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1.
Materials (Basel) ; 17(3)2024 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-38591591

RESUMO

To investigate the effect of the sintering temperature on the microstructure characteristics of porous NiTi alloys, two types of porous NiTi alloys with equal atomic ratios were fabricated via elemental powder sintering at 950 °C and 1000 °C. Afterwards, optical microscopy (OM), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were collectively applied to investigate the pore characteristics and microstructure of the fabricated porous NiTi alloy. The results show that when the sintering temperature increases from 950 °C to 1000 °C, the average pore size increases from 36.00 µm to 181.65 µm, owing to the integration of these newly formed small pores into these pre-existing large-sized pores. The measured density increases from 2.556 g/cm3 to 3.030 g/cm3, while the porosity decreases from 60.4% to 51.8%. This is due to the occurrence of shrinkage after the sufficient diffusion of atoms. Furthermore, the characterization results confirm that a change in the sintering temperature would not change the phase types within a porous NiTi alloy; namely, the matrix consists primarily of B2 NiTi, with a significant amount of Ni4Ti3 precipitates and a small amount of Ni3Ti precipitates and Ti2Ni precipitates. However, as the sintering temperature increases, the number of Ni4Ti3 precipitates decreases significantly. The formation of a Ni4Ti3 phase in the present study is closely related to the enrichment of Ni content in the matrix owing to the diffusion rate difference between Ni atoms and Ti atoms and the absence of a transient liquid phase (TLP) during the sintering process owing to the relatively low sintering temperature (lower than the eutectic temperature). Moreover, the increasing sintering temperature speeds up the atom diffusion, which contributes to a reduction in the enrichment of Ni as well as the number of formed Ni4Ti3 precipitates.

2.
J Pharm Biomed Anal ; 244: 116129, 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38579408

RESUMO

Oligosaccharides constitute fundamental components in numerous traditional Chinese medicines (TCMs). Conventional chromatographic methods for natural product analysis are not suitable for oligosaccharides due to their large polarity and structural similarity. Herein, an ultra-high performance liquid chromatography with charged aerosol detector (UHPLC-CAD) method was developed for the profiling of oligosaccharides using 9 neutral (DP3-DP11) reference oligosaccharides. Various factors, including columns, mobile phase, elution conditions, flow rate, and column temperature were systematically examined. Optimal separation was achieved using an Amide column with gradient elution within 18 min, at 0.5 mL/min flow rate and 30°C column temperature. Moreover, an ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) method was also optimized to provide structural information. The developed method was applied to detect oligosaccharides in several TCMs, including Morindae Officinalis Radix (MOR), Ziziphi Spinosae Semen (ZSS), Menthae Haplocalycis Herba (MHH) and Chrysanthemi Indici Flos (CIF), revealing 9 and 16 oligosaccharides being uncovered from MHH and CIF respectively for the first time. This study presents a versatile UHPLC-CAD and UHPLC-Q-TOF/MS method with the potential for advancing oligosaccharides discovery and contributing to the quality analysis of TCMs.

3.
J Colloid Interface Sci ; 665: 573-581, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38552574

RESUMO

Designing efficient and cost-effective electrocatalysts for overall water splitting remains a major challenge in hydrogen production. Herein, ammonia was introduced to pyrophosphate chelating solution assisted Ni particles preferential plating on porous Fe substrate to form coral-like Ni/NiFe-Pyro electrode. The pyrophosphate with multiple complex sites can couple with nickel and iron ions to form an integrated network structure, which also consists of metallic nickel due to the introduction of ammonia. The large network structure in Ni/NiFe-Pyro significantly enhances the synergistic effect between nickel and iron and then improves the electrocatalytic performance. As a result, the coral-like Ni/NiFe-Pyro@IF exhibits good electrocatalytic activity and stability for oxygen evolution reaction (OER) and hydrogen evolution reaction (HER). The electrolyzer assembled with Ni/NiFe-Pyro@IF as cathode and anode just needs a low water-splitting voltage of 1.54 V to obtain the current density of 10 mA cm-2. Meanwhile, the stability test of Ni/NiFe-Pyro@IF is performed at the current densities ranging from 10 to 400 mA cm-2 for 50 h without any significant decay, indicating robust catalytic stability for overall water splitting. This strategy for synthesizing metal/metal pyrophosphate composites may provide a new avenue for future studies of efficient bifunctional electrocatalysts.

4.
Eur J Med Chem ; 268: 116281, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38432058

RESUMO

Aberrant signaling via fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFR4 is a promising target for anticancer therapy. Herein, we designed and synthesized a series of bis-acrylamide covalent FGFR4 inhibitors and evaluated their inhibitory activity against FGFRs, FGFR4 mutants, and their antitumor activity. CXF-007, verified by mass spectrometry and crystal structures to form covalent bonds with Cys552 of FGFR4 and Cys488 of FGFR1, exhibited stronger selectivity and potent inhibitory activity for FGFR4 and FGFR4 cysteine mutants. Moreover, CXF-007 exhibited significant antitumor activity in hepatocellular carcinoma cell lines and breast cancer cell lines through sustained inhibition of the FGFR4 signaling pathway. In summary, our study highlights a novel covalent FGFR4 inhibitor, CXF-007, which has the potential to overcome drug-induced FGFR4 mutations and might provide a new strategy for future anticancer drug discovery.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos , Antineoplásicos/química , Transdução de Sinais , Células MCF-7 , Fosforilação , Neoplasias Hepáticas/tratamento farmacológico , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral
5.
Se Pu ; 42(3): 234-244, 2024 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-38503700

RESUMO

Ziziphi Spinosae Semen refers to the dried seed of Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou. The seed is composed of a reddish brown coat and a yellow kernel. A comparative study was conducted to investigate differences in the chemical composition and their relative contents between the seed coat and kernel of Ziziphi Spinosae Semen. First, the chemical compounds found in the seed coat and kernel were characterized and identified using ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). The analytical results tentatively identified 57 chemical compounds based on reference-compound comparison, literature retrieval, and chemical-database (e. g., MassBank) searches; these compounds included 14 triterpenes, 23 flavonoids, 7 alkaloids, 6 carboxylic acids, and 7 other types of compounds. The mass error of the identified compounds was within the mass deviation range of 5×10-6 (5 ppm). Next, two methods of multivariate statistical analysis, namely, principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA), were used to compare the differential compounds between the two seed parts. A total of 17 differential compounds were screened out via OPLS-DA based on a variable importance in projection (VIP) value of >5. The results revealed that betulinic acid, betulonic acid, alphitolic acid, and jujuboside Ⅰ mainly existed in the seed coat whereas the 13 other compounds, such as spinosin, jujuboside A, and 6‴-feruloylspinosin, mainly existed in the seed kernel. Therefore, these 17 differential compounds can be used to distinguish between the two seed parts. Finally, a semiquantitative method was established using UPLC and a charged aerosol detector (CAD) with inverse gradient compensation in the mobile phase. Six representative compounds with different types were selected to examine the CAD response consistency: magnoflorine (alkaloid), spinosin (flavone), 6‴-feruloylspinosin (flavone), jujuboside A (triterpenoid saponin), jujuboside B (triterpenoid saponin), and betulinic acid (triterpenoid acid). The results showed that the relative standard deviation (RSD) of the average response factors at different levels of these six compounds was 7.04% and that their response intensities were similar. Moreover, each compound in the fingerprint demonstrated good response consistency, and the peak areas obtained directly reflected the contents of each compound. Based on the semiquantitative fingerprints obtained, betulinic acid and oleic acid were considered the main components of the seed coat. The betulinic acid content in the seed coat was approximately 7 times higher than that in the seed kernel. Spinosin, jujuboside A, linoleic acid, betulinic acid, and oleic acid were the main components of the seed kernel. The spinosin content in the seed kernel was 18 times higher than that in the seed coat. In addition, the jujuboside A content in the seed kernel was 24 times higher than that in the seed coat. The proposed method can accurately determine the main components and compare the relative contents of these components in different seed parts. In summary, this study identified the differences in chemical components between the seed coat and kernel of Ziziphi Spinosae Semen and clarified the main components and their relative contents in these parts. The findings can not only provide a basis for the identification of chemical compounds and quality research on different parts of Ziziphi Spinosae Semen but also promote the development and utilization of this traditional Chinese medicine.


Assuntos
Alcaloides , Medicamentos de Ervas Chinesas , Flavonas , Saponinas , Triterpenos , Ziziphus , Medicamentos de Ervas Chinesas/química , Ácido Betulínico , Saponinas/química , Ácidos Oleicos , Cromatografia Líquida de Alta Pressão , Ziziphus/química , Sementes
6.
Anal Chem ; 96(8): 3553-3560, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38362858

RESUMO

Lead halide perovskite nanocrystals with excellent photophysical properties are promising electrochemiluminescence (ECL) candidates, but their poor stability greatly restricts ECL applications. Herein, hydrogen-bonded cocrystal-encapsulated CsPbBr3 perovskite nanocrystals (PeNCs@NHS-M) were synthesized by using PeNCs as nuclei for inducing the crystallization of melamine (M) and N-hydroxysuccinimide (NHS). The as-synthesized composite exhibits multiplicative ECL efficiencies (up to 24-fold that of PeNCs) without exogenous coreactants and with excellent stability in the aqueous phase. The enhanced stability can be attributed to the well-designed heterostructure of the PeNCs@NHS-M composite, which benefits from both moiety passivation and protection of the peripheral cocrystal matrix. Moreover, the heterostructure with covalent linkage facilitates charge transfer between PeNCs and NHS-M cocrystals, realizing effective ECL emission. Meanwhile, the NHS and M components act as coreactants for PeNCs, shortening the electron-transport distance and resulting in a significant increase in the ECL signal. Furthermore, by taking advantage of the specific binding effect between NHS-M and uranyl (UO22+), an ECL system with both a low detection limit (1 nM) and high selectivity for monitoring UO22+ in mining wastewater is established. The presence of UO22+ disrupted the charge-transfer effect within PeNCs@NHS-M, weakening the ECL signals. This work provides an efficient design strategy for obtaining stable and efficient ECLs from perovskite nanocrystals, offering a new perspective for the discovery and application of perovskite-based ECL systems.

7.
Phytochemistry ; 220: 113996, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38311150

RESUMO

The study entailed the investigation of the roots of Euphorbia wallichii, which resulted in the isolation of 29 ent-atisane diterpenoids (1-29), 14 of which were previously unknown. These previously undescribed ones were named euphorwanoids A-N (3-5, 7, 9, and 10-18). Various techniques, including comprehensive spectroscopic methods and calculated electronic circular dichroism, were employed to determine their molecular structures. Additionally, the absolute configurations of ten ent-atisane diterpenoids (1, 2, 5, 6, 8, 9, 11, 12, 14 and 16) were established through X-ray crystallographic analyses. All isolated compounds' potential to inhibit the influenza A virus in vitro were evaluated. Compounds 18, 20, and 24 exhibited notable antiviral activity against the A/Puerto Rico/8/1934 strain. Their effective concentrations for reducing viral activity (EC50 values) were found to be 8.56, 1.22, and 4.97 µM, respectively. An intriguing aspect of this research is that it marks the first instance of ent-atisane diterpenes displaying anti-H1N1 activity. Empirical NMR rules were established with Δδ to distinguish the R/S configurations of C-13 and C-16 in ent-atisanes.


Assuntos
Diterpenos , Euphorbia , Euphorbia/química , Estrutura Molecular , Diterpenos/química , Dicroísmo Circular , Espectroscopia de Ressonância Magnética
8.
iScience ; 27(3): 109172, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38414864

RESUMO

Energy metabolism in the context of erythropoiesis and related diseases remains largely unexplored. Here, we developed a primary cell model by differentiating hematopoietic stem progenitor cells toward the erythroid lineage and suppressing the mitochondrial oxidative phosphorylation (OXPHOS) pathway. OXPHOS suppression led to differentiation failure of erythroid progenitors and defects in ribosome biogenesis. Ran GTPase-activating protein 1 (RanGAP1) was identified as a target of mitochondrial OXPHOS for ribosomal defects during erythropoiesis. Overexpression of RanGAP1 largely alleviated erythroid defects resulting from OXPHOS suppression. Coenzyme Q10, an activator of OXPHOS, largely rescued erythroid defects and increased RanGAP1 expression. Patients with Diamond-Blackfan anemia (DBA) exhibited OXPHOS suppression and a concomitant suppression of ribosome biogenesis. RNA-seq analysis implied that the substantial mutation (approximately 10%) in OXPHOS genes accounts for OXPHOS suppression in these patients. Conclusively, OXPHOS disruption and the associated disruptive mitochondrial energy metabolism are linked to the pathogenesis of DBA.

9.
Transl Oncol ; 42: 101894, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38324961

RESUMO

PURPOSE: The presence of lymphovascular invasion (LVI) influences the management and outcomes of patients with clinical stage IA lung adenocarcinoma. The objective was the development of a deep learning (DL) signature for the prediction of LVI and stratification of prognosis. METHODS: A total of 2077 patients from three centers were retrospectively enrolled and divided into a training set (n = 1515), an internal validation set (n = 381), and an external set (n = 181). A -three-dimensional residual neural network was used to extract the DL signature and three models, namely, the clinical, DL, and combined models, were developed. Diagnostic efficiency was assessed by ROC curves and AUC values. Kaplan-Meier curves and Cox proportional hazards regression analyses were conducted to evaluate links between various factors and disease-free survival. RESULTS: The DL model could effectively predict LVI, shown by AUC values of 0.72 (95 %CI: 0.68-0.76) and 0.63 (0.54-0.73) in the internal and external validation sets, respectively. The incorporation of DL signature and clinical-radiological factors increased the AUC to 0.74 (0.71-0.78) and 0.77 (0.70-0.84) in comparison with the DL and clinical models (AUC of 0.71 [0.68-0.75], 0.71 [0.61-0.81]) in the internal and external validation sets, respectively. Pathologic LVI, LVI predicted by both DL and combined models were associated with unfavorable prognosis (all p < 0.05). CONCLUSION: The effectiveness of the DL signature in the diagnosis of LVI and prognosis prediction in patients with clinical stage IA lung adenocarcinoma was demonstrated. These findings suggest the potential of the model in clinical decision-making.

10.
Sensors (Basel) ; 24(3)2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38339746

RESUMO

Compared with traditional two-level inverters, multilevel inverters have many solid-state switches and complex composition methods. Therefore, diagnosing and treating inverter faults is a prerequisite for the reliable and efficient operation of the inverter. Based on the idea of intelligent complementary fusion, this paper combines the genetic algorithm-binary granulation matrix knowledge-reduction method with the extreme learning machine network to propose a fault-diagnosis method for multi-tube open-circuit faults in T-type three-level inverters. First, the fault characteristics of power devices at different locations of T-type three-level inverters are analyzed, and the inverter output power and its harmonic components are extracted as the basis for power device fault diagnosis. Second, the genetic algorithm-binary granularity matrix knowledge-reduction method is used for optimization to obtain the minimum attribute set required to distinguish the state transitions in various fault cases. Finally, the kernel attribute set is utilized to construct extreme learning machine subclassifiers with corresponding granularity. The experimental results show that the classification accuracy after attribute reduction is higher than that of all subclassifiers under different attribute sets, reflecting the advantages of attribute reduction and the complementarity of different intelligent diagnosis methods, which have stronger fault-diagnosis accuracy and generalization ability compared with the existing methods and provides a new way for hybrid intelligent diagnosis.

11.
J Med Chem ; 67(4): 2667-2689, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38348819

RESUMO

Fibroblast growth factor receptor 4 (FGFR4) has been considered as a potential anticancer target due to FGF19/FGFR4 mediated aberrant signaling in hepatocellular carcinoma (HCC). Several FGFR4 inhibitors have been reported, but none have gained approval. Herein, a series of 5-formyl-pyrrolo[3,2-b]pyridine-3-carboxamides and a series of 6-formylpyridyl ureas were characterized as selective reversible-covalent FGFR4 inhibitors. The representative 6-formylpyridyl urea 8z exhibited excellent potency against FGFR4WT, FGFR4V550L, and FGFR4V550M with IC50 values of 16.3, 12.6, and 57.3 nM, respectively. It also potently suppressed proliferation of Ba/F3 cells driven by FGFR4WT, FGFR4V550L, and FGFR4V550M, and FGFR4-dependent Hep3B and Huh7 HCC cells, with IC50 values of 1.2, 13.5, 64.5, 15.0, and 20.4 nM, respectively. Furthermore, 8z displayed desirable microsomal stability and significant in vivo efficacy in the Huh7 HCC cancer xenograft model in nude mice. The study provides a promising new lead for anticancer drug discovery directed toward overcoming FGFR4 gatekeeper mutation mediated resistance in HCC patients.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Humanos , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos , Ureia/farmacologia , Ureia/uso terapêutico , Camundongos Nus , Fatores de Crescimento de Fibroblastos/metabolismo , Linhagem Celular Tumoral
13.
Clin Cancer Res ; 30(6): 1143-1151, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38170574

RESUMO

PURPOSE: Patient-tailored minimal residual disease (MRD) monitoring based on circulating tumor DNA (ctDNA) sequencing of leukemia-specific mutations enables early detection of relapse for pre-emptive treatment, but its utilization in pediatric acute myelogenous leukemia (AML) is scarce. Thus, we aim to examine the role of ctDNA as a prognostic biomarker in monitoring response to the treatment of pediatric AML. EXPERIMENTAL DESIGN: A prospective longitudinal study with 50 children with AML was launched, and sequential bone marrow (BM) and matched plasma samples were collected. The concordance of mutations by next-generation sequencing-based BM-DNA and ctDNA was evaluated. In addition, progression-free survival (PFS) and overall survival (OS) were estimated. RESULTS: In 195 sample pairs from 50 patients, the concordance of leukemia-specific mutations between ctDNA and BM-DNA was 92.8%. Patients with undetectable ctDNA were linked to improved OS and PFS versus detectable ctDNA in the last sampling (both P < 0.001). Patients who cleared their ctDNA post three cycles of treatment had similar PFS compared with persistently negative ctDNA (P = 0.728). In addition, patients with >3 log reduction but without clearance in ctDNA were associated with an improved PFS as were patients with ctDNA clearance (P = 0.564). CONCLUSIONS: Thus, ctDNA-based MRD monitoring appears to be a promising option to complement the overall assessment of pediatric patients with AML, wherein patients with continuous ctDNA negativity have the option for treatment de-escalation in subsequent therapy. Importantly, patients with >3 log reduction but without clearance in ctDNA may not require an aggressive treatment plan due to improved survival, but this needs further study to delineate.


Assuntos
DNA Tumoral Circulante , Leucemia Mieloide Aguda , Humanos , Criança , DNA Tumoral Circulante/genética , Neoplasia Residual/genética , Neoplasia Residual/diagnóstico , Estudos Prospectivos , Estudos Longitudinais , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Medição de Risco , Biomarcadores Tumorais/genética
14.
iScience ; 27(1): 108712, 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38205257

RESUMO

Pathologic visceral pleural invasion (VPI) in patients with early-stage lung cancer can result in the upstaging of T1 to T2, in addition to having implications for surgical resection and prognostic outcomes. This study was designed with the goal of establishing and validating a CT-based deep learning (DL) model capable of predicting VPI status and stratifying patients based on their prognostic outcomes. In total, 2077 patients from three centers with pathologically confirmed clinical stage IA lung adenocarcinoma were enrolled. DL signatures were extracted with a 3D residual neural network. DL model was able to effectively predict VPI status. VPI predicted by the DL models, as well as pathologic VPI, was associated with shorter disease-free survival. The established deep learning signature provides a tool capable of aiding the accurate prediction of VPI in patients with clinical stage IA lung adenocarcinoma, thus enabling prognostic stratification.

15.
Small ; : e2310672, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38229539

RESUMO

At present, poor stability and carrier transfer efficiency are the main problems that limit the development of perovskite-based photoelectric technologies. In this work, hydrogen-bonded cocrystal-coated perovskite composite (PeNCs@NHS-M) is easily obtained by inducing rapid crystallization of melamine (M) and N-hydroxysuccinimide (NHS) with PeNCs as the nuclei. The outer NHS-M cocrystal passivates the undercoordinated lead atoms by forming covalent bonds, thereby greatly reducing the trap density while maintaining good structure stability for perovskite nanocrystals. Moreover, benefiting from the interfacial covalent band linkage and long-range ordered structures of cocrystals, the charge transfer efficiency is effectively enhanced and PeNCs@NHS-M displays superior photoelectric performance. Based on the excellent photoelectric performance and abundant active sites of PeNCs@NHS-M, photocatalytic reduction of uranium is realized. PeNCs@NHS-M exhibits U(VI) reduction removal capability of up to 810.1 mg g-1 in the presence of light. The strategy of cocrystals trapping perovskite nanocrystals provides a simple synthesis method for composites and opens up a new idea for simultaneously improving the stability and photovoltaic performance of perovskite.

16.
Medicine (Baltimore) ; 103(3): e35150, 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38241593

RESUMO

BACKGROUND: To explore the role of gender in the incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. METHODS: Two researchers search the PubMed Database, Embase Database and Cochrane Library Database from their establishment to October 2022, using Endnote software for document management and RevMan5.3 software for the meta-analysis of the included literature. A total of 11 studies are selected, including 5788 acute pulmonary embolism events and 391 patients (179 males and 212 females) with chronic thromboembolic pulmonary hypertension (CTEPH) under the stated conditions. The results show that there is no statistically significant difference in the incidence of CTEPH between males and females after PE (P = .28), with combined OR of 0.89 and 95% CI 0.72-1.10. RESULTS AND CONCLUSIONS: Gender is found to be absent as a factor in the incidence of CTEPH after acute pulmonary embolism. This may indicate that gender is not a risk factor for CTEPH and that female patients are not necessarily more likely to have a higher incidence than male patients. As such, accurate judgments should be made on the possible complications of all patients after acute pulmonary embolism, which will be conducive to early detection and intervention in the treatment of CTEPH.


Assuntos
Hipertensão Pulmonar , Embolia Pulmonar , Humanos , Masculino , Feminino , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/complicações , Incidência , Fatores Sexuais , Doença Crônica , Embolia Pulmonar/complicações , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/diagnóstico , Doença Aguda
17.
Commun Chem ; 7(1): 3, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38172256

RESUMO

Acquired drug resistance poses a challenge for single-target FGFR inhibitors, leading to the development of dual- or multi-target FGFR inhibitors. Sulfatinib is a multi-target kinase inhibitor for treating neuroendocrine tumors, selectively targeting FGFR1/CSF-1R. To elucidate the molecular mechanisms behind its binding and kinase selectivity, we determined the crystal structures of sulfatinib with FGFR1/CSF-1R. The results reveal common structural features and distinct conformational adaptability of sulfatinib in response to FGFR1/CSF-1R binding. Further biochemical and structural analyses disclose sensitivity of sulfatinib to FGFR/CSF-1R gatekeeper mutations. The insensitivity of sulfatinib to FGFR gatekeeper mutations highlights the indispensable interactions with the hydrophobic pocket for FGFR selectivity, whereas the rotatory flexibility may enable sulfatinib to overcome CSF-1RT663I. This study not only sheds light on the structural basis governing sulfatinib's FGFR/CSF-1R inhibition, but also provides valuable insights into the rational design of dual- or multi-target FGFR inhibitors with selectivity for CSF-1R and sensitivity to gatekeeper mutations.

19.
Blood ; 143(4): 320-335, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-37801708

RESUMO

ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer with resistant clonal propagation in recurrence. We performed high-throughput droplet-based 5' single-cell RNA with paired T-cell receptor (TCR) sequencing of paired diagnosis-relapse (Dx_Rel) T-ALL samples to dissect the clonal diversities. Two leukemic evolutionary patterns, "clonal shift" and "clonal drift" were unveiled. Targeted single-cell DNA sequencing of paired Dx_Rel T-ALL samples further corroborated the existence of the 2 contrasting clonal evolution patterns, revealing that dynamic transcriptional variation might cause the mutationally static clones to evolve chemotherapy resistance. Analysis of commonly enriched drifted gene signatures showed expression of the RNA-binding protein MSI2 was significantly upregulated in the persistent TCR clonotypes at relapse. Integrated in vitro and in vivo functional studies suggested that MSI2 contributed to the proliferation of T-ALL and promoted chemotherapy resistance through the posttranscriptional regulation of MYC, pinpointing MSI2 as an informative biomarker and novel therapeutic target in T-ALL.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Proteínas de Ligação a RNA , Humanos , Evolução Clonal/genética , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Recidiva , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Linfócitos T/metabolismo
20.
Blood Cells Mol Dis ; 104: 102793, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37659255

RESUMO

BACKGROUND: Unrelated umbilical cord blood transplantation (UCBT) for bone marrow failure (BMF) disorders using conditioning regimens without Anti-Thymocyte Globulin (ATG) has been used as an alternative transplantation for emerging patients without matched-sibling donors. Experience with this transplant modality in children is limited, especially as a secondary treatment for transplant failure patients. PROCEDURE: We retrospectively reviewed 17 consecutive bone marrow failure patients who underwent unrelated umbilical cord blood transplantation in our center and received conditioning regimens of Total Body Irradiation (TBI) or Busulfan (BU) + Fludarabine (FLU) + Cyclophosphamide (CY). RESULTS: Among the 17 BMF patients, 15 patients were treated with first cord blood transplantation and another 2 with secondary cord blood transplantation because of graft failure after first haploidentical stem cell transplantation at days +38 and +82. All patients engrafted with a median donor cell chimerism of 50 % at days +7 (range, 16 %-99.95 %) and finally rose to 100 % at days +30. Median time to neutrophil engraftment was 19 days (range, 12-30) and time to platelet engraftment was 32 days (range, 18-61). Pre-engraftment syndrome (PES) was found in 16 patients (94.11 %, 16/17). Cumulative incidence of grades II to IV acute GVHD was 58.8 % (95 % CI: 32.7-84.9 %), and 17.6 % (95 % CI: 2.6-37.9 %) of patients developed chronic GVHD. The 3-year overall survival (OS) and failure-free survival (FFS) rates were 92.86 ± 6.88 %. CONCLUSION: UCBT is an effective alternative treatment for bone marrow failure pediatric patients. TBI/BU + FLU + CY regimen ensure a high engraftment rate for unrelated umbilical cord blood transplantation, which overcomes the difficulty of graft failure. Secondary salvage use of cord blood transplantation may still be useful for patients who have failed after other transplantation.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Criança , Soro Antilinfocitário/uso terapêutico , Sangue Fetal , Estudos Retrospectivos , Condicionamento Pré-Transplante , Doença Enxerto-Hospedeiro/etiologia , Ciclofosfamida , Bussulfano/uso terapêutico , Transtornos da Insuficiência da Medula Óssea/terapia
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