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1.
Sci Total Environ ; 946: 174227, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38936710

RESUMO

The use of observation-dependent methods for crop productivity and food security assessment is challenging in data-sparse regions. This study presents a transferable framework and applies it to North Korea (NK) to assess rice productivity based on climate similarity, transferable machine-learning techniques, and extendable multi-source data. We initially divided the primary phenological stages of rice in the study region and extracted dynamic rice distributions based on Moderate Resolution Imaging Spectroradiometer products and phenological observations. We compared the performances of four representative environmentally driven models (Linear Regression, back-propagation Neural Network, Support Vector Machine, and Random Forest) in simulating rice productivity using an extensive dataset that included multi-angle vegetation monitoring, climate variables, and planting distribution information. The framework integrated an optimal environmentally driven model with agricultural management practices for transferability to predict rice productivity in NK over multiple years. Additionally, two crop growth scenarios (whole growth period (WGP) and seeding-heading period (SHP)) were compared to assess pre-harvest forecasting capabilities and identify dominant factors. Finally, independent datasets from the Food and Agriculture Organization, World Food Program, and Global Gridded Crop Models were used to validate the magnitude and spatial distribution of the predicted results. The results showed that phenological identification based on remote sensing can accurately capture rice growth characteristics and map rice distribution. Random Forest outperformed other models in simulating rice productivity variation, with r-squares of 0.87 and 0.83 in the WGP and SHP, respectively. The solar-induced chlorophyll fluorescence, maximum temperature, and evapotranspiration collectively determined approximately 40 % of the variation in yield simulated using Random Forest. Conversely, planting areas contributed over 42 % of the variation in rice production. Compared to Food and Agriculture Organization statistics, the environmentally driven framework explained 78.72 % and 76.89 % of the production variation and 69.42 % and 71.15 % of the yield variation in NK under the WGP and SHP, respectively. Moreover, the environmental management-driven framework captured over 90 % of the yield variation. The predicted spatial pattern of rice productivity exhibited significant concordance with the World Food Program and Global Gridded Crop Model reports. In summary, the proposed transferable framework for crop productivity assessment contributes to early warnings of production reduction and has the potential for scalability across various crops and data-sparse regions.

2.
Opt Express ; 32(10): 17362-17372, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38858921

RESUMO

Target detection is significant in many fields, including oceanic security, marine ecology, etc. In this paper, phase sensitive optical time domain reflectometry (Φ-OTDR) is introduced for the non-cooperative ship detection, with large-scale diversity technology and suspended sensitized optical cable. In outfield experiments, the ship's voiceprint information is obtained in high fidelity, the ship's power spectrum is analyzed, and the over-top detection is achieved. Moreover, an array orientation method based on adaptive phase difference correction (APDC) is proposed to track the ship, suppressing the delay jitter influence of acoustic transmission underwater. This is the first time that voiceprint information of the non-cooperative ship is high-fidelity acquired and deeply analyzed with Φ-OTDR and suspended sensitized optical cable, which is conducive to the detection and identification of marine targets, and proves the potential of Φ-OTDR in hydroacoustic detection applications.

3.
Anal Chem ; 95(39): 14573-14581, 2023 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-37729469

RESUMO

Discrimination and quantification of amino acid (AA) enantiomers are particularly important for diagnosing and treating diseases. Recently, dual-mode probes have gained a lot of research interest because they can catch more detecting information compared with the single-mode probes. Thus, it is of great significance to develop a dual-mode sensor realizing AA enantiomer discrimination conveniently and efficiently. In this work, carbon dot L-TCDs were prepared by N-methyl-1,2-benzenediamine dihydrochloride (OTD) and l-tryptophan. With the assistance of H2O2, L-TCDs show an excellent discrimination performance for enantiomers of glutamine (Gln) and valine (Val) in both fluorescent and colorimetric modes. The fluorescence enantioselectivity of Gln (FD/FL) and Val (FL/FD) is 5.29 and 4.13, respectively, and the colorimetric enantioselectivity of Gln (ID/IL) and Val (IL/ID) is 13.26 and 3.42, individually. The chiral recognition mechanism of L-TCDs was systematically studied. L-TCDs can be etched by H2O2, and the participation of AA enantiomers results in different amounts of the released OTD, which provides fluorescent and colorimetric signals for identifying and quantifying the enantiomers of Gln and Val. This work provides a more convenient and flexible dual-mode sensing strategy for discriminating AA enantiomers, which is expected to be of great value in facile and high-throughput chiral recognition.


Assuntos
Glutamina , Valina , Colorimetria/métodos , Carbono/química , Peróxido de Hidrogênio , Aminoácidos , Corantes
4.
ACS Appl Mater Interfaces ; 15(37): 43492-43502, 2023 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-37691550

RESUMO

The convergence of 3D bioprinting with powerful manufacturing capability and cellular self-organization that can reproduce intricate tissue microarchitecture and function is a promising direction toward building functional tissues and has yet to be demonstrated. Here, we develop a granular aggregate-prevascularized (GAP) bioink for engineering highly vascularized bone tissues by capitalizing on the condensate-mimicking, self-organization, and angiogenic properties of prevascularized mesenchymal spheroids. The GAP bioink utilizes prevascularized aggregates as building blocks, which are embedded densely in extracellular matrices conducive to spontaneous self-organization. We printed various complex structures with high cell density (∼1.5 × 108 cells/cm3), viability (∼80%), and shape fidelity using GAP bioink. After printing, the prevascularized mesenchymal spheroids developed an interconnected vascular network through angiogenic sprouting. We printed highly vascularized bone tissues using GAP bioink and found that prevascularized spheroids were more conducive to osteogenesis and angiogenesis. We envision that the design of the GAP bioink could be further integrated with human-induced pluripotent stem cell-derived organoids, which opens new avenues to create patient-specific vascularized tissues for therapeutic applications..


Assuntos
Bioimpressão , Humanos , Osso e Ossos , Osteogênese , Engenharia , Matriz Extracelular
6.
Adv Mater ; 35(22): e2205082, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36796025

RESUMO

Creating functional tissues and organs in vitro on demand is a major goal in biofabrication, but the ability to replicate the external geometry of specific organs and their internal structures such as blood vessels simultaneously remains one of the greatest impediments. Here, this limitation is addressed by developing a generalizable bioprinting strategy of sequential printing in a reversible ink template (SPIRIT). It is demonstrated that this microgel-based biphasic (MB) bioink can be used as both an excellent bioink and a suspension medium that supports embedded 3D printing due to its shear-thinning and self-healing behavior. When encapsulating human-induced pluripotent stem cells, the MB bioink is 3D printed to generate cardiac tissues and organoids by extensive stem cell proliferation and cardiac differentiation. By incorporating MB bioink, the SPIRIT strategy enables the effective printing of a ventricle model with a perfusable vascular network, which is not possible to fabricate using extant 3D printing strategies. This SPIRIT technique offers an unparalleled bioprinting capability to replicate the complex organ geometry and internal structure in a faster manner, which will accelerate the biofabrication and therapeutic applications of tissue and organ constructs.


Assuntos
Bioimpressão , Engenharia Tecidual , Humanos , Engenharia Tecidual/métodos , Alicerces Teciduais/química , Bioimpressão/métodos , Organoides , Impressão Tridimensional
7.
Stem Cell Reports ; 18(3): 720-735, 2023 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-36801005

RESUMO

Regenerating prolonged multi-lineage hematopoiesis from pluripotent stem cells (PSCs), an unlimited cell source, is a crucial aim of regenerative hematology. In this study, we used a gene-edited PSC line and revealed that simultaneous expression of three transcription factors, Runx1, Hoxa9, and Hoxa10, drove the robust emergence of induced hematopoietic progenitor cells (iHPCs). The iHPCs engrafted successfully in wild-type animals and repopulated abundant and complete myeloid-, B-, and T-lineage mature cells. The generative multi-lineage hematopoiesis distributed normally in multiple organs, persisted over 6 months, and eventually declined over time with no leukemogenesis. Transcriptome characterization of generative myeloid, B, and T cells at the single-cell resolution further projected their identities to natural cell counterparts. Thus, we provide evidence that co-expression of exogenous Runx1, Hoxa9, and Hoxa10 simultaneously leads to long-term reconstitution of myeloid, B, and T lineages using PSC-derived iHPCs as the cell source.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Células-Tronco Pluripotentes , Animais , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Diferenciação Celular/genética , Animais Selvagens , Hematopoese , Células Sanguíneas , Linhagem da Célula/genética
8.
Appl Opt ; 62(2): 342-347, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36630232

RESUMO

Mountain dynamic response monitoring plays important roles in geological disaster evolution monitoring and warning. A distributed mountain seismic monitoring and steady-state analysis method is demonstrated with distributed acoustic sensing (DAS) and a natural earthquake stimulus. In the field test, the seismic detection capability is first verified by comparing the recorded seismic waveforms from DAS and existing seismic stations. The vibration signal difference between steady-state and unsteady-state mountain parts is apparent; the operational modal analysis method is utilized to extract the response difference and to monitor the disaster evolution process. The proposed method has many advantages, including being easy to deploy, all-weather online monitoring, etc. It is believed that the proposed method will broaden the DAS application scope and promote the development of geological disaster early warning such as landslides and collapses.

9.
Cell Prolif ; 56(4): e13389, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36592612

RESUMO

The technology of adoptive transfer of T-cell receptor (TCR) engineered T cells is wildly investigated as it has the potential to treat solid cancers. However, the therapeutic application of TCR-T cells is hampered by the poor quality derived mainly from patients' peripheral blood, as well as heterogeneous TCRs caused by the mismatch between transgenic and endogenous TCRs. To improve the homogeneity, antigen-specificity and reduce possible autoreactivity, here we developed a technique to generate antigen-specific T cells from Rag2 gene-deleted pluripotent stem cells (PSCs) and further measured their anti-tumour efficacy. PSCs were first targeted with OT1 TCR into the Rag2 locus to prevent TCR rearrangement during T-cell development. The engineered PSCs were then differentiated through a two-step strategy, in vitro generation of haematopoietic progenitor cells, and in vivo development and maturation of TCR-T cells. Finally, the response to tumour cells was assessed in vitro and in vivo. The regenerated OT1-iT displayed monoclonal antigen-specific TCR expression, and phonotypic normalities in the spleen and lymph node tissues. Importantly, the OT1-iT cells eliminated tumour cells while releasing specific cytokines in vitro. Furthermore, adoptive transfer of OT1-iT cells suppresses solid tumour growth in tumour-bearing animals. Our study presents a novel and straightforward strategy for producing antigen-specific TCR-T cells in vivo from PSCs, allowing for allogeneic transplantation and therapy of solid tumours.


Assuntos
Imunoterapia Adotiva , Células-Tronco Pluripotentes , Camundongos , Animais , Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Citocinas/metabolismo , Proteínas de Ligação a DNA/metabolismo
10.
Cell Discov ; 8(1): 121, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36344493

RESUMO

Human pluripotent stem cell (hPSC)-induced NK (iNK) cells are a source of off-the-shelf cell products for universal immune therapy. Conventional methods for iNK cell regeneration from hPSCs include embryoid body (EB) formation and feeder-based expansion steps, which are time-consuming and cause instability and high costs of manufacturing. Here, we develop an EB-free, organoid aggregate method for NK cell regeneration from hPSCs. In a short time-window of 27-day induction, millions of hPSC input can output over billions of iNK cells without the necessity of NK cell expansion feeders. The iNK cells highly express classical toxic granule proteins, apoptosis-inducing ligands, as well as abundant activating and inhibitory receptors. Functionally, the iNK cells eradicate human tumor cells via mechanisms of direct cytotoxicity, apoptosis, and antibody-dependent cellular cytotoxicity. This study provides a reliable scale-up method for regenerating human NK cells from hPSCs, which promotes the universal availability of NK cell products for immune therapy.

11.
PLoS One ; 17(9): e0275249, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36170280

RESUMO

Based on annual data for 31 emerging and developing economies in the period 2000-2020, this paper explores the impact of global economic policy uncertainty on episodes of extreme international capital inflows. Following previous researches, we identify episodes of surges and stops. The results show that the global economic policy uncertainty can significantly increase the probability of surges and decrease the probability of stops in emerging and developing economies. The heterogeneity tests show that these effects vary with economic growth, financial development, the degree of economic globalization and global liquidity. Above effects are significant in the groups with higher economic growth, higher financial development, higher economic globalization and higher global liquidity. Further analyses show that as global economic policy uncertainty rises, its impact on surges and stops gradually declines. In addition, global economic policy uncertainty has a significant negative effect on the surge in advanced economies, which could confirm the above conclusion to a certain extent.


Assuntos
Desenvolvimento Econômico , Internacionalidade , Dióxido de Carbono , Incerteza
12.
Front Cell Dev Biol ; 10: 859769, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35573697

RESUMO

The intrinsic factors that determine the fundamental traits of engraftment ability and multi-lineage potential of hematopoietic stem cells (HSCs) remain elusive. The induction of bona fade HSCs from pluripotent stem cells (PSCs) in dishes is urgently demanded but remains a great challenge in translational medicine. Runx1, Hoxa9, Hlf, and Hoxa7 are developmentally co-expressed during endothelial-to-hematopoietic transition and adult haematopoiesis. However, the expression of these factors fails to be turned on during in vitro hematopoietic induction from PSCs. Here, we established an inducible gene over-expression embryonic stem cell (ESC) line in which exogenous Runx1, Hoxa9, Hlf, and Hoxa7 genes were tandemly knocked in. A population of induced hematopoietic progenitor cells (iHPCs) expressing Kit and Sca1 surface markers were successfully obtained in vitro from the gene edited-ESC line. Upon transplantation of the Runx1-Hoxa9-Hlf-Hoxa7 ESC-derived iHPCs into irradiated immunodeficient mice, they can dominantly contribute to B cells, low proportions of T cells and myeloid cells. However, Runx1-Hoxa9-Hlf ESC-derived iHPCs only produced B lineage cells with extremely low contributions. Our study unveils that the coordination of Runx1, Hoxa9, Hlf, and Hoxa7 led to generation of the hematopoietic progenitors with the capacity of multi-lineage hematopoietic reconstitution in the immunodeficient recipient mice.

13.
Sci Rep ; 12(1): 6856, 2022 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-35477990

RESUMO

The introduction of digital currency electronic payment (DCEP) by the Central Bank of China is conducive to the central bank's timely grasp of macroeconomic dynamics and the internationalization of RMB. As DCEP is one of the first digital currencies issued by the central bank to be used on a large scale internationally, it is necessary to conduct research on its user adoption. Therefore, this research extends the unified theory of acceptance and use of technology (UTAUT) to explore factors affecting the adoption of DCEP. The researchers cooperated with city banks that have started to use DCEP, and distributed questionnaires to users in the lobbies of these banks. A total of 295 valid questionnaires were empirically examined with Smart-PLS. The results indicate that perceived fairness, habits, social influence and national identity have significant effects on usage, with p values less than 0.05. National identity is shown to be a significant moderator of the relationships between perceived fairness, habit, perceived risk and usage, with p values less than 0.05. National identity is shown to have no moderating effect between social influence and usage, with a p value greater than 0.05. This research provides the central bank and the government with suggestions to increase user enthusiasm and reduce user perceived risks, thereby promoting the widespread use of DCEP.


Assuntos
Confidencialidade , Tecnologia , China , Inquéritos e Questionários
14.
Nat Food ; 3(7): 499-511, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-37117948

RESUMO

Adaptation based on social resilience is proposed as an effective measure to mitigate hunger and avoid food shocks caused by climate change. But these have not been investigated comprehensively in climate-sensitive regions. North Korea (NK) and its neighbours, South Korea and China, represent three economic levels that provide us with examples for examining climatic risk and quantifying the contribution of social resilience to rice production. Here our data-driven estimates show that climatic factors determined rice biomass changes in NK from 2000 to 2017, and climate extremes triggered reductions in production in 2000 and 2007. If no action is taken, NK will face a higher climatic risk (with continuous high-temperature heatwaves and precipitation extremes) by the 2080s under a high-emissions scenario, when rice biomass and production are expected to decrease by 20.2% and 14.4%, respectively, thereby potentially increasing hunger in NK. Social resilience (agricultural inputs and population development for South Korea; resource use for China) mitigated climate shocks in the past 20 years (2000-2019), even transforming adverse effects into benefits. However, this effect was not significant in NK. Moreover, the contribution of social resilience to food production in the undeveloped region (15.2%) was far below the contribution observed in the developed and developing regions (83.0% and 86.1%, respectively). These findings highlight the importance of social resilience to mitigate the adverse effects of climate change on food security and human hunger and provide necessary quantitative information.

15.
Chemosphere ; 291(Pt 2): 132813, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34752832

RESUMO

Selenium (Se) deficiency has been a public health concern for years. Arbuscular mycorrhizal fungi (AMF) play an essential role in improving Se uptake in crops, but related mechanisms still remain unclear. To explore the influence of AMF on uptake of Se in winter wheat, a pot experiment was conducted to inoculate wheat with Funneliformis mosseae (F.m) or not under different levels of selenate in soil. The present results indicated that inoculation of F.m significantly (p < 0.05) increased Se concentration in shoots and roots of wheat under low level of selenate (≤5.0 mg kg-1) treatments, while the contrary pattern was recorded under high level of selenate (15 and 20 mg kg-1) treatments. Moreover, inoculation of F.m significantly increased concentration of available Se in soil by 4.68-34.05%. Under selenate ≤5 mg kg-1 treatments, the expression of TaeSultr1;1 and TaeSultr1;3 in roots of mycorrhizal wheat was significantly up-regulated by 3.06-5.53 and 0.63-5.12 times, while reached saturation under selenate >5 mg kg-1 treatments. In addition, partial least squares path modeling (PLS-PM) showed that inoculation of AMF directly affected the expression of sulfate transporter and that both sulfate transporter and soil Se fractions played a significant positive effect on plant Se content. The present study indicated that AMF on Se concentration in winter wheat depends on the level of selenate spiked in soil and added to our understanding of the functions and applications of AMF on crop Se absorption.


Assuntos
Micorrizas , Selênio , Raízes de Plantas , Ácido Selênico , Solo , Triticum
16.
Talanta ; 239: 123088, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34838324

RESUMO

Both single-atom nanozymes (SAzymes) and protein-template metal nanoparticles have attracted comprehensive attention in several respects owing to their excellent catalytic performance, green facile synthesis process, and robustness. Herein, the peroxidase-like activity of single-atom copper anchored on bovine hemoglobin-template gadolinium nanoparticles (Cu,Gd@BHbFITC NPs) were successfully synthesized and two sensitive turn-on fluorescence strategies for tyrosinase (TYR) activity sensing were proposed for the first time. For strategy Ⅰ, TYR sensing was carried out from 1.00 to 7.80 U/mL with the detection limit (LOD) of 0.20 U/mL based on the fluorescence resonance energy transfer (FRET) between the fluorescein isothiocyanate (FITC) and the in situ generated polydopamine dots (PDA-dots). For strategy Ⅱ, The LOD of TYR was 0.05 U/mL with the linear range of 0.40-19.70 U/mL based on the elimination of inner-filter effect (IEF) between FITC and the reaction product (RC) of phenol and 4-Aminoantipyrine (AAP). The smartphone-assisted sensing platform was applied to construct the on-site detection of TYR with both strategies. The developed probe possessed good selectivity and was successfully utilized to TYR detection in serum samples.


Assuntos
Nanopartículas Metálicas , Peroxidase , Transferência Ressonante de Energia de Fluorescência , Monofenol Mono-Oxigenase , Peroxidases
17.
Cell Mol Immunol ; 19(4): 492-503, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34893754

RESUMO

Regeneration of functional B lymphopoiesis from pluripotent stem cells (PSCs) is challenging, and reliable methods have not been developed. Here, we unveiled the guiding role of three essential factors, Lhx2, Hoxa9, and Runx1, the simultaneous expression of which preferentially drives B lineage fate commitment and in vivo B lymphopoiesis using PSCs as a cell source. In the presence of Lhx2, Hoxa9, and Runx1 expression, PSC-derived induced hematopoietic progenitors (iHPCs) immediately gave rise to pro/pre-B cells in recipient bone marrow, which were able to further differentiate into entire B cell lineages, including innate B-1a, B-1b, and marginal zone B cells, as well as adaptive follicular B cells. In particular, the regenerative B cells produced adaptive humoral immune responses, sustained antigen-specific antibody production, and formed immune memory in response to antigen challenges. The regenerative B cells showed natural B cell development patterns of immunoglobulin chain switching and hypermutation via cross-talk with host T follicular helper cells, which eventually formed T cell-dependent humoral responses. This study exhibits de novo evidence that B lymphopoiesis can be regenerated from PSCs via an HSC-independent approach, which provides insights into treating B cell-related deficiencies using PSCs as an unlimited cell resource.


Assuntos
Linfopoese , Células-Tronco Pluripotentes , Linfócitos B , Medula Óssea , Diferenciação Celular , Linfopoese/genética , Células Precursoras de Linfócitos B
18.
Sensors (Basel) ; 21(22)2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34833536

RESUMO

Phase-sensitive optical time domain reflectometer (Φ-OTDR) has attracted attention in scientific research and industry because of its distributed dynamic linear response to external disturbances. However, the signal-to-noise ratio (SNR) of Φ-OTDR is still a limited factor by the weak Rayleigh Backscattering coefficient. Here, the multi-transverse modes heterodyne matched-filtering technology is proposed to improve the system SNR. The capture efficiency and nonlinear threshold are increased with multiple transverse modes in few-mode fibers; the incident light energy is permitted to be enlarged by a wider probe pulse by using heterodyne matched-filtering without spatial resolution being deteriorated. As far as we know, this is the first time that both multi-transverse modes integration method and digital heterodyne matched filtering method have been used to improve the SNR of Φ-OTDR simultaneously. Experimental results show that the noise floor is reduced by 11.4 dB, while the target signal is kept. We believe that this proposed method will help DAS find important applications in marine acoustic detection and seismic detection.

19.
Opt Express ; 29(3): 3147-3162, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33770920

RESUMO

In this letter, a distributed optical fiber hydrophone (DOFH) based on Φ-OTDR is demonstrated and tested in the field. The specially designed sensitized optical cable with sensitivity up to -146 dB rad/µPa/m is introduced, and an array signal processing model for DOFH is constructed to analyze the equivalence and specificity of the distributed array of acoustic sensors. In the field test, a 104-meter-long optical cable and a Φ-OTDR system based on heterodyne coherent detection (Het Φ-OTDR) is utilized, and underwater acoustic signal spatial spectrum estimation, beamforming and motion trajectory tracking with high accuracy can be realized. As far as we know, this is the first report on the field trial of DOFH based on Φ-OTDR. The DOFH has the potential to achieve an array range of tens of kilometers, with elements spaced up to the meter level and flexible configuration, which has a broad application prospect for marine acoustic detection.

20.
Leukemia ; 34(11): 2903-2913, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32733012

RESUMO

The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49-8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9-8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1-7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.


Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Terapia de Alvo Molecular , Mutação , Adulto , Idoso , Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Compostos de Anilina/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Medula Óssea/patologia , Análise Mutacional de DNA , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Isocitrato Desidrogenase/metabolismo , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
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