≥ 0·01% (p = 0·0007) and time to relapse (p = 0·0001).
Interpretation
Risk stratified directed reduced intensity treatment and collaboration decreases treatment deaths and relapses. Standardisation of genetic and MRD tests across centres and access to high quality drugs will lead to further improvements in survival
Aberrant overexpression of m6A writer and reader genes in pediatric B-Cell Acute Lymphoblastic Leukemia (B-ALL)
No full textBackground
m6A modification, regulated by writers (METTL3, METTL14), erasers (ALKBH5, FTO), and readers (IGF2BPs), is implicated in various cancers, including leukemias.
Methods
In our study, we examined a cohort of 227 pediatric B-ALL patients (152 primary and 75 relapsed) and assessed the expression profiles of m6A machinery genes, including both writers and erasers, as well as the IGF2BP RNA-binding proteins, which are known as m6A readers. We also quantified the absolute percentage of m6A (m6A%). The correlation between m6A machinery gene expression and patient prognosis was studied using univariate and multivariate analyses.
Results
Our analysis revealed a significant upregulation of m6A writers (METTL3 and METTL14), erasers (FTO), and m6A readers (IGF2BPs 1 and 3) in B-ALL patients, both in the primary and relapsed groups. m6A% levels were markedly higher in B-ALL samples than in controls. Multivariate analysis revealed that the expression of IGF2BP3, METTL3, and FTO genes, independently predicted lower overall survival and event-free survival in primary B-ALL patients.
Conclusions
Despite the collective dysregulation of the m6A machinery, the writers and readers appear to have a more dominant phenotype, as evidenced by the significantly elevated m6A% levels. This is the first study to analyze and establish the role of m6A machinery gene expression and its correlation with survival outcomes in a large group of B-ALL patients. These findings could aid in the development of new therapeutics targeting the m6A machinery and help predict relapse in pediatric B-ALL patients
Integrative Genetic and Transcriptomic Subtyping Improves Prognosis Prediction in B-Lineage Acute Lymphoblastic Leukemia
No full textWhole-transcriptomic sequencing (WTS) has remarkably advanced our understanding of B-lineage acute lymphoblastic leukemia (B-ALL), allowing for detailed gene expression profiling and discovery of novel therapeutically relevant subtypes. The aim of this study was to evaluate the diagnostic and prognostic relevance of combining WTS with traditional genetic methods in risk-stratifying B-ALL. In a cohort of 394 patients (301 children and 93 adults), conventional techniques such as fluorescence in situ hybridization, cytogenetics, and reverse-transcription PCR identified sentinel chromosomal abnormalities like BCR::ABL1, TCF3::PBX1, ETV6::RUNX1, and KMT2A-R (rearranged), and ploidy status. WTS was performed on selected 257 patients to identify subtypes such as Ph-like, DUX4-R, PAX5-altered (PAX5-ALT), MEF2D-R, BCL2-R, UBTF-R, PAX5 P80R, NUTM1-R, ZNF384-R, ZNF384-like, ETV6::RUNX1-like, IKZF1 N159Y, and HLF-R. We used a multipronged strategy to identify the borderline subtypes such as Ph-like, PAX5-ALT, and CRLF2 (non–Ph-like), by integrating gene expression signatures using t-distributed stochastic neighbor embedding, subtype-defining mutations, gene fusions, and copy number assessments. Our integrated approach not only identifies prognostically relevant sentinel molecular subtypes but also increases subtype assignment in upto ∼95% of B-ALL patients. The pro-B immunophenotype was found to be more frequent in UBTF-R and MEF2D-R ALL. Ph-like ALL was associated with poor remission rates and higher minimal residual disease positivity, while DUX4-R showed favorable prognosis. We further categorized pediatric patients into 3 risk groups: favorable (hyperdiploid, ETV6::RUNX1, and DUX4-R), poor (BCR::ABL1, Ph-like, KMT2A-R, TCF3::PBX1, iAMP21, and hypodiploid), and intermediate (PAX5-ALT, PAX5 P80R, NUTM1-R, MEF2D-R, CRLF2 [non-Ph-like], UBTF-R, ZNF384-R, ZNF384-like, BCL2-R, IKZF1 N159Y, ETV6::RUNX1-like, and B-rest). Event-free survival and overall survival were significantly associated with this risk stratification. In adults, Ph-like ALL showed worse prognosis, particularly, in BCR::ABL1-negative ALL patients. Among the DUX4-R B-ALL, those with IKZF1 deletion had worse event-free survival and overall survival. We also identified several novel gene rearrangements in different subtypes of B-ALL. Our study demonstrated that integrating WTS with traditional methods provides a comprehensive, accurate, and cost-effective strategy for risk assessment and treatment planning for B-ALL
Cyano-bridged bimetallic polymer network-derived Pd<sub>3</sub>Fe intermetallic for qqueous rechargeable zinc-air batteries
No full textThe rational design and synthesis of bifunctionally active and durable oxygen electrocatalysts have garnered significant attention for electrochemical energy conversion and storage. Intermetallic nanostructures are particularly promising for these applications due to their unique catalytic properties and exceptional durability. In this study, we present a fascinating synthetic approach for the direct synthesis of a bifunctional oxygen electrocatalyst based on nitrogen-doped carbon-encapsulated ordered Pd3Fe (o-Pd3Fe@NC) intermetallic, using a cyano-bridged bimetallic single-source precursor tailored for aqueous rechargeable zinc-air batteries (ZABs). Through temperature-controlled annealing of a bipyridine-containing Pd–Fe cyano-bridged polymer network, a catalytically active o-Pd3Fe@NC catalyst is obtained. The spatial confinement of Pd(II) and Fe(II) within the polymer network facilitates the controlled growth of the o-Pd3Fe nanostructure. This intermetallic catalyst exhibits bifunctional activity for both the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). The o-Pd3Fe@NC catalyst achieves an ORR onset potential of 0.98 V and demonstrates remarkable long-term stability, sustaining performance over 30,000 cycles in alkaline electrolytes without noticeable degradation. The rechargeable liquid and flexible ZABs constructed with the o-Pd3Fe@NC air cathode deliver outstanding energy performance, achieving maximum power densities of 212.9 and 109 mW cm-2, respectively. The liquid ZAB delivers a specific capacity of 816 mAh gZn-1 and exhibits excellent charge–discharge cycling stability, maintaining a consistent charge–discharge voltage gap over 200 h. The flexible ZAB retains its charge-storage performance across all bending angles
Dopant and exfoliation induced simultaneous modification of charge density and C─C coupling sites for efficient CO<sub>2</sub> photoreduction to ethylene
No full textThe photochemical conversion of CO2 into C2+ products has emerged as an attractive method for synthesizing valuable chemicals and fuels using abundant solar energy. However, the challenge lies in enhancing the efficiency and selectivity of C2+ product formation. In this study, we employed a heteroatom doping strategy to optimize the photocatalytic parameters and achieve excellent efficiency and selectivity in the photocatalytic CO2 reduction to C2+ product formation. Our experimental analysis revealed that the local electronic structure of the catalyst, modified by In-doping, enables enhanced efficiency. Additionally, the incorporation of Cu facilitates the coupling of C1 intermediates, resulting in excellent selectivity towards C2+ products. The CO2 reduction performance is further enhanced through exfoliation, which increases the exposure of active sites and extends the charge carrier lifetime by reducing the charge diffusion length. We report that the rate of formation of C2H4 reached 54.3 μmol.h-1.g-1 with an outstanding selectivity of 91% over the exfoliated CuIn-doped AgBiP2S6 catalyst. By elucidating the role of heteroatom doping and exfoliation in enhancing both the efficiency and selectivity of C2+ product formation, our study contributes to advancing the development of sustainable and efficient photocatalytic CO2 conversion technologies
Exploring the electronic modulation in controlling the activity and selectivity of Ni-Au-In based catalyst in atmospheric pressure CO<sub>2</sub> hydrogenation
No full textNickel-based catalysts are widely used for the hydrogenation of CO2 but encounter stability challenges during prolonged reactions and at elevated temperatures. At atmospheric pressure, nickel primarily promotes methane formation in CO2 hydrogenation reactions. In this work, we demonstrate that the stability and activity of nickel can be significantly enhanced through gold (Au) modification. Furthermore, we achieve a near-complete selectivity switch from methane to CO by incorporating indium (In), mediated through the formation of Au-In alloy. This catalyst exhibits excellent CO2 conversion and CO selectivity at relatively lower temperatures (400℃), addressing a major bottleneck in the Reverse Water-Gas Shifts (RWGS) reaction. XPS studies demonstrate an interesting electron transfer mechanism facilitated by gold, which involves the formation of electron-rich Au species (Auδ-) and the development of Au-In alloys. This process improves the reducibility of nickel oxide while allowing a fraction of nickel to remain in its metallic form, managing a facile hydrogenation process and regulating the shift in selectivity from CH4 to CO
Transition metal‐based perovskite derivatives for selective CO<sub>2</sub> photoreduction: role of orbital occupancy
No full textTransition metals are renowned for their effective catalytic properties. Incorporating transition metals into halide perovskite derivatives is a key strategy for tuning the properties of perovskites to enhance their photocatalytic performance. Understanding the d-orbital occupancy and spin activity of these transition metals in the CO2 photoreduction process is essential for fully realizing the photocatalytic potential of these materials. In this study, layered perovskite derivatives are synthesized using cobalt (Co) and copper (Cu) as transition metal components. We observed that Cu and Co exhibit complementary absorption properties attributed to their d-orbital configuration. Additionally, (DMAP)2CuCl4 (DMAP = 4-Dimethylaminopyridine) exhibited the highest performance in CO2 photoreduction with remarkable selectivity for CH4 formation (≈97%). Pressure-dependent experiments showed that higher pressures enhance catalytic activity by improving CO2 saturation and adsorption, accelerating the reaction rate and boosting product yield. The ferromagnetism, hysteresis, and strong spin species detection of (DMAP)2CuCl4 enhance carrier separation and charge availability, boosting CO2 conversion efficiency. Further, the first-principles-based atomistic computations reveal that a more delocalized conduction band edge makes mobile electrons available for CO2 reduction in (DMAP)2CuX4. These findings guide the design of selective CO2 reduction photocatalysts and highlight layered perovskite derivatives for sustainable energy solutions
Genetic diversity analysis of Rhododendron arboreum in western Himalaya indicates altitudinal population differentiation and mid-elevation enrichment of heterozygotes
No full textGenetic diversity of Rhododendron arboreum, a keystone tree species in the Himalaya facing threats from habitat-loss, limited regeneration, overexploitation, and climate-change, was assessed. We sampled trees of the species across nine populations occupying different altitudes in Uttarakhand's Garhwal region. The species' genome was sequenced by using next-generation sequencing to identify SSR markers. The genomic data produced ~ 72 million reads, leading to the assembly of 265,673 scaffolds, with 66,742 unique microsatellite loci identified. Out of 140 SSR primer pairs designed, 102 were successfully amplified, with 55 being polymorphic. Genetic diversity metrics, population structure, and genetic variation were evaluated using GenAlEx, STRUCTURE, PCoA, NJ tree, and AMOVA. The diversity indices revealed that genetic diversity was low in populations at the higher and lower elevations, whilst those located at the mid-elevations were more diverse. Observed heterozygosity was higher than expected for all the populations considered. Population genetic structure analysis identified four genetic clusters that aligned with geographical proximity and altitudes. Pairwise FST values indicated a significant genetic differentiation among the populations. AMOVA revealed that genetic variation was largely attributed to heterozygosity within the trees. These results highlight the substantial genetic diversity and differentiation in R. arboreum populations, influenced by geographic and elevational factors. These findings emphasize the need to preserve their germplasm. Importantly, this diversity is also essential for tree breeding programs, conservation efforts, and gaining insights into the species' evolutionary dynamics. With the availability of new and reliable markers, their applicability may also be tested in related species
The Role of Solar Wind Dynamic Pressure in Determining the Intensity of the Geomagnetic Storm
No full textSuper intense storms are unique, and their impacts are remarkable. The present study focuses on the super intense geomagnetic storms (SYM-H ≤ −300 nT) in solar cycles 23 and 25 to address critical questions such as what made a geomagnetic storm a super intense one, and the pivotal role of solar wind and interplanetary magnetic field parameters. The storms with significant steepening of SYM—H are examined, a factor Pdyn.Bz is introduced and correlation coefficient analysis is carried out. To address the complexity of storms, the correlations of solar wind energy input (Einj) with Pdyn.Bz and Esw are investigated and are found to be well correlated with coefficients of 0.94 and 0.89, respectively. The time integrated values of SYM-H during the storm period provide a higher correlation with VBz and Pdyn.Bz than peak SYM-H values. The ideal combination of high values of Pdyn and VBz, that is, Pdyn ≥ 10 nPa and VBz ≥ 5 mV/m and duration play a major role in developing steep SYM-H (<−400 nT) as seen for the super intense geomagnetic storms. We can clearly state that the combination of high Pdyn and steady southward Bz is a key factor in deciding the intensity of the storm as the longer the duration of the combination led to larger peak values of SYM-H. MHD simulations have evidently shown that the crucial role of high solar wind density values for longer duration contributes to the steepening of SYM-H leading to super-intense geomagnetic storms
Assessing the Rayleigh Surface Wave Characteristics From Ionospheric Observations During the Mw 9.1 Tohoku‐Oki Earthquake
No full textThis study re-examines ionospheric responses to the Mw 9.1 Tohoku-Oki earthquake of 11 March 2011, using data from nearly 1200 GEONET GPS receivers distributed across Japan. The focus is on co-seismic ionospheric perturbations (CIP) induced by Rayleigh surface waves, referred to here as Rayleigh wave-generated co-seismic ionospheric perturbations (RAW-CIP). Significant RAW-CIP signatures were observed in Total Electron Content (TEC) time series from multiple GPS satellites. From the spatiotemporal evolution of these perturbations, their propagation velocities and amplitude variations were estimated. Concurrently, seismic data from 64 broadband stations across Japan were analyzed to derive period-dependent group velocities using dispersion curve analysis and amplitudes of Rayleigh surface waves. A comparative assessment revealed that Rayleigh waves with periods between 10 and 50 s were most effective in coupling with the ionosphere. The average propagation velocities of these surface waves showed good agreement with those of RAW-CIP, and their amplitude variations also correlated well. These findings highlight that low-frequency Rayleigh surface waves can be reliably characterized using ionospheric observations, as they effectively manifest in the ionosphere