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1.
Med Phys ; 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-39023181

RESUMEN

BACKGROUND: The Monte Carlo (MC) method is an accurate technique for particle transport calculation due to the precise modeling of physical interactions. Nevertheless, the MC method still suffers from the problem of expensive computational cost, even with graphics processing unit (GPU) acceleration. Our previous works have investigated the acceleration strategies of photon transport simulation for single-energy CT. But for multi-energy CT, conventional individual simulation leads to unnecessary redundant calculation, consuming more time. PURPOSE: This work proposes a novel GPU-based shared MC scheme (gSMC) to reduce unnecessary repeated simulations of similar photons between different spectra, thereby enhancing the efficiency of scatter estimation in multi-energy x-ray exposures. METHODS: The shared MC method selects shared photons between different spectra using two strategies. Specifically, we introduce spectral region classification strategy to select photons with the same initial energy from different spectra, thus generating energy-shared photon groups. Subsequently, the multi-directional sampling strategy is utilized to select energy-and-direction-shared photons, which have the same initial direction, from energy-shared photon groups. Energy-and-direction-shared photons perform shared simulations, while others are simulated individually. Finally, all results are integrated to obtain scatter distribution estimations for different spectral cases. RESULTS: The efficiency and accuracy of the proposed gSMC are evaluated on the digital phantom and clinical case. The experimental results demonstrate that gSMC can speed up the simulation in the digital case by ∼37.8% and the one in the clinical case by ∼20.6%, while keeping the differences in total scatter results within 0.09%, compared to the conventional MC package, which performs an individual simulation. CONCLUSIONS: The proposed GPU-based shared MC simulation method can achieve fast photon transport calculation for multi-energy x-ray exposures.

2.
Chembiochem ; : e202400311, 2024 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-39037826

RESUMEN

Electron imaging of biological samples stained with heavy metals has enabled visualization of subcellular structures critical in chemical-, structural-, and neuro-biology. In particular, osmium tetroxide OsO4 has been widely adopted for selective lipid imaging. Despite the ubiquity of its use, the osmium speciation in lipid membranes and the process for contrast generation in electron microscopy (EM) have continued to be open questions, limiting efforts to improve staining protocols and therefore high-resolution nanoscale imaging of biological samples. Following our recent success using photoemission electron microscopy (PEEM) to image mouse brain tissues with synaptic resolution, we have used PEEM to determine the nanoscale electronic structure of Os-stained biological samples. Os(IV), in the form of OsO2, generates nanoaggregates in lipid membranes, leading to a strong spatial variation in the electronic structure and electron density of states. OsO2 has a metallic electronic structure that drastically increases the electron density of states near the Fermi level. Depositing metallic OsO2 in lipid membranes allows for strongly enhanced EM signals and conductivity of biological materials. The identification of the chemical species and understanding of the membrane contrast mechanism of Os-stained biological specimens provides a new opportunity for the development of staining protocols for high-resolution, high-contrast EM imaging.

3.
Eur J Med Chem ; 276: 116602, 2024 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-38971049

RESUMEN

Zuranolone (SAGE-217) is a neuroactive steroid (γ-aminobutyric acid)A (GABAA) receptor positive allosteric modulator (PAM) as the first oral drug approved by the FDA in 2023, which is used to treat patients with postpartum depression (PPD). SAGE-217 has a "black box" warning with impairing ability to drive or engage in other potentially hazardous activities. In addition, SAGE-217 can cause CNS depressant effects such as somnolence and confusion, suicidal thoughts and behavior and embryo-fetal toxicity. Based on the structure-activity relationship (SAR) of SAGE-217, a total of 28 neuroactive steroids with novel pharmacophore at C-21 modulated SAGE-217 derivatives were designed and synthesized. The biological activities were evaluated by both synaptic α1ß2γ2 GABAA receptor and extrasynaptic α4ß3δ GABAA receptor cell assays. The optimal compound S28 exhibited much more potent potency and similar efficacy at extrasynaptic GABAA receptor than SAGE-217. Different from above, compound S28 exhibited similar potency and lower efficacy at synaptic GABAA receptor than SAGE-217, which were consistent with the analysis of molecular docking and dynamics simulation results. The appropriate lower efficacy at synaptic GABAA receptor of compound S28 might contribute to reduce the side effects of excessive sedation. Furthermore, compound S28 was demonstrated to have excellent in vivo pharmacokinetic (PK) parameters, robust in vivo pharmacodynamic (PD) effects and good safety profiles. Therefore, compound S28 represents a potentially promising treatment of PPD candidate that warrants further investigation.

4.
Plant J ; 2024 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-39073914

RESUMEN

Pear is a widely cultivated fruit crop, but its distribution and sustainable production are significantly limited by salt stress. This study used RNA-Seq time-course analysis, WGCNA, and functional enrichment analysis to uncover the molecular mechanisms underlying salt stress tolerance in Pyrus ussuriensis. We identified an ABA-related regulatory module, PbGBF3-PbAPL2-PbSDH1, as crucial in this response. PbGBF3, a bZIP transcription factor, enhances salt tolerance by upregulating PbAPL2 and PbSDH1. Overexpression of PbGBF3 improved salt tolerance in Pyrus communis calli and Arabidopsis, while silencing it reduced tolerance in Pyrus betulifolia. Functional assays showed that PbGBF3 binds to the promoters of PbAPL2 and PbSDH1, increasing their expression. PbAPL2 and PbSDH1, key enzymes in starch synthesis and the sorbitol pathway, respectively, enhance salt tolerance by increasing AGPase activity, soluble sugar content, and SDH activity, improving ROS scavenging and ion balance. Our findings suggest that the PbGBF3-PbAPL2 and PbGBF3-PbSDH1 modules positively regulate salt tolerance by enhancing ABA signaling and reducing ABA-mediated growth inhibition. These insights provide a foundation for developing salt-tolerant pear cultivars.

5.
Phytomedicine ; 132: 155585, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-39068811

RESUMEN

BACKGROUND: Hepatic fibrosis (HF) runs through multiple stages of liver diseases and promotes these diseases progression. Oxysophoridine (OSR), derived from Sophora alopecuroides l., is a bioactive alkaloid that has been reported to antagonize alcoholic hepatic injury. However, whether OSR suppresses HF and the mechanisms involved in Nrf2 remain unknown. PURPOSE: Since the dysregulation of inflammation and oxidative stress is responsible for the excessive accumulation of extracellular matrix (ECM) and fibrosis in the liver. We hypothesized that OSR may attenuate HF by inhibiting inflammation and oxidative stress through activating Nrf2 signaling. METHODS: In this study, we employed LPS-stimulated HSC-T6 cells, RAW264.7 cells, and a CCl4-induced C57BL/6 mouse fibrotic model to evaluate its suppressing inflammation and oxidative stress, as well as fibrosis. RESULTS: The result showed that OSR significantly reduced α-SMA and TGF-ß1 at a low dose of 10 µM in vitro and at a dose of 50 mg/kg in vivo, which is comparable to Silymarin, the only Chinese herbal active ingredient that has been marketed for anti-liver fibrosis. Moreover, OSR effectively suppressed the expression of iNOS at a dose of 10 µM and COX-2 at a dose of 40 µM, respectively. Furthermore, OSR demonstrated inhibitory effects on the IL-1ß, IL-6, and TNF-α in vitro and almost extinguished cytokine storm in vivo. OSR exhibited antioxidative effects by reducing MDA and increasing GSH, thereby protecting the cell membrane against oxidative damage and reducing LDH release. Moreover, OSR effectively upregulated the protein levels of Nrf2, HO-1, and p62, but decreased p-NF-κB p65, p-IκBα, and Keap1. Alternatively, mechanisms involved in Nrf2 were verified by siNrf2 interference, siNrf2 interference revealed that the anti-fibrotic effect of OSR was attributed to its activation of Nrf2. CONCLUSION: The present study provided an effective candidate for HF involved in both activation of Nrf2 and blockage of NF-κB, which has not been reported in the published work. The present study provides new insights for the identification of novel drug development for HF.

6.
BMC Plant Biol ; 24(1): 470, 2024 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-38811892

RESUMEN

Ring rot, caused by Botryosphaeria dothidea, is an important fungal disease of pear fruit during postharvest storage. Melatonin, as a plant growth regulator, plays an important role in enhancing the stress resistance of pear fruits. It enhances the resistance of pear fruits to ring rot by enhancing their antioxidant capacity. However, the underlying mechanism remains unclear. In this study, we examined the effect of melatonin on the growth of B. dothidea. Results showed that melatonin did not limit the growth of B. dothidea during in vitro culture. However, metabolomics and transcriptomics analyses of 'Whangkeumbae' pear (Pyrus pyrifolia) revealed that melatonin increased the activity of antioxidant enzymes, including peroxidase (POD), superoxide dismutase (SOD), and polyphenol oxidase (PPO), in the fruit and activated the phenylpropanoid metabolic pathway to improve fruit resistance. Furthermore, melatonin treatment significantly increased the contents of jasmonic acid and phlorizin in pear fruit, both of which could improve disease resistance. Jasmonic acid regulates melatonin synthesis and can also promote phlorizin synthesis, ultimately improving the resistance of pear fruit to ring rot. In summary, the interaction between melatonin and jasmonic acid and phlorizin enhances the antioxidant defense response and phenylpropanoid metabolism pathway of pear fruit, thereby enhancing the resistance of pear fruit to ring rot disease. Our results provide new insights into the application of melatonin in the resistance to pear fruit ring rot.


Asunto(s)
Ascomicetos , Ciclopentanos , Resistencia a la Enfermedad , Frutas , Melatonina , Oxilipinas , Florizina , Enfermedades de las Plantas , Pyrus , Pyrus/microbiología , Pyrus/metabolismo , Pyrus/genética , Ciclopentanos/metabolismo , Ciclopentanos/farmacología , Oxilipinas/metabolismo , Ascomicetos/fisiología , Melatonina/farmacología , Melatonina/metabolismo , Resistencia a la Enfermedad/efectos de los fármacos , Enfermedades de las Plantas/microbiología , Frutas/microbiología , Frutas/metabolismo , Florizina/farmacología , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Antioxidantes/metabolismo , Reguladores del Crecimiento de las Plantas/metabolismo
7.
Luminescence ; 39(4): e4749, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38658767

RESUMEN

Lipid droplet, an intracellular lipid reservoir, is vital for energy metabolism and signal transmission in cells. The viscosity directly affects the metabolism of lipid droplets, and the abnormal viscosity is associated with the occurrence and development of various diseases. Therefore, it is indispensable to develop techniques that can detect viscosity changes in intracellular lipid droplets. Based on twisted intramolecular charge transfer (TICT) mechanism, a novel small-molecule lipid droplet-targeted viscosity fluorescence probe PPF-1 was designed. The probe was easy to synthesize, it had a large Stokes shift, stable optical properties, and low bio-toxicity. Compared to being in methanol solution, the fluorescence intensity of PPF-1 in glycerol solution was increased 26.7-fold, and PPF-1 showed excellent ability to target lipid droplets. Thus, the probe PPF-1 could provide an effective means of detecting viscosity changes of lipid droplets and was of great value for physiological diagnosis of related diseases, pathological analysis, and medical research.


Asunto(s)
Colorantes Fluorescentes , Gotas Lipídicas , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Viscosidad , Gotas Lipídicas/química , Humanos , Estructura Molecular , Imagen Óptica , Espectrometría de Fluorescencia
8.
Technol Health Care ; 32(4): 2039-2056, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38339943

RESUMEN

BACKGROUND: The term 'dementia' covers a range of progressive brain diseases from which many elderly people suffer. Traditional cognitive and pathological tests are currently used to detect dementia, however, applications using Artificial Intelligence (AI) methods have recently shown improved results from improved detection accuracy and efficiency. OBJECTIVE: This research paper investigates the efficacy of one type of data analytics called supervised learning to detect Alzheimer's disease (AD) - a common dementia condition. METHODS: The aim is to evaluate cognitive tests and common biological markers (biomarkers) such as cerebrospinal fluid (CSF) to develop predictive classification systems for dementia detection. RESULTS: A data analytics process has been proposed, implemented, and tested against real data obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) repository. CONCLUSION: The models showed good power in predicting AD levels, notably from specified cognitive tests' scores and tauopathy related features.


Asunto(s)
Enfermedad de Alzheimer , Biomarcadores , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Anciano , Demencia/diagnóstico , Pruebas Neuropsicológicas , Aprendizaje Automático Supervisado , Masculino , Femenino , Inteligencia Artificial , Pruebas de Estado Mental y Demencia
9.
Plant Physiol Biochem ; 207: 108426, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38340689

RESUMEN

In nature, light intensity usually fluctuates and a sudden shade-sun transition can induce photodamage to photosystem I (PSI) in many angiosperms. Photosynthetic regulation in fluctuating light (FL) has been studied extensively in C3 plants; however, little is known about how C4 plants cope FL to prevent PSI photoinhibition. We here compared photosynthetic responses to FL between maize (Zea mays, C4) and tomato (Solanum lycopersicum, C3) grown under full sunlight. Maize leaves had significantly higher cyclic electron flow (CEF) activity and lower photorespiration activity than tomato. Upon a sudden shade-sun transition, maize showed a significant stronger transient PSI over-reduction than tomato, resulting in a significant greater PSI photoinhibition in maize after FL treatment. During the first seconds upon shade-sun transition, CEF was stimulated in maize at a much higher extent than tomato, favoring the rapid formation of trans-thylakoid proton gradient (ΔpH), which was helped by a transient down-regulation of chloroplast ATP synthase activity. Therefore, modulation of ΔpH by regulation of CEF and chloroplast ATP synthase adjusted PSI redox state at donor side, which partially compensated for the deficiency of photorespiration. We propose that C4 plants use different photosynthetic strategies for coping with FL as compared with C3 plants.


Asunto(s)
Complejo de Proteína del Fotosistema I , Zea mays , Complejo de Proteína del Fotosistema I/metabolismo , Zea mays/metabolismo , ATPasas de Translocación de Protón de Cloroplastos , Fotosíntesis/fisiología , Luz , Transporte de Electrón , Complejo de Proteína del Fotosistema II/metabolismo , Hojas de la Planta/metabolismo
10.
ACS Energy Lett ; 9(1): 201-208, 2024 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-38230374

RESUMEN

Aqueous zinc-ion batteries (ZIBs) employing zinc metal anodes are gaining traction as batteries for moderate to long duration energy storage at scale. However, corrosion of the zinc metal anode through reaction with water limits battery efficiency. Much research in the past few years has focused on additives that decrease hydrogen evolution, but the precise mechanisms by which this takes place are often understudied and remain unclear. In this work, we study the role of an acetonitrile antisolvent additive in improving the performance of aqueous ZnSO4 electrolytes using experimental and computational techniques. We demonstrate that acetonitrile actively modifies the interfacial chemistry during Zn metal plating, which results in improved performance of acetonitrile-containing electrolytes. Collectively, this work demonstrates the effectiveness of solvent additive systems in battery performance and durability and provides a new framework for future efforts to optimize ion transport and performance in ZIBs.

11.
Eur J Med Chem ; 264: 115934, 2024 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-38007911

RESUMEN

Breast cancer is one of the most common malignant tumors in women worldwide, with the majority of cases showing expression of estrogen receptors (ERs). Although drugs targeting ER have significantly improved survival rates in ER-positive patients, drug resistance remains an unmet clinical need. Fulvestrant, which overcomes selective estrogen receptor modulator (SERM) and AI (aromatase inhibitor) resistance, is currently the only long-acting selective estrogen receptor degrader (SERD) approved for both first and second-line settings. However, it fails to achieve satisfactory efficacy due to its poor solubility. Therefore, we designed and synthesized a series of novel scaffold (THC) derivatives, identifying their activities as ER antagonists and degraders. G-5b, the optimal compound, exhibited binding, antagonistic, degradation or anti-proliferative activities comparable to fulvestrant in ER+ wild type and mutants breast cancer cells. Notably, G-5b showed considerably improved stability and solubility. Research into the underlying mechanism indicated that G-5b engaged the proteasome pathway to degrade ER, subsequently inhibiting the ER signaling pathway and leading to the induction of apoptosis and cell cycle arrest events. Furthermore, G-5b displayed superior in vivo pharmacokinetics and pharmacodynamics properties, coupled with a favorable safety profile in the MCF-7 tamoxifen-resistant (MCF-7/TR) tumor xenograft model. Collectively, G-5b has emerged as a highly promising lead compound, offering potent antagonistic and degradation activities, positioning it as a novel long-acting SERD worthy of further refinement and optimization.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Antagonistas del Receptor de Estrógeno , Fulvestrant , Antagonistas de Estrógenos/farmacología , Tamoxifeno/farmacología , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Receptor alfa de Estrógeno/metabolismo
12.
Anal Methods ; 16(2): 293-300, 2024 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-38115761

RESUMEN

Viscosity, an essential parameter of the cellular microenvironment, has the ability to indicate the condition of living cells. It is closely linked to numerous diseases like Alzheimer's disease, diabetes, and cardiovascular disorders. Therefore, it is necessary to design tools to effectively monitor viscosity changes, which could provide promising avenues for therapeutic interventions in these diseases. Herein, we report a novel mitochondria-targeting fluorescent probe GX-VS which was suitable for the detection of viscosity changes in vivo and in vitro. The probe GX-VS had many advantages such as long emission wavelength (650 nm), large Stokes shift (105 nm), significant fluorescence enhancement (59-fold), high sensitivity, good biocompatibility and so on. Biological experiments showed that the probe could target mitochondria and detect viscosity alterations in HeLa cells. Moreover, it has been successfully utilized to monitor viscosity changes induced by lipopolysaccharides (LPS) in inflammatory zebrafishes and living mice, which further underscored the capacity of GX-VS to explore fluctuations in viscosity within living organisms.


Asunto(s)
Colorantes Fluorescentes , Pez Cebra , Humanos , Ratones , Animales , Células HeLa , Viscosidad , Mitocondrias
13.
ACS Appl Mater Interfaces ; 15(41): 48072-48084, 2023 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-37805993

RESUMEN

Predictive understanding of the molecular interaction of electrolyte ions and solvent molecules and their chemical reactivity on electrodes has been a major challenge but is essential for addressing instabilities and surface passivation that occur at the electrode-electrolyte interface of multivalent magnesium batteries. In this work, the isolated intrinsic reactivities of prominent chemical species present in magnesium bis(trifluoromethanesulfonimide) (Mg(TFSI)2) in diglyme (G2) electrolytes, including ionic (TFSI-, [Mg(TFSI)]+, [Mg(TFSI):G2]+, and [Mg(TFSI):2G2]+) as well as neutral molecules (G2) on a well-defined magnesium vanadate cathode (MgV2O4) surface, have been studied using a combination of first-principles calculations and multimodal spectroscopy analysis. Our calculations show that nonsolvated [Mg(TFSI)]+ is the strongest adsorbing species on the MgV2O4 surface compared with all other ions while partially solvated [Mg(TFSI):G2]+ is the most reactive species. The cleavage of C-S bonds in TFSI- to form CF3- is predicted to be the most desired pathway for all ionic species, which is followed by the cleavage of C-O bonds of G2 to yield CH3+ or OCH3- species. The strong stabilization and electron transfer between ionic electrolyte species and MgV2O4 is found to significantly favor these decomposition reactions on the surface compared with intrinsic gas-phase dissociation. Experimentally, we used state-of-the-art ion soft landing to selectively deposit mass-selected TFSI-, [Mg(TFSI):G2]+, and [Mg(TFSI):2G2]+ on a MgV2O4 thin film to form a well-defined electrolyte-MgV2O4 interface. Analysis of the soft-landed interface using X-ray photoelectron, X-ray absorption near-edge structure, electron energy-loss spectroscopies, as well as transmission electron microscopy confirmed the presence of decomposition species (e.g., MgFx, carbonates) and the higher amount of MgFx with [Mg(TFSI):G2]+ formed in the interfacial region, which corroborates the theoretical observation. Overall, these results indicate that Mg2+ desolvation results in electrolyte decomposition facilitated by surface adsorption, charge transfer, and the formation of passivating fluorides on the MgV2O4 cathode surface. This work provides the first evidence of the primary mechanisms leading to electrolyte decomposition at high-voltage oxide surfaces in multivalent batteries and suggests that the design of new, anodically stable electrolytes must target systems that facilitate cation desolvation.

14.
BMC Geriatr ; 23(1): 568, 2023 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-37716937

RESUMEN

BACKGROUND: Accurately predicting the future development trend of population aging is conducive to accelerating the development of the elderly care industry. This study constructed a combined optimization grey prediction model to predict the structure and density of elderly population. METHODS: In this paper, a GT-FGM model is proposed, which combines Theta residual optimization with fractional-order accumulation operator. Fractional-order accumulation can effectively weaken the randomness of the original data sequence. Meanwhile, Theta residual optimization can adjust parameter by minimizing the mean absolute error. And the population statistics of Shanghai city from 2006 to 2020 were selected for prediction analysis. By comparing with the other traditional grey prediction methods, three representative error indexes (MAE, MAPE, RMSE) were conducting for error analysis. RESULTS: Compared with the FGM model, GM (1,1) model, Verhulst model, Logistic model, SES and other classical prediction methods, the GT-FGM model shows significant forecasting advantages, and its multi-step rolling prediction accuracy is superior to other prediction methods. The results show that the elderly population density in nine districts in Shanghai will exceed 0.5 by 2030, among which Huangpu District has the highest elderly population density, reaching 0.6825. There has been a steady increase in the elderly population over the age of 60. CONCLUSIONS: The GT-FGM model can improve the prediction accuracy effectively. The elderly population in Shanghai shows a steady growth trend on the whole, and the differences between districts are obvious. The government should build a modern pension industry system according to the aging degree of the population in each region, and promote the balanced development of each region.


Asunto(s)
Envejecimiento , Pensiones , Humanos , Anciano , China/epidemiología , Modelos Logísticos
17.
Sci Total Environ ; 899: 165648, 2023 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-37482363

RESUMEN

In the context of dual carbon targets, a reliable prediction of China's carbon dioxide emissions is of great significance to the design and formulation of emission reduction policies by Chinese government. To this end, a novel grey Verhulst model with four parameters is proposed in this paper according to the evolution law and the data characteristics of China's carbon dioxide emissions. The new model solves the defect of poor structural adaptability of the traditional grey Verhulst model by introducing a nonlinear correction term. Besides, the range of values for the order of the grey generation operator of the new model is expanded from a positive real number to any real number (r ∈ R+ â†’ r ∈ R) by expanding the value range of the Gamma function. The new model is used to simulate China's carbon dioxide emissions, and its comprehensive mean relative percentage error is only 0.65 %, which is better than that of the other three grey models (2.39 %, 2.34 %, 2.35 % respectively). It shows that the proposed new model has better modeling ability. Finally, the new model is applied to predict China's carbon dioxide emissions, and the results show that it will still increase year by year, reaching 13,687 million tons by 2028 (only 11,420 million tons in 2021). Therefore, some countermeasures and suggestions are proposed to control China's carbon dioxide emissions in this paper.

18.
JAMA Oncol ; 9(9): 1230-1237, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37440217

RESUMEN

Importance: The efficacy of niraparib maintenance therapy with an individualized starting dose (ISD) warrants further investigation in a broad population with newly diagnosed advanced ovarian cancer (aOC), including patients without postoperative residual disease. Objective: To evaluate the efficacy and safety of niraparib with an ISD in a broad population with newly diagnosed aOC (R0 resection permitted). Design, Setting, and Participants: This multicenter, randomized, double-blind, placebo-controlled, phase 3 study was conducted in China and enrolled 384 patients with newly diagnosed aOC who received primary or interval debulking surgery and responded to treatment with first-line platinum-based chemotherapy. By data cutoff (September 30, 2021), median follow-up for progression-free survival (PFS) was 27.5 (IQR, 24.7-30.4) months. Interventions: Patients were randomized 2:1 to receive niraparib or placebo with ISD (200 mg/d for those with a body weight of <77 kg and/or platelet count of <150 ×103/µL [to convert to ×109/µL, multiply by 1] at baseline; 300 mg/d otherwise) stratified by germline BRCA variant status, tumor homologous recombination deficiency status, neoadjuvant chemotherapy, and response to first-line platinum-based chemotherapy. Main Outcomes and Measurements: The primary end point was blinded, independent central review-assessed PFS in the intention-to-treat population. Results: A total of 384 patients were randomized (255 niraparib [66.4%]; median [range] age, 53 [32-77] years; 129 placebo [33.6%]; median [range] age, 54 [33-77] years), and 375 (247 niraparib [65.9%], 128 placebo [34.1%]) received treatment at a dose of 200 mg per day. Median PFS with niraparib vs placebo was 24.8 vs 8.3 months (hazard ratio [HR], 0.45; 95% CI, 0.34-0.60; P < .001) in the intention-to-treat population; not reached vs 10.8 months (HR, 0.40; 95% CI, 0.23-0.68) and 19.3 vs 8.3 months (HR, 0.48; 95% CI, 0.34-0.67) in patients with and without germline BRCA variants, respectively; not reached vs 11.0 months (HR, 0.48; 95% CI, 0.34-0.68) and 16.6 vs 5.5 months (HR, 0.41; 95% CI, 0.22-0.75) in homologous recombination deficient and proficient patients, respectively; and 24.8 vs 8.3 months (HR, 0.44; 95% CI, 0.32-0.61) and 16.5 vs 8.3 months (HR, 0.27; 95% CI, 0.10-0.72) in those with optimal and suboptimal debulking, respectively. Similar proportions of niraparib-treated and placebo-treated patients (6.7% vs 5.4%) discontinued treatment due to treatment-emergent adverse events. Conclusion and Relevance: This randomized clinical trial found that niraparib maintenance therapy prolonged PFS in patients with newly diagnosed aOC regardless of postoperative residual disease or biomarker status. The ISD was effective and safe in the first-line maintenance setting. Trial Registration: ClinicalTrials.gov Identifier: NCT03709316.


Asunto(s)
Neoplasias Ováricas , Humanos , Femenino , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Supervivencia sin Progresión , Indazoles/efectos adversos , Método Doble Ciego , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
19.
Luminescence ; 38(9): 1618-1623, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37376960

RESUMEN

As a fundamental physical parameter, viscosity influences the diffusion in biological processes. The changes in intracellular viscosity led to the occurrence of relevant diseases. Monitoring changes in cellular viscosity is important for distinguishing abnormal cells in cell biology and oncologic pathology. Here, we devised and synthesized a viscosity-sensitive fluorescent probe LBX-1. LBX-1 showed high sensitivity, providing a large Stokes shift as well as an enhancement in fluorescent intensity (16.1-fold) from methanol solution to glycerol solution. Furthermore, the probe LBX-1 could localize in mitochondria because of the ability of the probe to penetrate the cell membrane and accumulate in mitochondria. These results suggested that the probe could be utilized in monitoring the changes in mitochondrial viscosity in complex biological systems.


Asunto(s)
Colorantes Fluorescentes , Mitocondrias , Humanos , Colorantes Fluorescentes/metabolismo , Células HeLa , Viscosidad , Mitocondrias/metabolismo , Membrana Celular/metabolismo
20.
Plant Physiol ; 193(1): 855-873, 2023 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-37279567

RESUMEN

Banana (Musa spp.) fruits, as typical tropical fruits, are cold sensitive, and lower temperatures can disrupt cellular compartmentalization and lead to severe browning. How tropical fruits respond to low temperature compared to the cold response mechanisms of model plants remains unknown. Here, we systematically characterized the changes in chromatin accessibility, histone modifications, distal cis-regulatory elements, transcription factor binding, and gene expression levels in banana peels in response to low temperature. Dynamic patterns of cold-induced transcripts were generally accompanied by concordant chromatin accessibility and histone modification changes. These upregulated genes were enriched for WRKY binding sites in their promoters and/or active enhancers. Compared to banana peel at room temperature, large amounts of banana WRKYs were specifically induced by cold and mediated enhancer-promoter interactions regulating critical browning pathways, including phospholipid degradation, oxidation, and cold tolerance. This hypothesis was supported by DNA affinity purification sequencing, luciferase reporter assays, and transient expression assay. Together, our findings highlight widespread transcriptional reprogramming via WRKYs during banana peel browning at low temperature and provide an extensive resource for studying gene regulation in tropical plants in response to cold stress, as well as potential targets for improving cold tolerance and shelf life of tropical fruits.


Asunto(s)
Conservación de Alimentos , Frutas , Musa , Musa/genética , Musa/fisiología , Frutas/fisiología , Frío , Histonas/metabolismo , Cromatina , Proteínas de Plantas/metabolismo , Elementos de Facilitación Genéticos , Código de Histonas , Factores de Transcripción/metabolismo , Lípidos de la Membrana/metabolismo
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