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1.
RSC Adv ; 14(16): 11027-11036, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38586443

RESUMO

Polylactic acid (PLA) is a high-modulus, high-strength bio-based thermoplastic polyester with good biodegradability, which is currently a promising environmentally friendly material. However, its inherent brittleness has hindered its widespread use. In this study, we reported a simple and non-toxic strategy for toughening PLA, using biodegradable materials such as polyethylene glycol (PEG) and citric acid (CA) as precursors. Through reactive melt blending with PLA, PEG and CA form PEGCA copolyesters in situ during blending. At the same time, CA can react with PLA and PEG, forming a copolyester structure at the interface of the two phases, improving the interfacial compatibility between PEG and PEGCA with PLA. Fourier transform infrared spectroscopy confirms this. Experimental results show that when the content of PEG/CA reaches 15% (PLA/PEG/CA-15%) in the blends, the impact strength of the blend was 4.47 kJ m-2, and the maximum elongation at break was as high as 360.1%, which were about 2 and 44 times higher than those of pure PLA, respectively. Moreover, the tensile strength was still maintained at the level of 70%. This work can expand the application of PLA in food packaging and medical supplies.

2.
Lancet ; 403(10434): e21-e31, 2024 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-38582569

RESUMO

BACKGROUND: Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence for the benefits and harms of weight-lowering drugs. METHODS: This systematic review and network meta-analysis included searches of PubMed, Embase, and Cochrane Library (CENTRAL) from inception to March 23, 2021, for randomised controlled trials of weight-lowering drugs in adults with overweight and obesity. We performed frequentist random-effect network meta-analyses to summarise the evidence and applied the Grading of Recommendations Assessment, Development, and Evaluation frameworks to rate the certainty of evidence, calculate the absolute effects, categorise interventions, and present the findings. The study was registered with PROSPERO, CRD 42021245678. FINDINGS: 14 605 citations were identified by our search, of which 132 eligible trials enrolled 48 209 participants. All drugs lowered bodyweight compared with lifestyle modification alone; all subsequent numbers refer to comparisons with lifestyle modification. High to moderate certainty evidence established phentermine-topiramate as the most effective in lowering weight (odds ratio [OR] of ≥5% weight reduction 8·02, 95% CI 5·24 to 12·27; mean difference [MD] of percentage bodyweight change -7·98, 95% CI -9·27 to -6·69) followed by GLP-1 receptor agonists (OR 6·33, 95% CI 5·00 to 8·00; MD -5·79, 95% CI -6·34 to -5·25). Naltrexone-bupropion (OR 2·69, 95% CI 2·10 to 3·44), phentermine-topiramate (2·40, 1·68 to 3·44), GLP-1 receptor agonists (2·22, 1·74 to 2·84), and orlistat (1·71, 1·42 to 2·05) were associated with increased adverse events leading to drug discontinuation. In a post-hoc analysis, semaglutide, a GLP-1 receptor agonist, showed substantially larger benefits than other drugs with a similar risk of adverse events as other drugs for both likelihood of weight loss of 5% or more (OR 9·82, 95% CI 7·09 to 13·61) and percentage bodyweight change (MD -11·40, 95% CI -12·51 to -10·29). INTERPRETATION: In adults with overweight and obesity, phentermine-topiramate and GLP-1 receptor agonists proved the best drugs in reducing weight; of the GLP-1 agonists, semaglutide might be the most effective. FUNDING: 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.


Assuntos
Obesidade , Sobrepeso , Adulto , Humanos , Sobrepeso/tratamento farmacológico , Metanálise em Rede , Topiramato/uso terapêutico , Obesidade/tratamento farmacológico , Redução de Peso , Fentermina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
Nat Commun ; 15(1): 2686, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38538586

RESUMO

With the development of wearable devices and hafnium-based ferroelectrics (FE), there is an increasing demand for high-performance flexible ferroelectric memories. However, developing ferroelectric memories that simultaneously exhibit good flexibility and significant performance has proven challenging. Here, we developed a high-performance flexible field-effect transistor (FeFET) device with a thermal budget of less than 400 °C by integrating Zr-doped HfO2 (HZO) and ultra-thin indium tin oxide (ITO). The proposed FeFET has a large memory window (MW) of 2.78 V, a high current on/off ratio (ION/IOFF) of over 108, and high endurance up to 2×107 cycles. In addition, the FeFETs under different bending conditions exhibit excellent neuromorphic properties. The device exhibits excellent bending reliability over 5×105 pulse cycles at a bending radius of 5 mm. The efficient integration of hafnium-based ferroelectric materials with promising ultrathin channel materials (ITO) offers unique opportunities to enable high-performance back-end-of-line (BEOL) compatible wearable FeFETs for edge intelligence applications.

4.
J Exp Bot ; 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38497908

RESUMO

In plants, the glutamine synthetase - glutamic acid synthetase (GS/GOGAT) cycle plays important roles in nitrogen metabolism, growth, development, and stress resistance. Excess ammonium (NH4+) restricts plant growth, but GS can help to alleviate NH4+ toxicity. In this study, 84K poplar (Populus alba × P. glandulosa) showed reduced biomass accumulation and leaf chlorosis under high-NH4+ stress. These symptoms were less severe in lines overexpressing the gene encoding glutamine synthetase (PagGS1;2-OE), and more severe in lines with inhibition of PagGS1;2 expression (PagGS1;2-RNAi). Compared with the wild type(WT), the PagGS1;2-OE lines showed significantly increased GS and GOGAT activities and higher contents of free amino acids, soluble protein, total nitrogen, and chlorophyll under high-NH4+ stress. In contrast, the antioxidant capacity and NH4+ assimilation capacity of PagGS1;2-RNAi lines were decreased under high-NH4+ stress. The total carbon (C) content and C/N ratio (C/N) of roots and leaves of PagGS1;2-OE lines were significantly higher than those of WT under high-NH4+ stress. Overexpression of PagGS1;2 led to increased accumulation of various amino acids (3-methylaspartic acid, glutamic acid, proline, serine, and histidine); reduced contents of carbohydrates (fructose, starch, galactose, glucose 1-phosphate, fructose 6-phosphate); and increased contents of sugar alcohols (sedum heptanose, maltose, mannitol, galactose, sorbitol) in the roots under high-NH4+ stress. Under high-NH4+ stress, genes related to amino acid biosynthesis, sucrose and starch degradation, galactose metabolism, and the antioxidant system were significantly up-regulated in the roots of PagGS1;2-OE lines, compared with those of wild type. Thus, PagGS1;2 overexpression affected C metabolism and amino acid metabolism pathways under high-NH4+ stress, which helped to maintain the balance of C and N metabolism and alleviate the symptoms of NH4+ toxicity. Modification of the GS/GOGAT cycle by genetic engineering is a promising strategy to improve NH4+ tolerance of forest trees.

5.
Nano Lett ; 24(6): 2018-2024, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38315050

RESUMO

In recent years, memristors have successfully demonstrated their significant potential in artificial neural networks (ANNs) and neuromorphic computing. Nonetheless, ANNs constructed by crossbar arrays suffer from cross-talk issues and low integration densities. Here, we propose an eight-layer three-dimensional (3D) vertical crossbar memristor with an ultrahigh rectify ratio (RR > 107) and an ultrahigh nonlinearity (>105) to overcome these limitations, which enables it to reach a >1 Tb array size without reading failure. Furthermore, the proposed 3D RRAM shows advanced endurance (>1010 cycles), retention (>104 s), and uniformity. In addition, several synaptic functions observed in the human brain were mimicked. On the basis of the advanced performance, we constructed a novel 3D ANN, whose learning efficiency and recognition accuracy were enhanced significantly compared with those of conventional single-layer ANNs. These findings hold promise for the development of highly efficient, precise, integrated, and stable VLSI neuromorphic computing systems.

6.
Artigo em Inglês | MEDLINE | ID: mdl-38305868

RESUMO

PURPOSE: Giredestrant is a potent, orally bioavailable, small-molecule selective estrogen receptor antagonist and degrader (SERD) that is being developed for the treatment of patients with estrogen receptor (ER)-positive breast cancer. In vitro, giredestrant was primarily metabolized by UGT1A4. The goal of this study was to investigate if UGT1A4 polymorphism had a clinically relevant impact on giredestrant exposure. METHODS: Genotyping and pharmacokinetic data were obtained from 118 and 61 patients in two clinical studies, GO39932 [NCT03332797] and acelERA Breast Cancer [NCT04576455], respectively. RESULTS: The overall allelic frequencies of UGT1A4*2 and UGT1A4*3 were 3.3% and 11%, respectively. Giredestrant exposure was consistent between patients with wild-type UGT1A4 and UGT1A4*2 and *3 polymorphisms, with no clinically relevant difference observed. In addition, haplotype analysis indicated that no other UGT1A4 variants were significantly associated with giredestrant exposure. CONCLUSION: Therefore, this study indicates that UGT1A4 polymorphism status is unlikely a clinically relevant factor to impact giredestrant exposure and giredestrant can be administered at the same dose level regardless of patients' UGT1A4 polymorphism status.

7.
BMC Med Res Methodol ; 24(1): 45, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38389063

RESUMO

BACKGROUND: Scoping reviews have emerged as a valuable method for synthesizing emerging evidence, providing a comprehensive contextual overview, and influencing policy and practice developments. The objective of this study is to provide an overview of scoping reviews conducted in Chinese academic institutions over the last decades. METHOD: We conducted a comprehensive search of nine databases and six grey literature databases for scoping reviews conducted in Chinese academic institutions. The reporting quality of the included reviews was assessed using the Preferred Reporting Items for PRISMA-ScR checklist. We performed both quantitative and qualitative analyses, examining the conduct of the scoping reviews and exploring the breadth of research topics covered. We used Chi-squared and Wilcoxon rank-sum tests to compare methodological issues and reporting quality in English and Chinese-language reviews. RESULTS: A total of 392 reviews published between 2013 and 2022 were included, 238 English-reported reviews and 154 Chinese-reported reviews, respectively. The primary purposes of these reviews were to map and summarize the evidence, with a particular focus on health and nursing topics. 98.7% of reviews explicitly used the term "scoping review", and the Arksey and O'Malley framework was the most frequently cited framework. Thirty-five English-reported scoping reviews provided a protocol for scoping review. PubMed was the most common source in English-reported reviews and CNKI in Chinese-reported reviews. Reviews published in English were more likely to search the grey literature (P = 0.005), consult information specialists (P < 0.001) and conduct an updated search (P = 0.012) than those in Chinese. Reviews published in English had a significantly high score compared to those published in Chinese (16 vs. 14; P < 0.001). The reporting rates in English-reported reviews were higher than those in Chinese reviews for seven items, but lower for structured summary (P < 0.001), eligibility criteria (P < 0.001), data charting process (P = 0.009) and data items (P = 0.015). CONCLUSION: There has been a significant increase in the number of scoping reviews conducted in Chinese academic institutions each year since 2020. While the research topics covered are diverse, the overall reporting quality of these reviews is need to be improved. And there is a need for greater standardization in the conduct of scoping reviews in Chinese academic institutions.


Assuntos
Revisões Sistemáticas como Assunto , China , Bases de Dados Factuais , Idioma , Revisões Sistemáticas como Assunto/normas
8.
Plant Sci ; 341: 112012, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38311248

RESUMO

Cold stress is one of the most destructive abiotic stresses limiting plant growth and development. CBF (C-repeat binding factor) transcription factors and their roles in cold response have been identified in Arabidopsis as well as several other plant species. However, the biological functions and related molecular mechanisms of CBFs in birch (Betula platyphylla Suk.) remain undetermined. In this study, five cold-responsive BpCBF genes, BpCBF1, BpCBF2, BpCBF7, BpCBF10 and BpCBF12 were cloned. Via protoplast transformation, BpCBF7 was found to be localized in nucleus. The result of yeast one hybrid assay validated the binding of BpCBF7 to the CRT/DRE (C-repeat/dehydration responsive element) elements in the promoter of BpERF1.1 gene. By overexpressing and repressing BpCBFs in birch plants, it was proven that BpCBFs play positive roles in the cold tolerance. At the metabolic level, BpCBFs OE lines had lower ROS accumulation, as well as higher activities of antioxidant enzymes (SOD, POD and CAT) and higher accumulation of protective substances (soluble sugar, soluble protein and proline). Via yeast one hybrid and co-transformation of effector and reporter vectors assay, it was proven that BpCBF7 can regulate the expression of BpERF5 and BpZAT10 genes by directly binding to their promoters. An interacting protein of BpCBF7, BpWRKY17, was identified by yeast two hybrid library sequencing and the interaction was validated with in vivo methods. These results indicates that BpCBFs can increase the cold tolerance of birch plants, partly by gene regulation and protein interaction. This study provides a reference for the research on CBF transcription factors and genetic improvement of forest trees upon abiotic stresses.


Assuntos
Arabidopsis , Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Proteínas de Plantas/metabolismo , Fatores de Transcrição/metabolismo , Betula/fisiologia , Resposta ao Choque Frio/genética , Arabidopsis/genética , Regulação da Expressão Gênica de Plantas , Temperatura Baixa , Plantas Geneticamente Modificadas/metabolismo
9.
Curr Biol ; 34(2): R47-R49, 2024 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-38262354

RESUMO

Humans are responsible for the release of many non-native animals into the wild. However, these releases occur randomly and are difficult to monitor. Here, using two of the worst invasive herpetofauna as model taxa, we applied an iEcology approach and found a high magnitude of human-mediated releases in China, suggesting this approach can be used to monitor introductions and advise management bodies in a timely manner.


Assuntos
Mídias Sociais , Animais , Humanos , China
10.
Int J Mol Sci ; 25(2)2024 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-38256092

RESUMO

Secondary development is a key biological characteristic of woody plants and the basis of wood formation. Exogenous nitrogen can affect the secondary growth of poplar, and some regulatory mechanisms have been found in the secondary xylem. However, the effect of nitrogen on cambium has not been reported. Herein, we investigated the effects of different nitrogen concentrations on cambium development using combined transcriptome and metabolome analysis. The results show that, compared with 1 mM NH4NO3 (M), the layers of hybrid poplar cambium cells decreased under the 0.15 mM NH4NO3 (L) and 0.3 mM NH4NO3 (LM) treatments. However, there was no difference in the layers of hybrid poplar cambium cells under the 3 mM NH4NO3 (HM) and 5 mM NH4NO3 (H) treatments. Totals of 2365, 824, 649 and 398 DEGs were identified in the M versus (vs.) L, M vs. LM, M vs. HM and M vs. H groups, respectively. Expression profile analysis of the DEGs showed that exogenous nitrogen affected the gene expression involved in plant hormone signal transduction, phenylpropanoid biosynthesis, the starch and sucrose metabolism pathway and the ubiquitin-mediated proteolysis pathway. In M vs. L, M vs. LM, M vs. HM and M vs. H, differential metabolites were enriched in flavonoids, lignans, coumarins and saccharides. The combined analysis of the transcriptome and metabolome showed that some genes and metabolites in plant hormone signal transduction, phenylpropanoid biosynthesis and starch and sucrose metabolism pathways may be involved in nitrogen regulation in cambium development, whose functions need to be verified. In this study, from the point of view that nitrogen influences cambium development to regulate wood formation, the network analysis of the transcriptome and metabolomics of cambium under different nitrogen supply levels was studied for the first time, revealing the potential regulatory and metabolic mechanisms involved in this process and providing new insights into the effects of nitrogen on wood development.


Assuntos
Câmbio , Populus , Câmbio/genética , Reguladores de Crescimento de Plantas , Transcriptoma , Metaboloma , Nitrogênio , Populus/genética , Amido , Sacarose
11.
Glob Chang Biol ; 30(1): e17137, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38273500

RESUMO

Understanding the determinants of the range expansion of invasive alien species is crucial for developing effective prevention and control strategies. Nevertheless, we still lack a global picture of the potential factors influencing the invaded range expansion across taxonomic groups, especially for the world's worst invaders with high ecological and economic impacts. Here, by extensively collecting data on 363 distributional ranges of 19 of world's worst invasive terrestrial vertebrates across 135 invaded administrative jurisdictions, we observed remarkable variations in the range expansion across species and taxonomic groups. After controlling for taxonomic and geographic pseudoreplicates, model averaging analyses based on generalized additive mixed-effect models showed that species in invaded regions having climates more similar to those of their native ranges tended to undergo a larger range expansion. In addition, as proxies of propagule pressure and human-assisted transportation, the number of introduction events and the road network density were also important predictors facilitating the range expansion. Further variance partitioning analyses validated the predominant role of climate match in explaining the range expansion. Our study demonstrated that regions with similar climates to their native ranges could still be prioritized to prevent the spread of invasive species under the sustained global change.


Assuntos
Clima , Espécies Introduzidas , Animais , Humanos , Vertebrados , Mudança Climática , Ecossistema
12.
Mater Horiz ; 11(2): 490-498, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-37966103

RESUMO

Emulating the human nervous system to build next-generation computing architectures is considered a promising way to solve the von Neumann bottleneck. Transistors based on ferroelectric layers are strong contenders for the basic unit of artificial neural systems due to their advantages of high speed and low power consumption. In this work, the potential of Fe-TFTs integrating the HfLaO ferroelectric film and ultra-thin ITO channel for artificial synaptic devices is demonstrated for the first time. The Fe-TFTs can respond significantly to pulses as low as 14 ns with an energy consumption of 93.1 aJ, which is at the leading level for similar devices. In addition, Fe-TFTs exhibit essential synaptic functions and achieve a recognition rate of 93.2% for handwritten digits. Notably, a novel reconfigurable approach involving the combination of two types of electrical pulses to realize Boolean logic operations ("AND", "OR") within a single Fe-TFT has been introduced for the first time. The simulations of array-level operations further demonstrated the potential for parallel computing. These multifunctional Fe-TFTs reveal new hardware options for neuromorphic computing chips.

13.
Clin Cancer Res ; 30(4): 754-766, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-37921755

RESUMO

PURPOSE: Giredestrant is an investigational next-generation, oral, selective estrogen receptor antagonist and degrader for the treatment of estrogen receptor-positive (ER+) breast cancer. We present the primary analysis results of the phase Ia/b GO39932 study (NCT03332797). PATIENTS AND METHODS: Patients with ER+, HER2-negative locally advanced/metastatic breast cancer previously treated with endocrine therapy received single-agent giredestrant (10, 30, 90, or 250 mg), or giredestrant (100 mg) ± palbociclib 125 mg ± luteinizing hormone-releasing hormone (LHRH) agonist. Detailed cardiovascular assessment was conducted with giredestrant 100 mg. Endpoints included safety (primary), pharmacokinetics, pharmacodynamics, and efficacy. RESULTS: As of January 28, 2021, with 175 patients enrolled, no dose-limiting toxicity was observed, and the MTD was not reached. Adverse events (AE) related to giredestrant occurred in 64.9% and 59.4% of patients in the single-agent ± LHRH agonist and giredestrant + palbociclib ± LHRH agonist cohorts, respectively (giredestrant-only-related grade 3/4 AEs were reported in 4.5% of patients across the single-agent cohorts and 3.1% of those with giredestrant + palbociclib). Dose-dependent asymptomatic bradycardia was observed, but no clinically significant changes in cardiac-related outcomes: heart rate, blood pressure, or exercise duration. Clinical benefit was observed in all cohorts (48.6% of patients in the single-agent cohort and 81.3% in the giredestrant + palbociclib ± LHRH agonist cohort), with no clear dose relationship, including in patients with ESR1-mutated tumors. CONCLUSIONS: Giredestrant was well tolerated and clinically active in patients who progressed on prior endocrine therapy. Results warrant further evaluation of giredestrant in randomized trials in early- and late-stage ER+ breast cancer.


Assuntos
Neoplasias da Mama , Carbolinas , Piperazinas , Piridinas , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Receptores de Estrogênio , Hormônio Liberador de Gonadotropina/agonistas
14.
Int J Mol Sci ; 24(24)2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38139109

RESUMO

Exogenous nitrogen and carbon can affect plant cell walls, which are composed of structural carbon. Sucrose synthase (SUS), invertase (INV), hexokinase (HXK), phosphoglucomutase (PGM), and UDP-glucose pyrophosphorylase (UGP) are the key enzymes of sucrose metabolism involved in cell wall synthesis. To understand whether these genes are regulated by carbon and nitrogen to participate in structural carbon biosynthesis, we performed genome-wide identification, analyzed their expression patterns under different carbon and nitrogen treatments, and conducted preliminary functional verification. Different concentrations of nitrogen and carbon were applied to poplar (Populus trichocarpa Torr. and Gray), which caused changes in cellulose, lignin, and hemicellulose contents. In poplar, 6 SUSs, 20 INVs, 6 HXKs, 4 PGMs, and 2 UGPs were identified. Moreover, the physicochemical properties, collinearity, and tissue specificity were analyzed. The correlation analysis showed that the expression levels of PtrSUS3/5, PtrNINV1/2/3/5/12, PtrCWINV3, PtrVINV2, PtrHXK5/6, PtrPGM1/2, and PtrUGP1 were positively correlated with the cellulose content. Meanwhile, the knockout of PtrNINV12 significantly reduced the cellulose content. This study could lay the foundation for revealing the functions of SUSs, INVs, HXKs, PGMs, and UGPs, which affected structural carbon synthesis regulated by nitrogen and carbon, proving that PtrNINV12 is involved in cell wall synthesis.


Assuntos
Populus , Populus/metabolismo , Celulose/metabolismo , Lignina/metabolismo , Carbono/metabolismo , Nitrogênio/metabolismo , Regulação da Expressão Gênica de Plantas
15.
Cancer Res Commun ; 3(12): 2551-2559, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-38019116

RESUMO

PURPOSE: We describe the clinical pharmacology characterization of giredestrant in a first-in-human study. EXPERIMENTAL DESIGN: This phase Ia/Ib dose-escalation/-expansion study (NCT03332797) evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of giredestrant in estrogen receptor-positive HER2-negative locally advanced/metastatic breast cancer. The single-agent dose-escalation stage evaluated giredestrant 10, 30, 90, or 250 mg once daily. The dose-expansion stage evaluated single-agent giredestrant at 30, 100, and 250 mg once daily. Dose-escalation and -expansion phases also evaluated giredestrant 100 mg combined with palbociclib 125 mg. RESULTS: Following single-dose oral administration, giredestrant was rapidly absorbed and generally showed a dose-proportional increase in exposure at doses ranging from 10 to 250 mg. At the 30 mg clinical dose, maximum plasma concentration was 266 ng/mL (50.1%) and area under the concentration-time curve from 0 to 24 hours at steady state was 4,320 ng·hour/mL (59.4%). Minimal giredestrant concentrations were detected in urine, indicating that renal excretion is unlikely to be a major elimination route for giredestrant. Mean concentration of 4beta-hydroxycholesterol showed no apparent increase over time at both the clinical dose (30 mg) and a supratherapeutic dose (90 mg), suggesting that giredestrant may have low CYP3A induction potential in humans. No clinically relevant drug-drug interaction was observed between giredestrant and palbociclib. Giredestrant exposure was not affected by food and was generally consistent between White and Asian patients. CONCLUSIONS: This study illustrates how the integration of clinical pharmacology considerations into early-phase clinical trials can inform the design of pivotal studies and accelerate oncology drug development. SIGNIFICANCE: This work illustrates how comprehensive clinical pharmacology characterization can be integrated into first-in-human studies in oncology. It also demonstrates the value of understanding clinical pharmacology attributes to inform eligibility, concomitant medications, and combination dosing and to directly influence late-stage trial design and accelerate development.


Assuntos
Neoplasias da Mama , Farmacologia Clínica , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Interações Medicamentosas
16.
Int J Mol Sci ; 24(19)2023 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-37834448

RESUMO

The WRKY transcription factor (TF) family is one the largest plant-specific transcription factor families. It has been proven to play significant roles in multiple plant biological processes, especially stress response. Although many WRKY TFs have been identified in various plant species, WRKYs in white birch (Betula platyphylla Suk.) remain to be studied. Here, we identified a total of 68 BpWRKYs, which could be classified into four main groups. The basic physiochemical properties of these TFs were analyzed using bioinformatics tools, including molecular weight, isoelectric point, chromosome location, and predicted subcellular localization. Most BpWRKYs were predicted to be located in the nucleus. Synteny analysis found 17 syntenic gene pairs among BpWRKYs and 52 syntenic gene pairs between BpWRKYs and AtWRKYs. The cis-acting elements in the promoters of BpWRKYs could be enriched in multiple plant biological processes, including stress response, hormone response, growth and development, and binding sites. Tissue-specific expression analysis using qRT-PCR showed that most BpWRKYs exhibited highest expression levels in the root. After ABA, salt (NaCl), or cold treatment, different BpWRKYs showed different expression patterns at different treatment times. Furthermore, the results of the Y2H assay proved the interaction between BpWRKY17 and a cold-responsive TF, BpCBF7. By transient expression assay, BpWRKY17 and BpWRKY67 were localized in the nucleus, consistent with the previous prediction. Our study hopes to shed light for research on WRKY TFs and plant stress response.


Assuntos
Proteínas de Plantas , Fatores de Transcrição , Fatores de Transcrição/metabolismo , Proteínas de Plantas/metabolismo , Estresse Fisiológico/genética , Betula/genética , Betula/metabolismo , Regulação da Expressão Gênica de Plantas , Filogenia
17.
Pharmacol Res ; 196: 106919, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37722517

RESUMO

Community-acquired pneumonia (CAP) is one of the most common infectious diseases, and its morbidity and mortality increase with age. Resistance and mutations development make the use of anti-infective therapy challenging. Chinese patent medicines (CPMs) are often used to treat CAP in China and well tolerable. However, currently there are no evidence-based guideline for the treatment of CAP with CPMs, and the misuse of CPMs is common. Therefore, we established a guideline panel to develop this guideline. We identified six clinical questions through two rounds of survey, and we then systematically searched relevant evidence and performed meta-analyses, evidence summaries and GRADE decision tables to draft recommendations, which were then voted on by a consensus panel using the Delphi method. Finally, we developed ten recommendations based on evidence synthesis and expert consensus. For the treatment of severe CAP in adults, we recommend Tanreqing injection, Reduning injection, Xuebijing injection, Shenfu injection, and Shenmai injection respectively. For the treatment of non-severe CAP in adults, we recommend Tanreqing injection, Reduning injection, Lianhua Qingwen capsule/granule, Qingfei Xiaoyan Pill and Shufeng Jiedu capsule respectively. CPMs have great potential to help in the fight against CAP worldwide, but more high-quality studies are still needed to strengthen the evidence.

18.
Int J Biol Macromol ; 250: 126204, 2023 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-37573914

RESUMO

Different carbon nanotubes (CNTs) contents on high-toughness polylactic acid (PLA)/poly (butylene adipate-co-terephthalate) (PBAT) blends were prepared by one-step melt blending using multifunctional epoxy oligomers (ADR) as reactive compatibilizer. During reactive blending, the PLA or PBAT chains were grafted onto the CNTs by allowing the carboxyl or hydroxyl groups to react with epoxy groups and form a branched CNTs-based copolymer. The branched copolymer at the interface between PLA and PBAT was dispersed through emulsion to improve the polymer-polymer or polymer-nanoparticle entanglement between the molecular chains. Interfacial adhesion, interface layer stability, and system viscoelasticity and compatibility were improved as indicated by rheological curves and dynamic mechanical analysis. The strength and toughness of the sample were simultaneously improved by the addition of CNTs and ADR. The impact strength reached 35.3 kJ/m2, which was approximately 7 times that of the PLA/PBAT blend, and the tensile strength was also increased from 33.6 MPa to 42.8 MPa. The properties of PLA/PBAT blend synergistically modified by ADR and CNTs were obviously better than those of PLA/PBAT blend modified by ADR or CNTs. The toughening synergistic effect of ADR and CNTs on PLA/PBAT was observed with efficiency reaching 3.05. With the further understanding of the toughening mechanism, the branched CNTs-based copolymers and CNTs clusters induce a synergistic effect, which increased the interfacial adhesion and ability of energy dissipation and stress transmission.

19.
Int J Mol Sci ; 24(13)2023 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-37445753

RESUMO

CBF (C-repeat binding factor) transcription factor subfamily belongs to AP2/ERF (Apetala 2/ethylene-responsive factor) transcription factor family, known for playing a vital role in plant abiotic stress response. Although some CBF transcription factors have been identified in several species, such as Arabidopsis, tobacco, tomato and poplar, research of CBF focus mainly on model plant Arabidopsis and have not been reported in Betula platyphylla yet. In this study, a total of 20 BpCBF subfamily members were identified. The conserved domains, physicochemical properties, exon-intron gene structure and the structure of conserved protein motifs of BpCBFs were analyzed via bioinformatic tools. The collinearity analysis of CBF genes was performed between Betula platyphylla and Arabidopsis thaliana, Betula platyphylla, and Populus trichocarpa. The cis-acting elements in the promoter region of BpCBFs were identified, which were mainly environmental stress-related and hormone-related element components. In this case, the expression patterns of the 20 BpCBFs upon ABA or salt treatment were investigated. Most of these transcription factors were responsive to ABA or salt stress in different plant tissues. The up-regulation trend upon cold treatment of the six cold-responsive genes validated by qRT-PCR was consistent with the result of RNA-seq. BpCBF7 showed transcription activating activity. This study sheds light on the responses of BpCBFs to abiotic stress and provides a reference for further study of CBF transcription factors in woody plants.


Assuntos
Arabidopsis , Fatores de Transcrição , Fatores de Transcrição/metabolismo , Arabidopsis/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estresse Fisiológico/genética , Plantas/metabolismo , Regulação da Expressão Gênica de Plantas , Filogenia
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