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1.
Rinsho Ketsueki ; 65(8): 798-809, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-39231711

RESUMO

Myelofibrosis should be diagnosed according to the WHO classification (2022, 5th Ed.) and International Consensus Conference 2022 criteria. Testing for driver mutations in the three genes JAK2, CALR, and MPL is recommended to ensure a definitive diagnosis. Ruxolitinib is the only JAK inhibitor currently approved in Japan, but momelotinib is under regulatory review. The MOMENTUM study showed similar spleen volume reduction at 24 weeks and MFSAF-TSS reduction as the COMFORT study of ruxolitinib. Momelotinib acts on ACVR1 and, therefore, improves anemia through suppression of hepcidin. Anemia and/or transfusion dependency are known to be associated with overall survival duration. Consequently, supportive care measures such as ESA and danazol in lieu of transfusion should be considered in addition to JAK inhibitor selection. Mean survival after discontinuation of JAK inhibitors is 11 to 14 months. Pacritinib (not approved in Japan) is suitable for MF patients with thrombocytopenia. JAK inhibitor selection and supportive care by ESA or danazol in lieu of transfusion should be considered. Many classes of drugs other than JAK inhibitors for myelofibrosis are under investigation.


Assuntos
Benzamidas , Inibidores de Janus Quinases , Nitrilas , Mielofibrose Primária , Pirazóis , Pirimidinas , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/diagnóstico , Humanos , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/farmacologia , Hidrocarbonetos Aromáticos com Pontes
2.
Anal Chem ; 96(36): 14490-14498, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39185815

RESUMO

Bacterial infections have emerged as a significant contributor to global mortality and morbidity rates. Herein, we introduce a dual fluorescence "turn-on" supramolecular sensor array composed of three assembled complexes (C1-C3), formed from three positively charged fluorophores (A1-A3) and one cucurbit[7]uril (CB[7]). The ability of this three-element array to simultaneously recognize 10 bacterial species within just 30 s was remarkable, boasting an impressive 100% accuracy. Additionally, the array excelled at distinguishing among various bacterial mixtures and enabled the quantitative detection of common bacterial strains. Notably, it has been skillfully applied to differentiate 10 bacterial samples in urine, achieving excellent differentiation and showcasing promising potential for medical diagnostic applications.


Assuntos
Hidrocarbonetos Aromáticos com Pontes , Corantes Fluorescentes , Imidazóis , Imidazóis/química , Hidrocarbonetos Aromáticos com Pontes/química , Corantes Fluorescentes/química , Bactérias/isolamento & purificação , Humanos , Espectrometria de Fluorescência , Compostos Heterocíclicos com 2 Anéis , Compostos Macrocíclicos , Imidazolidinas
3.
Sci Rep ; 14(1): 19075, 2024 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-39154055

RESUMO

Human induced pluripotent stem cell-derived sensory neuron (iPSC-dSN) models are a valuable resource for the study of neurotoxicity but are affected by poor replicability and reproducibility, often due to a lack of optimization. Here, we identify experimental factors related to culture conditions that substantially impact cellular drug response in vitro and determine optimal conditions for improved replicability and reproducibility. Treatment duration and cell seeding density were both found to be significant factors, while cell line differences also contributed to variation. A replicable dose-response in viability was demonstrated after 48-h exposure to docetaxel or paclitaxel. Additionally, a replicable dose-dependent reduction in neurite outgrowth was demonstrated, demonstrating the applicability of the model for the examination of additional phenotypes. Overall, we have established an optimized iPSC-dSN model for the study of taxane-induced neurotoxicity.


Assuntos
Sobrevivência Celular , Células-Tronco Pluripotentes Induzidas , Células Receptoras Sensoriais , Taxoides , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/citologia , Taxoides/farmacologia , Células Receptoras Sensoriais/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/farmacologia , Síndromes Neurotóxicas/etiologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Diferenciação Celular/efeitos dos fármacos , Paclitaxel/farmacologia , Paclitaxel/toxicidade , Linhagem Celular , Células Cultivadas
4.
Sci Rep ; 14(1): 19530, 2024 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-39174604

RESUMO

Macular edema is a known side effect of taxane-based anticancer drugs. We retrospectively investigated data from 11 centers between January 2016 and December 2021. Among 14,260 patients, 30 (0.21%) developed macular edema; from these, the number of cases associated with nab-paclitaxel was 16 (0.43%), significantly higher than the number of cases associated with paclitaxel or docetaxel (P < 0.01). Visual acuity (VA) and retinal choroidal change were examined in 27 patients, with a follow-up of at least 3 months. The patients' mean age was 67.2 years; 14 (51.3%) were male and four (14.8%) had unilateral onset. The mean interval between anticancer drug initiation and the first ophthalmology visit was 290.1 days. Among the 20 patients who discontinued anticancer drugs, VA and edema significantly improved 2 months after discontinuation (LogMAR VA: 0.50 vs. 0.28, central retinal thickness: 472.7 µm vs. 282.5 µm, both P < 0.01). No significant changes were observed in the central choroidal thickness. A correlation was found between duration of taxane treatment and VA immediately before discontinuation of anticancer drugs (ß = 0.00050; 95% confidence interval: 0.00036-0.00097; P < 0.05). Although taxane-induced macular edema is reversible, slower anticancer drug discontinuation worsened VA, highlighting the need for regular ophthalmologic evaluation during treatments.


Assuntos
Edema Macular , Taxoides , Acuidade Visual , Humanos , Feminino , Edema Macular/induzido quimicamente , Edema Macular/tratamento farmacológico , Masculino , Idoso , Estudos Retrospectivos , Japão/epidemiologia , Pessoa de Meia-Idade , Taxoides/efeitos adversos , Incidência , Prognóstico , Acuidade Visual/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Docetaxel/efeitos adversos , Paclitaxel/efeitos adversos , Retina/efeitos dos fármacos , Retina/patologia , Retina/diagnóstico por imagem
5.
Metab Eng ; 85: 201-212, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39197725

RESUMO

In the quest for innovative cancer therapeutics, paclitaxel remains a cornerstone in clinical oncology. However, its complex biosynthetic pathway, particularly the intricate oxygenation steps, has remained a puzzle in the decades following the characterization of the last taxane hydroxylase. The high divergence and promiscuity of enzymes involved have posed significant challenges. In this study, we adopted an innovative approach, combining in silico methods and functional gene analysis, to shed light on this elusive pathway. Our molecular docking investigations using a library of potential ligands uncovered TB574 as a potential missing enzyme in the paclitaxel biosynthetic pathway, demonstrating auspicious interactions. Complementary in vivo assays utilizing engineered S. cerevisiae strains as novel microbial cell factory consortia not only validated TB574's critical role in forging the elusive paclitaxel intermediate, T5αAc-1ß,10ß-diol, but also achieved the biosynthesis of paclitaxel precursors at an unprecedented yield including T5αAc-1ß,10ß-diol with approximately 40 mg/L. This achievement is highly promising, offering a new direction for further exploration of a novel metabolic engineering approaches using microbial consortia. In conclusion, our study not only furthers study the roles of previously uncharacterized enzymes in paclitaxel biosynthesis but also forges a path for pioneering advancements in the complete understanding of paclitaxel biosynthesis and its heterologous production. The characterization of T1ßOH underscores a significant leap forward for future advancements in paclitaxel production using heterologous systems to improve cancer treatment and pharmaceutical production, thereby holding immense promise for enhancing the efficacy of cancer therapies and the efficiency of pharmaceutical manufacturing.


Assuntos
Paclitaxel , Saccharomyces cerevisiae , Paclitaxel/biossíntese , Paclitaxel/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimologia , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Simulação de Acoplamento Molecular , Engenharia Metabólica , Taxoides/metabolismo , Hidrocarbonetos Aromáticos com Pontes
6.
Oral Oncol ; 158: 106997, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39159526

RESUMO

OBJECTIVES: Pembrolizumab +/- chemotherapy is standard therapy for r/m HNSCC. Despite regulatory approval of platinum/5FU/pembrolizumab, a taxane is often substituted for 5FU for convenience and tolerability. We aimed to characterize nationwide use patterns and compare outcomes between platinum/taxane/pembrolizumab vs platinum/5FU/pembrolizumab. METHODS: Patients in a US nationwide database with r/m HNSCC treated from 2017 to 2022 with pembrolizumab plus platinum chemotherapy were included. Demographic and cancer-specific characteristics were summarized. Overall survival (OS) was estimated using Kaplan-Meier methodology, and compared between groups using log-rank test and multivariable Cox regression. Time on treatment, number of cycles, receipt of second-line therapy, and toxicities were compared between groups. RESULTS: Of 438 patients, 320 (73 %) received 5FU and 118 (27 %) received a taxane. Taxane use became more frequent over time and was higher in academic vs community practices (51 % vs 23 %, p < 0.001). OS did not differ between taxane and 5FU groups (mOS 12.2 vs 13.4 months, p = 0.662). On multivariable Cox regression, HR for death associated with taxane vs 5FU was 0.99 (95 %CI 0.71-1.38). Receipt of 2L therapy was numerically higher for 5FU patients (46 %) compared to taxane patients (35 %, p = 0.071). Grade ≥ 3 anemia was more common in taxane patients (33 % vs 20 %, p = 0.003), whereas grade ≥ 3 lymphopenia and thrombocytopenia were numerically higher in 5FU patients. CONCLUSION: In patients with r/m HNSCC undergoing chemoimmunotherapy, taxane vs 5FU use varies by practice setting and geographical region. Platinum/taxane/pembrolizumab was associated with similar survival as platinum/5FU/pembrolizumab; these results suggest that chemoimmunotherapy with taxane is a reasonable alternative to 5FU.


Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Fluoruracila , Recidiva Local de Neoplasia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Taxoides , Humanos , Feminino , Masculino , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Pessoa de Meia-Idade , Taxoides/uso terapêutico , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila/uso terapêutico , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/mortalidade , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Platina/uso terapêutico , Adulto , Metástase Neoplásica , Estudos Retrospectivos
8.
J Am Chem Soc ; 146(36): 25383-25393, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39196894

RESUMO

The regulation of the cell membrane potential plays a crucial role in governing the transmembrane transport of various ions and cellular life processes. However, in situ and on-demand modulation of cell membrane potential for ion channel regulation is challenging. Herein, we have constructed a supramolecular assembly system based on water-soluble cationic oligo(phenylenevinylene) (OPV) and cucurbit[7]uril (CB[7]). The controllable disassembly of OPV/4CB[7] combined with the subsequent click reaction provides a step-by-step adjustable surface positive potential. These processes can be employed in situ on the plasma membrane to modulate the membrane potential on-demand for precisely controlling the activation of the transient receptor potential vanilloid 1 (TRPV1) ion channel and up-regulating exogenous calcium-responsive gene expression. Compared with typical optogenetics, electrogenetics, and mechanogenetics, our strategy provides a perspective supramolecular genetics toolbox for the regulation of membrane potential and downstream intracellular gene regulation events.


Assuntos
Imidazóis , Potenciais da Membrana , Imidazóis/química , Humanos , Hidrocarbonetos Aromáticos com Pontes/química , Polivinil/química , Membrana Celular/metabolismo , Membrana Celular/química , Canais de Cátion TRPV/metabolismo , Células HEK293 , Cálcio/metabolismo , Cálcio/química , Canais de Cálcio/metabolismo , Canais de Cálcio/química , Compostos Heterocíclicos com 2 Anéis , Compostos Macrocíclicos , Imidazolidinas
9.
Int J Mol Sci ; 25(16)2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39201534

RESUMO

The purpose of this study was to investigate whether and how albiflorin, a natural monoterpene glycoside, affects the release of glutamate, one of the most important neurotransmitters involved in neurotoxicity, from cerebrocortical nerve terminals (synaptosomes) in rats. The results showed that albiflorin reduced 4-aminopyridine (4-AP)-elicited glutamate release from synaptosomes, which was abrogated in the absence of extracellular Ca2+ or in the presence of the vesicular glutamate transporter inhibitor or a P/Q-type Ca2+ channel inhibitor, indicating a mechanism of action involving Ca2+-dependent depression of vesicular exocytotic glutamate release. Albiflorin failed to alter the increase in the fluorescence intensity of 3,3-diethylthiacarbocyanine iodide (DiSC3(5)), a membrane-potential-sensitive dye. In addition, the suppression of protein kinase A (PKA) abolished the effect of albiflorin on glutamate release. Albiflorin also reduced the phosphorylation of PKA and synaptosomal-associated protein of 25 kDa (SNAP-25) and synapsin I at PKA-specific residues, which correlated with decreased available synaptic vesicles. The results of transmission electron microscopy (TEM) also observed that albiflorin reduces the release competence of synaptic vesicles evoked by 4-AP in synaptosomes. In conclusion, by studying synaptosomally released glutamate, we suggested that albiflorin reduces vesicular exocytotic glutamate release by decreasing extracellular Ca2+ entry via P/Q-type Ca2+ channels and reducing PKA-mediated synapsin I and SNAP-25 phosphorylation.


Assuntos
Córtex Cerebral , Proteínas Quinases Dependentes de AMP Cíclico , Ácido Glutâmico , Sinaptossomos , Animais , Ácido Glutâmico/metabolismo , Sinaptossomos/metabolismo , Sinaptossomos/efeitos dos fármacos , Ratos , Córtex Cerebral/metabolismo , Córtex Cerebral/efeitos dos fármacos , Masculino , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Canais de Cálcio Tipo Q/metabolismo , Ratos Sprague-Dawley , Canais de Cálcio Tipo P/metabolismo , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Cálcio/metabolismo , Fosforilação/efeitos dos fármacos , Sinapsinas/metabolismo
10.
Talanta ; 280: 126722, 2024 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-39186860

RESUMO

Photodynamic therapy (PDT) has attracted widespread attention as a novel non-invasive anticancer approach. However, the diminished photosensitivity and limited oxygen exposure caused by the aggregation of traditional photosensitizers greatly impair its overall therapeutic efficacy. Herein, a series of water-soluble aggregation-induced emission luminogens (AIEgens) with triphenylamine as skeleton were synthesized and exhibited bright Near-infrared (NIR) emission and strong reactive oxygen species (ROS) generation. Through host-guest complexation between the multicharged triphenylamine units on AIEgens and cucurbit[10]uril (CB[10]) host molecule, supramolecular nanoassemblies were constructed and exhibited negligible phototoxicity to normal cells due to their limited oxygen contact. In contrast, the efficient release of AIEgens from nanoassemblies through competitive binding of overexpressed peptides in cancer cells with CB[10], enabled the full exploitation of the photosensitivity of AIEgens to produce highly efficient ROS, achieving selective ablation of cancer cells. Moreover, due to the restriction of intramolecular motion (RIM) upon anchored on organelle membranes through electrostatic interactions, the cationic AIEgens with weak fluorescence in physiological environment exhibited intense fluorescence emission, thus realizing imaging-guided PDT. This work may open up an avenue for the development of simple and feasible smart responsive nanomaterials for cancer treatment using supramolecular host-guest complexation strategy.


Assuntos
Fotoquimioterapia , Fármacos Fotossensibilizantes , Espécies Reativas de Oxigênio , Humanos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/síntese química , Espécies Reativas de Oxigênio/metabolismo , Imagem Óptica , Sobrevivência Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Neoplasias/tratamento farmacológico , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Linhagem Celular Tumoral , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Imidazóis/química , Imidazóis/farmacologia , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia
11.
Clin Transl Sci ; 17(8): e70018, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39189872

RESUMO

Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, splenomegaly, anemia, and constitutional symptoms, with a median survival of ≈6 years from diagnosis. While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis-related anemia, a negative prognostic factor for survival. Momelotinib is a novel JAK1/JAK2/activin A receptor type 1 (ACVR1) inhibitor approved in the US, European Union, and the UK and is the first JAK inhibitor indicated specifically for patients with myelofibrosis with anemia. Momelotinib not only addresses the splenomegaly and symptoms associated with myelofibrosis by suppressing the hyperactive JAK-STAT (signal transducer and activator of transcription) pathway but also improves anemia and reduces transfusion dependency through ACVR1 inhibition. The recommended dose of momelotinib is 200 mg orally once daily, which was established after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Momelotinib is metabolized primarily by CYP3A4 and excreted as metabolites in feces and urine. Steady-state maximum concentration is 479 ng/mL (CV%, 61%), with a mean AUCtau of 3288 ng.h/mL (CV%, 60%); its major metabolite, M21, is active (≈40% of pharmacological activity of parent), with a metabolite-to-parent AUC ratio of 1.4-2.1. This review describes momelotinib's mechanism of action, detailing how the JAK-STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk/benefit assessment.


Assuntos
Pesquisa Translacional Biomédica , Humanos , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/metabolismo , Benzamidas/farmacologia , Benzamidas/farmacocinética , Benzamidas/efeitos adversos , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Animais , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes
12.
Genes Genomics ; 46(9): 1107-1122, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39126602

RESUMO

BACKGROUND AND RESEARCH PURPOSE: Paeoniflorin and albiflorin are monoterpene glycosides that exhibit various medicinal properties in Paeonia species. This study explored the terpene biosynthesis pathway and analyzed the distribution of these compounds in different tissues of two Korean landraces of Paeonia lactiflora to gain insights into the biosynthesis of monoterpene glycosides in P. lactiflora and their potential applications. MATERIALS AND METHODS: Two Korean landraces, Hongcheon var. and Hwacheon var, of P. lactiflora were used for the analyses. Contents of the paeoniflorin and albiflorin were analyzed using HPLC. RNA was extracted, sequenced, and subjected to transcriptome analysis. Differential gene expression, KEGG, and GO analyses were performed. Paeoniflorin biosynthesis genes were isolated from the transcriptomes using the genes in Euphorbia maculata with the NBLAST program. Phylogenetic analysis of of 1-Deoxy-D-xylulose 5-phosphate synthase (DOXPS), geranyl pyrophosphate synthase (GPPS), and pinene synthase (PS) was carried out with ClustalW and MEGA v5.0. RESULTS AND DISCUSSION: Analysis of paeoniflorin and albiflorin content in different tissues of the two P. lactiflora landraces revealed significant variation. Transcriptome analysis yielded 36,602 unigenes, most of which were involved in metabolic processes. The DEG analysis revealed tissue-specific expression patterns with correlations between landraces. The isolation of biosynthetic genes identified 173 candidates. Phylogenetic analysis of the key enzymes in these pathways provides insights into their evolutionary relationships. The sequencing and analysis of DOXPS, GPPS, PS revealed distinct clades and subclades, highlighting their evolutionary divergence and functional conservation. Our findings highlight the roots as the primary sites of paeoniflorin and albiflorin accumulation in P. lactiflora, underscoring the importance of tissue-specific gene expression in their biosynthesis. CONCLUSION: this study advances our understanding of monoterpene glycoside production and distribution in Paeonia, thereby guiding further plant biochemistry investigations.


Assuntos
Glucosídeos , Monoterpenos , Paeonia , Paeonia/genética , Paeonia/metabolismo , Glucosídeos/metabolismo , Glucosídeos/biossíntese , Monoterpenos/metabolismo , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Filogenia , Regulação da Expressão Gênica de Plantas , Transcriptoma/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Vias Biossintéticas/genética
13.
World J Surg Oncol ; 22(1): 214, 2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-39164763

RESUMO

BACKGROUND: TCbHP (taxane + carboplatin + trastuzumab + pertuzumab) is the preferred neoadjuvant therapy regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, no consensus exists regarding whether specific populations may be exempt from carboplatin, allowing for de-escalation to the THP (taxane + trastuzumab + pertuzumab) regimen. Additionally, the optimal number of cycles for neoadjuvant THP remains unclear. We compared the efficacy and safety of neoadjuvant TCbHP and THP regimens, providing clinicians with a nuanced perspective to guide their treatment regimen selection. METHODS: This multicenter real-world study included patients with HER2-positive breast cancer undergoing neoadjuvant TCbHP or THP between March 2019 and February 2023. Efficacy was assessed through the pathological complete response (pCR) rate, while safety was evaluated through monitoring adverse events. RESULTS: Among 220 patients, 103 received 6 cycles of TCbHP (TCbHP×6), 83 received 6 cycles of THP (THP×6), and 34 received 4 cycles of THP (THP×4). The TCbHP×6 cohort exhibited a 66% pCR rate compared with 53% in the THP×6 cohort (P = 0.072). Subgroup analysis revealed that in patients aged ≤ 50 years, those with hormone receptor (HR)-negative status, and those with clinical stage T2, the pCR rate of the TCbHP×6 regimen was significantly higher than the THP×6 regimen (P < 0.05). The TCbHP×6 cohort reported higher frequencies of any-grade adverse events (99% versus 86.7%) and grade 3-4 events (49.5% versus 12%) than the THP×6 cohort. Propensity score matching identified 27 patient pairs between the THP×6 and THP×4 cohorts, indicating a significantly higher pCR rate for the THP×6 regimen than the THP×4 regimen (63% versus 29.6%, P = 0.029). CONCLUSIONS: The TCbHP×6 regimen is favored for individuals aged ≤ 50 years and those aged > 50, ≤60 years with HR-negative status or clinical stage T2-4. For patients in compromised general condition or lacking the specified indications, the THP×6 regimen emerges as a lower-toxicity alternative with satisfactory efficacy. To ensure treatment efficacy, a minimum of 6 cycles of neoadjuvant THP is required.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Carboplatina , Terapia Neoadjuvante , Receptor ErbB-2 , Taxoides , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Terapia Neoadjuvante/métodos , Carboplatina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptor ErbB-2/metabolismo , Pessoa de Meia-Idade , China/epidemiologia , Adulto , Taxoides/administração & dosagem , Seguimentos , Trastuzumab/administração & dosagem , Trastuzumab/uso terapêutico , Prognóstico , Estudos Retrospectivos , Idoso , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem
14.
Spectrochim Acta A Mol Biomol Spectrosc ; 323: 124906, 2024 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-39111032

RESUMO

A novel CB[6]-based supramolecular assembly [K(ANS)(CB[6])2(DMF)2(H2O)0.5] (1) (CB[6] = cucurbit[6]uril, ANS- = 8-amino-1-naphthalene sulfonic acid ion) was successfully synthesized under solvothermal condition. Performance studies have shown that 1 exhibited excellent chemical stability and recycling performance. Meanwhile, 1 exhibited remarkable potential as a fluorescence sensor for the detection of 2,4,6-trinitrophenol (TNP), 4-nitrophenol (4-NP), and rifampicin (RFP) in both aqueous environments and practical samples. This sensing capability is achieved through fluorescence quenching, which offers fast response times and exceptional sensitivity, with detection limits of 0.19 µM for both TNP and 4-NP, and 0.21 µM for RFP. Even more remarkably, an anti-counterfeiting ink based on 1 and a portable test hydrogel were devised for encrypting information and visually detecting using a smartphone application. This work has the potential to expand the utilization of CB[6]-based materials in optical applications.


Assuntos
Antibacterianos , Hidrocarbonetos Aromáticos com Pontes , Imidazóis , Espectrometria de Fluorescência , Hidrocarbonetos Aromáticos com Pontes/química , Espectrometria de Fluorescência/métodos , Imidazóis/química , Antibacterianos/análise , Antibacterianos/química , Nitrocompostos/análise , Nitrocompostos/química , Limite de Detecção , Corantes Fluorescentes/química , Compostos Heterocíclicos com 2 Anéis , Compostos Macrocíclicos , Imidazolidinas
15.
Acta Cir Bras ; 39: e393524, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39140524

RESUMO

PURPOSE: It has been reported that exhaustive exercise (EE) causes myocyte injury, and eventually damages the function of the myocardia. Albiflorin (AF) has anti-inflammatory, antioxidant, and anti-apoptosis effects. In this study, we determined whether AF could mitigate the EE-induced myocardial injury and research the potential mechanisms. METHODS: The rat model of EE was built by forced treadmill running method. Rats were intraperitoneally injected with AF before EE once daily for one week. The relative factors levels were examined by commercial kits. The apoptosis was appraised using a TdT-mediated dUTP nick end labeling assay kit. The ACSL4, GPX4, Nrf2, pAKT/AKT, and HO-1 contents were assessed by western blot. RESULTS: AF lessened EE-induced cardiac myocytes ischemic/hypoxic injury and reduced the contents of myocardial injury biomarkers in the serum. AF lessened EE-induced cardiac myocyte apoptosis, inflammatory response, oxidative stress, and ferroptosis in myocardial tissues. However, the influences of AF were overturned by the co-treatment of AF and LY294002. AF activated the AKT/Nrf2/HO-1 signaling pathway in myocardial tissues in vivo. CONCLUSIONS: AF could curb cardiac myocytes ferroptosis, thus diminishing the EE-induced myocardial injury through activating the AKT/Nrf2/HO-1 cascade.


Assuntos
Ferroptose , Miócitos Cardíacos , Fator 2 Relacionado a NF-E2 , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Masculino , Transdução de Sinais/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Ratos Sprague-Dawley , Heme Oxigenase-1/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Hidrocarbonetos Aromáticos com Pontes
16.
Artigo em Inglês | MEDLINE | ID: mdl-39068869

RESUMO

In this study, high-performance liquid chromatography was used to determine four components of Shaoyao Gancao Decoction (SGD), and the effect of purification was evaluated using fingerprints, similarity analysis and cell experiments. An effective method for isolation and purification of SGD was established. The adsorption/desorption properties of SGD were evaluated using resin screening, isothermal analysis, adsorption kinetics, and dynamic adsorption-desorption experiments. It was shown that the Langmuir equation fitted the isotherm data well and that a pseudo-second-order model accurately described kinetic adsorption on AB-8 resin. Analysis of thermodynamic parameters showed that the adsorption process was exothermic. Under the optimal process conditions, the concentrations of albiflorin, paeoniflorin, liquiritin and ammonium glycyrrhizinate in the product were 73.05, 134.04, 45.04 and 75.00 mg/g, respectively. The yields of the four components were 71.89 %-86.19 %. Cell experiments showed that the purified SGD retained anti-inflammatory activity. This research lays the foundation for the separation and purification of SGD and subsequent preparation research.


Assuntos
Medicamentos de Ervas Chinesas , Glucosídeos , Monoterpenos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Glucosídeos/isolamento & purificação , Glucosídeos/química , Monoterpenos/isolamento & purificação , Monoterpenos/química , Adsorção , Flavanonas/isolamento & purificação , Flavanonas/química , Flavanonas/análise , Animais , Ácido Glicirrízico/isolamento & purificação , Ácido Glicirrízico/química , Ácido Glicirrízico/análise , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/isolamento & purificação , Camundongos , Resinas Sintéticas/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/química , Humanos , Células RAW 264.7
17.
Leuk Res ; 144: 107547, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38968731

RESUMO

FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately one third of acute myeloid leukemia (AML) patients. FLT3-Internal tandem duplication (FLT3-ITD) mutations are the most common FLT3 mutations and are associated with a poor prognosis. Gilteritinib is a FLT3 inhibitor that is US FDA approved for treating adult patients with relapsed/refractory AML and a FLT3 mutation. While gilteritinib monotherapy has improved patient outcome, few patients achieve durable responses. Combining gilteritinib with venetoclax (VEN) appears to make further improvements, though early results suggest that patients with prior exposure to VEN fair much worse than those without prior exposure. MRX-2843 is a promising inhibitor of FLT3 and MERTK. We recently demonstrated that MRX-2843 is equally potent as gilteritinib in FLT3-ITD AML cell lines in vitro and primary patient samples ex vivo. In this study, we investigated the combination of VEN and MRX-2843 against FLT3-ITD AML cells. We found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-mutated AML cell lines and primary patient samples. Importantly, we found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-ITD AML cells with acquired resistance to cytarabine (AraC) or VEN+AraC. VEN and MRX-2843 significantly reduce colony-forming capacity of FLT3-ITD primary AML cells. Mechanistic studies show that MRX-2843 decreases Mcl-1 and c-Myc protein levels via transcriptional regulation and combined MRX-2843 and VEN significantly decreases oxidative phosphorylation in FLT3-ITD AML cells. Our findings highlight a promising combination therapy against FLT3-ITD AML, supporting further in vitro and in vivo testing.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Sulfonamidas , c-Mer Tirosina Quinase , Tirosina Quinase 3 Semelhante a fms , Humanos , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Sulfonamidas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , c-Mer Tirosina Quinase/genética , c-Mer Tirosina Quinase/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Mutação , Linhagem Celular Tumoral , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Sequências de Repetição em Tandem , Compostos de Anilina , Hidrocarbonetos Aromáticos com Pontes , Pirimidinas , Pirróis
18.
J Mol Graph Model ; 131: 108810, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38852429

RESUMO

Host-guest complex has attracted much attention because of their fantastic capability. Accurate prediction of their binding affinity and enthalpy is essential to the rational design of guest molecules. The attach-pull-release (APR) method proposed by Henriksen et al. (J. Chem. Theory Comput., 2015, 11:4377.) shows good prediction capability of binding affinity especially for host-guest system. In order to further evaluate the performance of APR method in practice, we have conducted the calculations on the macrocycle cucurbit [7]urils (CB7) encapsulated with four structurally similar alkaloids (berberine, coptisine, epiberberine and palmatine) with two force fields (GAFF and GAFF2) and three water models (TIP3P, SPC/E and OPC). Compared to the experimental data, the calculation by the combination of GAFF2 and SPC/E force field presents the best performance, of which the Pearson correlation coefficients (R2) is 0.95, and the root-mean-square-deviation is 3.04 kcal/mol. While the predictions from GAFF force field all overestimated the binding affinity, suggesting a systematic error may be involved. Comparison of calculation also indicates that the accuracy of prediction was susceptible to the combination of force field. Therefore, it would be necessary to repeat the simulation with different combination of force fields in practice.


Assuntos
Alcaloides , Hidrocarbonetos Aromáticos com Pontes , Simulação de Dinâmica Molecular , Termodinâmica , Alcaloides/química , Hidrocarbonetos Aromáticos com Pontes/química , Imidazóis/química , Água/química , Compostos Heterocíclicos com 2 Anéis , Compostos Macrocíclicos , Imidazolidinas
19.
Nature ; 632(8025): 543-549, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38862025

RESUMO

The carbon skeleton of any organic molecule serves as the foundation for its three-dimensional structure, playing a pivotal role in determining its physical and biological properties1. As such, taxane diterpenes are one of the most well-known natural product families, primarily owing to the success of their most prominent compound, paclitaxel, an effective anticancer therapeutic for more than 25 years2-6. In contrast to classical taxanes, the bioactivity of cyclotaxanes (also referred to as complex taxanes) remains significantly underexplored. The carbon skeletons of these two groups of taxanes differ significantly, and so would typically their own distinct synthetic approaches. Here we report a versatile synthetic strategy based on the interconversion of complex molecular frameworks, providing general access to the wider taxane diterpene family. A range of classical and cyclotaxane frameworks was prepared including, among others, the total syntheses of taxinine K (2), canataxapropellane (5) and dipropellane C from a single advanced intermediate. The synthetic approach deliberately eschews biomimicry, emphasizing instead the power of stereoelectronic control in orchestrating the interconversion of polycyclic frameworks.


Assuntos
Hidrocarbonetos Aromáticos com Pontes , Técnicas de Química Sintética , Diterpenos , Taxoides , Produtos Biológicos/síntese química , Produtos Biológicos/química , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Carbono/química , Diterpenos/síntese química , Diterpenos/química , Estereoisomerismo , Taxoides/química , Taxoides/síntese química , Paclitaxel/química
20.
BMC Cancer ; 24(1): 777, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38937667

RESUMO

BACKGROUND: Evaluation publications typically summarize the results of studies to demonstrate the effectiveness of an intervention, but little is shared concerning any changes implemented during the study. We present a process evaluation protocol of a home-based gait, balance, and resistance exercise intervention to ameliorate persistent taxane-induced neuropathy study according to 7 key elements of process evaluation. METHODS: The process evaluation is conducted parallel to the longitudinal, randomized control clinical trial examining the effects of the home-based gait, balance, and resistance exercise program for women with persistent peripheral neuropathy following treatment with taxanes for breast cancer (IRB approval: Pro00040035). The flowcharts clarify how the intervention should be implemented in comparable settings, fidelity procedures help to ensure the participants are comfortable and identify their individual needs, and the process evaluation allows for the individual attention tailoring and focus of the research to avoid protocol deviation. CONCLUSIONS: The publication of the evaluation protocol plan adds transparency to the findings of clinical trials and favors process replication in future studies. The process evaluation enables the team to systematically register information and procedures applied during recruitment and factors that impact the implementation of the intervention, thereby allowing proactive approaches to prevent deviations from the protocol. When tracking an intervention continuously, positive or negative intervention effects are revealed early on in the study, giving valuable insight into inconsistent results. Furthermore, a process evaluation adds a participant-centered element to the research protocols, which allows a patient-centered approach to be applied to data collection. TRIAL REGISTRATION: ClinicalTrials.gov NCT04621721, November 9, 2020, registered prospectively. PROTOCOL VERSION: April 27, 2020, v2.


Assuntos
Neoplasias da Mama , Doenças do Sistema Nervoso Periférico , Taxoides , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Exercício Físico , Terapia por Exercício/métodos , Estudos Longitudinais , Educação de Pacientes como Assunto/métodos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/terapia , Projetos de Pesquisa , Taxoides/efeitos adversos , Taxoides/uso terapêutico
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