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1.
Clin Transl Sci ; 17(9): e70006, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39286959

RESUMEN

Venetoclax, a small molecule inhibitor of BCL-2, has demonstrated efficacy in treating acute leukemias and has been recommended as one of the first-line anti-leukemia therapies. Although venetoclax has been suggested to probably possess the ability to penetrate the central nervous system (CNS), current data to elucidate the characteristics of venetoclax in cerebrospinal fluid (CSF), bone marrow (BM), and plasma are still lacking. This study investigated the real-world characteristics of venetoclax concentrations in CSF, BM, and plasma in acute leukemia patients. Thirteen acute leukemia patients treated with venetoclax were included, with paired samples of CSF, BM, and plasma collected and venetoclax concentrations measured using LC-MS/MS. With the results, the median venetoclax concentrations were 2030 ng/mL in plasma, 16.7 ng/mL in CSF, and 1390 ng/mL in BM. The percentages of CSF/plasma and BM/plasma were 0.74% and 70.37%, respectively. While no direct correlation was observed between CSF and plasma venetoclax levels, there was a trend toward an improved CSF/plasma percentage over time following the last administration of venetoclax. In contrast, a strong correlation was found between BM and plasma levels. This study demonstrated that venetoclax could reach its effective concentration in most patients, suggesting its potential clinical utility in the management of CNS involvement in acute leukemia.


Asunto(s)
Médula Ósea , Compuestos Bicíclicos Heterocíclicos con Puentes , Sulfonamidas , Humanos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/líquido cefalorraquídeo , Compuestos Bicíclicos Heterocíclicos con Puentes/sangre , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Sulfonamidas/líquido cefalorraquídeo , Sulfonamidas/sangre , Masculino , Persona de Mediana Edad , Femenino , Anciano , Médula Ósea/efectos de los fármacos , Adulto , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/líquido cefalorraquídeo , Antineoplásicos/sangre , Espectrometría de Masas en Tándem , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/líquido cefalorraquídeo , Leucemia Mieloide Aguda/sangre , Anciano de 80 o más Años , Cromatografía Liquida , Leucemia/tratamiento farmacológico , Leucemia/líquido cefalorraquídeo , Leucemia/sangre , Adulto Joven
2.
Adv Mater ; : e2410209, 2024 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-39300868

RESUMEN

Organic materials are promising candidates for the electrodes of aqueous zinc-ion batteries due to their nonmetallic nature, environmental friendliness, and cost-effectiveness. However, they often suffer from significant dissolution during the charge-discharge process, which poses a major hurdle to their practical applications. Inspired by membrane-less organelles in cells, a simple and versatile strategy is proposed-constructing a Janus catholyte/cathode structured electrode based on liquid-liquid phase separation, in which redox-active organic molecules are confined in the liquid state within the activated carbon, thereby eliminating the volume effect and preventing their diffusion into the electrolyte. The customization of phase separation systems by leveraging the hydrophobicity/hydrophilicity differences of various anions is successfully demonstrated. This approach allows for precise regulation of ion cluster/coordination structures, enabling the confinement of active substances while ensuring efficient ion transport. Consequently, the as-constructed Zn||Janus catholyte/cathode cells exhibit superior reversible rate capacity (186 mA h g-1 at 5.0 A g-1) and remarkable cycling performance (retention of 72.5% after 12 000 cycles). The strategy in building Janus catholyte/cathode structured electrodes breaks free from the limitations imposed by traditional solid-state electrodes, offering tremendous opportunities for exploring diverse advanced battery systems.

3.
Angew Chem Int Ed Engl ; : e202412830, 2024 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-39157915

RESUMEN

In the electrochemical nitrogen reduction reaction (NRR), a leverage relationship exists between NH3-producing activity and selectivity because of the competing hydrogen evolution reaction (HER), which means that high activity with strong protons adsorption causes low product selectivity. Herein, we design a novel metal-organic hydrogen bonding framework (MOHBF) material to modulate this leverage relationship by a hydrogen-bond-regulated proton transfer pathway. The MOHBF material was composited with reduced graphene oxide (rGO) to form a Ni-N2O2 molecular catalyst (Ni-N2O2/rGO). The unique structure of O atoms in Ni-O-C and N-O-H could form hydrogen bonds with H2O molecules to interfere with protons being directly adsorbed onto Ni active sites, thus regulating the proton transfer mechanism and slowing the HER kinetics, thereby modulating the leverage relationship. Moreover, this catalyst has abundant Ni-single-atom sites enriched with Ni-N/O coordination, conducive to the adsorption and activation of N2. The Ni-N2O2/rGO exhibits simultaneously enhanced activity and selectivity of NH3 production with a maximum NH3 yield rate of 209.7 µg h-1 mgcat.-1 and a Faradaic efficiency of 45.7%, outperforming other reported single-atom NRR catalysts.

5.
Environ Pollut ; 360: 124565, 2024 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-39033842

RESUMEN

Antibiotics and triazole fungicides coexist in varying concentrations in natural aquatic environments, resulting in complex mixtures. These mixtures can potentially affect aquatic ecosystems. Accurately distinguishing synergistic and antagonistic mixtures and predicting mixture toxicity are crucial for effective mixture risk assessment. We tested the toxicities of 75 binary mixtures of antibiotics and fungicides against Auxenochlorella pyrenoidosa. Both regression and classification models for these mixtures were developed using machine learning models: random forest (RF), k-nearest neighbors (KNN), and kernel k-nearest neighbors (KKNN). The KKNN model emerged as the best regression model with high values of determination coefficient (R2 = 0.977), explained variance in prediction leave-one-out (Q2LOO = 0.894), and explained variance in external prediction (Q2F1 = 0.929, Q2F2 = 0.929, and Q2F3 = 0.923). The RF model, the leading classifier, exhibited high accuracy (accuracy = 1 for the training set and 0.905 for the test set) in distinguishing the synergistic and antagonistic mixtures. These results provide crucial value for the risk assessment of mixtures.


Asunto(s)
Antibacterianos , Fungicidas Industriales , Aprendizaje Automático , Fungicidas Industriales/toxicidad , Antibacterianos/toxicidad , Contaminantes Químicos del Agua/toxicidad , Medición de Riesgo
6.
Blood ; 2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39046762

RESUMEN

Atypical acute promyelocytic leukemia (aAPL) presents a complex landscape of retinoic acid receptor (RAR) fusion genes beyond the well-known PML::RARA fusion. Among these, 31 individually rare RARA and RARG fusion genes have been documented, often reported in the canonical X::RAR bipartite fusion form. Intriguingly, some artificially mimicked bipartite X::RAR fusions respond well to all-trans retinoic acid (ATRA) in vitro, contrasting with the ATRA resistance observed in patients. To unravel the underlying mechanisms, we conducted a comprehensive molecular investigation into the fusion transcripts in 27 RARA fusion gene-positive aAPL (RARA-aAPL) and 21 RARG-aAPL cases. Our analysis revealed an unexpected novel form of X::RAR::X or X::RAR::Y-type tripartite fusions in certain RARA- and all RARG-aAPL cases, with shared features and notable differences between these two disease subgroups. In RARA-aAPL cases, the occurrence of RARA 3' splices was associated with their 5' fusion partner genes, mapping across the coding region of helix 11_12 (H11_12) within the ligand-binding domain (LBD), resulting in LBD-H12 or H11_12 truncation. In RARG-aAPL cases, RARG 3' splices were consistently localized to the terminus of exon 9, leading to LBD-H11_12 truncation. Significant differences were also observed between RARA and RARG 5' splice patterns. Our analysis also revealed extensive involvement of transposable elements in constructing RARA and RARG 3' fusions, suggesting transposition mechanisms for fusion gene ontogeny. Both protein structural analysis and experimental results highlighted the pivotal role of LBD-H11_12/H12 truncation in driving ATRA unresponsiveness and leukemogenesis in tripartite fusion-positive aAPL, through a protein allosteric dysfunction mechanism.

7.
BMC Plant Biol ; 24(1): 634, 2024 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-38971744

RESUMEN

BACKGROUND: Engelhardia (Juglandaceae) is a genus of significant ecological and economic importance, prevalent in the tropics and subtropics of East Asia. Although previous efforts based on multiple molecular markers providing profound insights into species delimitation and phylogeography of Engelhardia, the maternal genome evolution and phylogeny of Engelhardia in Juglandaceae still need to be comprehensively evaluated. In this study, we sequenced plastomes from 14 samples of eight Engelhardia species and the outgroup Rhoiptelea chiliantha, and incorporated published data from 36 Juglandaceae and six outgroup species to test phylogenetic resolution. Moreover, comparative analyses of the plastomes were conducted to investigate the plastomes evolution of Engelhardia and the whole Juglandaceae family. RESULTS: The 13 Engelhardia plastomes were highly similar in genome size, gene content, and order. They exhibited a typical quadripartite structure, with lengths from 161,069 bp to 162,336 bp. Three mutation hotspot regions (TrnK-rps16, ndhF-rpl32, and ycf1) could be used as effective molecular markers for further phylogenetic analyses and species identification. Insertion and deletion (InDels) may be an important driving factor for the evolution of plastomes in Juglandoideae and Engelhardioideae. A total of ten codons were identified as the optimal codons in Juglandaceae. The mutation pressure mostly contributed to shaping codon usage. Seventy-eight protein-coding genes in Juglandaceae experienced relaxed purifying selection, only rpl22 and psaI genes showed positive selection (Ka/Ks > 1). Phylogenetic results fully supported Engelhardia as a monophyletic group including two sects and the division of Juglandaceae into three subfamilies. The Engelhardia originated in the Late Cretaceous and diversified in the Late Eocene, and Juglandaceae originated in the Early Cretaceous and differentiated in Middle Cretaceous. The phylogeny and divergence times didn't support rapid radiation occurred in the evolution history of Engelhardia. CONCLUSION: Our study fully supported the taxonomic treatment of at the section for Engelhardia species and three subfamilies for Juglandaceae and confirmed the power of phylogenetic resolution using plastome sequences. Moreover, our results also laid the foundation for further studying the course, tempo and mode of plastome evolution of Engelhardia and the whole Juglandaceae family.


Asunto(s)
Evolución Molecular , Filogenia , Genoma de Plastidios , Genoma de Planta
8.
Adv Mater ; 36(33): e2406451, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38888505

RESUMEN

Zinc metal is recognized as the most promising anode for aqueous energy storage but suffers from severe dendrite growth and poor reversibility. However, the coulombic efficiency lacks specificity for zinc dendrite growth, particularly in Zn||Zn symmetric cells. Herein, a novel indicator (fD) based on the characteristic crystallization peaks is proposed to evaluate the growth and distribution of zinc dendrites. As a proof of concept, triethylenetetramine (TETA) is adopted as an electrolyte additive to manipulate the zinc flux for uniform deposition, with a corroborating low fD value. A highly durable zinc symmetric cell is achieved, lasting over 2500 h at 10 mA cm-2 and 400 h at a large discharge of depth (10 mA cm-2, 10 mAh cm-2). Supported by the low fD value, the Zn||TETA-ZnSO4||MnO2 batteries overcome the sudden short circuit and fast capacity fading. The study provides a feasible method to evaluate zinc dendrites and sheds light on the design of highly reversible zinc anodes.

9.
Adv Mater ; 36(28): e2401549, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38739735

RESUMEN

Residual solvents in vinylidene fluoride (VDF)-based solid polymer electrolytes (SPEs) have been recognized as responsible for their high ionic conductivity. However, side reactions by the residual solvents with the lithium (Li) metal induce poor stability, which has been long neglected. This study proposes a strategy to achieve a delicate equilibrium between ion conduction and electrode stability for VDF-based SPEs. Specifically, 2,2,2-trifluoro-N,N-dimethylacetamide (FDMA) is developed as the nonside reaction solvent for poly(vinylidene fluoride-co-hexafluoropropylene) (PVHF)-based SPEs, achieving both high ionic conductivity and significantly improved electrochemical stability. The developed FDMA solvent fosters the formation of a stable solid electrolyte interphase (SEI) through interface reactions with Li metal, effectively mitigating side reactions and dendrite growth on the Li metal electrode. Consequently, the Li||Li symmetric cells and Li||LiFePO4 cells demonstrate excellent cycling performance, even under limited Li (20 µm thick) supply and high-loading cathodes (>10 mg cm-2, capacity >1 mAh cm-2) conditions. The stable Li||LiCoO2 cells operation with a cutoff voltage of 4.48 V indicates the high-voltage stability of the developed SPE. This study offers valuable insights into the development of advanced VDF-based SPEs for enhanced lithium metal battery performance and longevity.

11.
Zhongguo Zhong Yao Za Zhi ; 49(9): 2410-2421, 2024 May.
Artículo en Chino | MEDLINE | ID: mdl-38812142

RESUMEN

Sequential catalysis by ent-copalyl diphosphate(CPS) and ent-kaurene synthase(KS) is a critical step for plants to initiate the biosynthesis of gibberellin with geranylgeranyl pyrophosphate(GGPP) as the substrate. This study mined the transcriptome data of Stellera chamaejasme and cloned two key diterpene synthase genes, SchCPS and SchKS, involved in the gibberellin pathway. The two genes had the complete open reading frames of 2 595 bp and 1 701 bp, encoding two hydrophilic proteins composed of 864 and 566 amino acid residues and with the relative molecular mass of 97.9 kDa and 64.6 kDa and the theoretical isoelectric points of 5.61 and 6.12, respectively. Sequence comparison and phylogenetic tree showed that SchCPS contained LHS, PNV, and DxDD motifs conserved in the CPS family and was categorized in the TPS-c subfamily, while SchKS contained DDxxD, NSE/DTE and PIx motifs conserved in the KS family and was categorized in the TPS-e subfamily. Functional validation showed that SchCPS catalyzed the protonation and cyclization of GGPP to ent-CPP, while SchKS acted on ent-CPP dephosphorylation and re-cyclization to ent-kaurene. In this study, the full-length sequences of SchCPS and SchKS were cloned and functionally verified for the first time, which not only enriched the existing CPS and KS gene libraries but also laid a foundation for the cloning and biosynthesis pathway analysis of more genes involved in the synthesis of active components in S. chamaejasme.


Asunto(s)
Transferasas Alquil y Aril , Filogenia , Proteínas de Plantas , Thymelaeaceae , Transferasas Alquil y Aril/genética , Transferasas Alquil y Aril/metabolismo , Transferasas Alquil y Aril/química , Thymelaeaceae/genética , Thymelaeaceae/enzimología , Thymelaeaceae/química , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/química , Secuencia de Aminoácidos , Diterpenos de Tipo Kaurano/metabolismo , Diterpenos de Tipo Kaurano/química , Alineación de Secuencia , Clonación Molecular
12.
Plant Sci ; 344: 112109, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38704094

RESUMEN

Advances in next-generation sequencing (NGS) have significantly reduced the cost and improved the efficiency of obtaining single nucleotide polymorphism (SNP) markers, particularly through restriction site-associated DNA sequencing (RAD-seq). Meanwhile, the progression in whole genome sequencing has led to the utilization of an increasing number of reference genomes in SNP calling processes. This study utilized RAD-seq data from 242 individuals of Engelhardia roxburghiana, a tropical tree of the walnut family (Juglandaceae), with SNP calling conducted using the STACKS pipeline. We aimed to compare both reference-based approaches, namely, employing a closely related species as the reference genome versus the species itself as the reference genome, to evaluate their respective merits and limitations. Our findings indicate a substantial discrepancy in the number of obtained SNPs between using a closely related species as opposed to the species itself as reference genomes, the former yielded approximately an order of magnitude fewer SNPs compared to the latter. While the missing rate of individuals and sites of the final SNPs obtained in the two scenarios showed no significant difference. The results showed that using the reference genome of the species itself tends to be prioritized in RAD-seq studies. However, if this is unavailable, considering closely related genomes is feasible due to their wide applicability and low missing rate as alternatives. This study contributes to enrich the understanding of the impact of SNP acquisition when utilizing different reference genomes.


Asunto(s)
Genoma de Planta , Secuenciación de Nucleótidos de Alto Rendimiento , Polimorfismo de Nucleótido Simple , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Análisis de Secuencia de ADN/métodos
13.
Adv Mater ; 36(26): e2401924, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38593988

RESUMEN

With the increasing need for reliable storage systems, the conversion-type chemistry typified by bromine cathodes attracts considerable attention due to sizeable theoretical capacity, cost efficiency, and high redox potential. However, the severe loss of active species during operation remains a problem, leading researchers to resort to concentrated halide-containing electrolytes. Here, profiting from the intrinsic halide exchange in perovskite lattices, a novel low-dimensional halide hybrid perovskite cathode, TmdpPb2[IBr]6, which serves not only as a halogen reservoir for reversible three-electron conversions but also as an effective halogen absorbent by surface Pb dangling bonds, C─H…Br hydrogen bonds, and Pb─I…Br halogen bonds, is proposed. As such, the Zn||TmdpPb2[IBr]6 battery delivers three remarkable discharge voltage plateaus at 1.21 V (I0/I-), 1.47 V (I+/I0), and 1.74 V (Br0/Br-) in a typical halide-free electrolyte; meanwhile, realizing a high capacity of over 336 mAh g-1 at 0.4 A g-1 and high capacity retentions of 88% and 92% after 1000 cycles at 1.2 A g-1 and 4000 cycles at 3.2 A g-1, respectively, accompanied by a high coulombic efficiency of ≈99%. The work highlights the promising conversion-type cathodes based on metal-halide perovskite materials.

14.
J Hematol Oncol ; 17(1): 18, 2024 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-38627786

RESUMEN

The chemo-free concept represents a new direction for managing adult patients with Ph-positive acute lymphoblastic leukemia (Ph + ALL). The tyrosine kinase inhibitors (TKIs), blinatumomab and venetoclax serve as the backbone of chemo-free regimens; several prospective studies involving these drugs have demonstrated high remission rates and promising, albeit short, survival outcomes. This review summarizes the latest updates on chemo-free regimens in the treatment of adult patients with Ph + ALL, presented at the 2023 ASH annual meeting.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/uso terapéutico , Congresos como Asunto
15.
Angew Chem Int Ed Engl ; 63(23): e202401501, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38589296

RESUMEN

Compared to sp2-hybridized graphene, graphdiynes (GDYs) composed of sp and sp2 carbon are highly promising as efficient catalysts for electrocatalytic oxygen reduction into oxygen peroxide because of the high catalytic reactivity of the electron-rich sp-carbon atoms. The desired catalytic capacity of GDY, such as catalytic selectivity and efficiency, can theoretically be achieved by strategically steering the sp-carbon contents or the topological arrangement of the acetylenic linkages and aromatic bonds. Herein, we successfully tuned the electrocatalytic activity of GDYs by regulating the sp-to-sp2 carbon ratios with different organic monomer precursors. As the active sp-carbon atoms possess electron-sufficient π orbitals, they can donate electrons to the lowest unoccupied molecular orbital (LUMO) orbitals of O2 molecules and initiate subsequent O2 reduction, GDY with the high sp-carbon content of 50 at % exhibits excellent capability of catalyzing O2 reduction into H2O2. It demonstrates exceptional H2O2 selectivity of over 95.0 % and impressive performance in practical H2O2 production, Faraday efficiency (FE) exceeding 99.0 %, and a yield of 83.3 nmol s-1 cm-2. Our work holds significant importance in effectively steering the inherent properties of GDYs by purposefully adjusting the sp-to-sp2 carbon ratio and highlights their immense potential for research and applications in catalysis and other fields.

16.
Br J Haematol ; 204(6): 2301-2318, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38685813

RESUMEN

T-cell acute lymphoblastic leukaemia (T-ALL) is a highly aggressive and heterogeneous lymphoid malignancy with poor prognosis in adult patients. Aberrant activation of the NOTCH1 signalling pathway is involved in the pathogenesis of over 60% of T-ALL cases. Ubiquitin-specific protease 28 (USP28) is a deubiquitinase known to regulate the stability of NOTCH1. Here, we report that genetic depletion of USP28 or using CT1113, a potent small molecule targeting USP28, can strongly destabilize NOTCH1 and inhibit the growth of T-ALL cells. Moreover, we show that USP28 also regulates the stability of sterol regulatory element binding protein 1 (SREBP1), which has been reported to mediate increased lipogenesis in tumour cells. As the most critical transcription factor involved in regulating lipogenesis, SREBP1 plays an important role in the metabolism of T-ALL. Therefore, USP28 may be a potential therapeutic target, and CT1113 may be a promising novel drug for T-ALL with or without mutant NOTCH1.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Ubiquitina Tiolesterasa , Humanos , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Ubiquitina Tiolesterasa/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico
17.
Hematology ; 29(1): 2335856, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38581291

RESUMEN

Philadelphia chromosome-positive acute lymphoblastic leukemia (PH + ALL) is the most common cytogenetic abnormality of B-ALL in adults and is associated with poor prognosis. Previously, the only curative treatment option in PH + ALL was allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Since 2000, targeted therapy combined with chemotherapy, represented by the tyrosine kinase inhibitor Imatinib, has become the first-line treatment for PH + ALL. Currently, the remission rate and survival rate of Imatinib are superior to those of simple chemotherapy, and it can also improve the efficacy of transplantation. More recently, some innovative immune-targeted therapy greatly improved the prognosis of PH + ALL, such as Blinatumomab and Inotuzumab Ozogamicin. For patients with ABL1 mutations and those who have relapsed or are refractory to other treatments, targeted oral small molecule drugs, monoclonal antibodies, Bispecific T cell Engagers (BiTE), and chimeric antigen receptor (CAR) T cells immunotherapy are emerging as potential treatment options. These new therapeutic interventions are changing the treatment landscape for PH + ALL. In summary, this review discusses the current advancements in targeted therapeutic agents shift in the treatment strategy of PH + ALL towards using more tolerable chemotherapy-free induction and consolidation regimens confers better disease outcomes and might obviate the need for HSCT.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Mesilato de Imatinib/uso terapéutico , Cromosoma Filadelfia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inhibidores de Proteínas Quinasas/uso terapéutico
18.
Toxics ; 12(3)2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38535950

RESUMEN

Ampicillin (AMP) and cefazolin (CZO) are commonly used ß-lactam antibiotics which are extensively globally produced. Additionally, AMP and CZO are known to have relatively high ecotoxicity. Notably, the mix of AMP and CZO creates a synergistic effect that is more harmful to the environment, and how exposure to AMP-CZO can induce synergism in algae remains virtually unknown. To yield comprehensive mechanistic insights into chemical toxicity, including dose-response relationships and variations in species sensitivity, the integration of multiple endpoints with de novo transcriptomics analyses were used in this study. We employed Selenastrum capricornutum to investigate its toxicological responses to AMP and CZO at various biological levels, with the aim of elucidating the underlying mechanisms. Our assessment of multiple endpoints revealed a significant growth inhibition in response to AMP at the relevant concentrations. This inhibition was associated with increased levels of reactive oxygen species (ROS) and perturbations in nitrogen metabolism, carbohydrate metabolism, and energy metabolism. Growth inhibition in the presence of CZO and the AMP-CZO combination was linked to reduced viability levels, elevated ROS production, decreased total soluble protein content, inhibited photosynthesis, and disruptions in the key signaling pathways related to starch and sucrose metabolism, ribosome function, amino acid biosynthesis, and the production of secondary metabolites. It was concluded from the physiological level that the synergistic effect of Chlorophyll a (Chla) and Superoxide dismutase (SOD) activity strengthened the growth inhibition of S. capricornutum in the AMP-CZO synergistic group. According to the results of transcriptomic analysis, the simultaneous down-regulation of LHCA4, LHCA1, LHCA5, and sodA destroyed the functions of the photosynthetic system and the antioxidant system, respectively. Such information is invaluable for environmental risk assessments. The results provided critical knowledge for a better understanding of the potential ecological impacts of these antibiotics on non-target organisms.

19.
Sci Total Environ ; 926: 171771, 2024 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-38521260

RESUMEN

Assessing the interactions between environmental pollutants and these mixtures is of paramount significance in understanding their negative effects on aquatic ecosystems. However, existing research often lacks comprehensive investigations into the physiological and biochemical mechanisms underlying these interactions. This study aimed to reveal the toxic mechanisms of cyproconazole (CYP), imazalil (IMA), and prochloraz (PRO) and corresponding these mixtures on Auxenochlorella pyrenoidosa by analyzing the interactions at physiological and biochemical levels. Higher concentrations of CYP, IMA, and PRO and these mixtures resulted in a reduction in chlorophyll (Chl) content and increased total protein (TP) suppression, and malondialdehyde (MDA) content exhibited a negative correlation with algal growth. The activity of catalase (CAT) and superoxide dismutase (SOD) decreased with increasing azole fungicides and their mixture concentrations, correlating positively with growth inhibition. Azole fungicides induced dose-dependent apoptosis in A. pyrenoidosa, with higher apoptosis rates indicative of greater pollutant toxicity. The results revealed concentration-dependent toxicity effects, with antagonistic interactions at low concentrations and synergistic effects at high concentrations within the CYP-IMA mixtures. These interactions were closely linked to the interactions observed in Chl-a, carotenoid (Car), CAT, and cellular apoptosis. The antagonistic effects of CYP-PRO mixtures on A. pyrenoidosa growth inhibition can be attributed to the antagonism observed in Chl-a, Chl-b, Car, TP, CAT, SOD, and cellular apoptosis. This study emphasized the importance of gaining a comprehensive understanding of the physiological and biochemical interactions within algal cells, which may help understand the potential mechanism of toxic interaction.


Asunto(s)
Chlorophyta , Fungicidas Industriales , Contaminantes Químicos del Agua , Fungicidas Industriales/toxicidad , Azoles/toxicidad , Ecosistema , Chlorophyta/metabolismo , Clorofila A , Superóxido Dismutasa/metabolismo , Contaminantes Químicos del Agua/toxicidad
20.
Hematol Oncol ; 42(2): e3260, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38415873

RESUMEN

Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy (DAV) has shown safety and efficacy in eligible patients with newly diagnosed acute myeloid leukemia (AML). However, there are no direct comparisons between DAV and 3 + 7 daunorubicin and cytarabine chemotherapy (DA) alone. We performed a propensity score-matched analysis to compare the outcomes of DAV group with historical DA group and identify the clinical and molecular characteristics of patients who might benefit from the DAV regimen. The DAV group had a higher Complete remission (CR) rate than the DA group (90% vs. 55%, p = 0.008). 25 (96%) patients in the DAV group had a higher MRD-negative CRc rate compared with 13 (62%) patients in the DA group (p = 0.006). After a median follow-up duration of 19.15 (IQR 17.13-21.67) months, the DAV group had an improved overall survival (p = 0.001) and event-free survival (p = 0.069), but not disease-free survival (p = 0.136). Collectively, DAV regimen induced high CR rates and deep MRD-negative CRc rates after one cycle of induction therapy, as well as prolonged the overall survival, in young adult patients with AML who were eligible for intensive chemotherapy. The addition of venetoclax to intensive chemotherapy should be considered in the future to achieve better survival advantages in eligible AML patients.


Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Sulfonamidas , Adulto Joven , Humanos , Puntaje de Propensión , Leucemia Mieloide Aguda/tratamiento farmacológico , Daunorrubicina , Citarabina , Respuesta Patológica Completa
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