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1.
Asian J Neurosurg ; 19(1): 82-86, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38751397

RESUMO

Staphylococcus aureus is found in the normal skin and mucosa of approximately 30% of healthy populations and is the most common pathogen in human disease associated with bacteria. They are divided into methicillin-sensitive S . aureus (MSSA) and methicillin-resistant S. aureus (MRSA). The S. aureus strains carrying the Panton-Valentine leukocidin genes (SA-PVL) were initially believed to belong to the MRSA group; however, recent reports showed they also belonged to the MSSA group (MSSA-PVL). SA-PVL is common in skin and soft-tissue infections but rare in musculoskeletal infections, especially in spondylodiscitis. We are reporting a case suffering from cervical spondylodiscitis and epidural abscess associated with MSSA carrying the Panton-Valentine leukocidin genes.

3.
Materials (Basel) ; 17(8)2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38673132

RESUMO

Antibacterial coatings are becoming increasingly attractive for application in the field of biomaterials. In this framework, we developed polymer coating zirconia with antibacterial activity using the "grafting from" methodology. First, 1-(4-vinylbenzyl)-3-butylimidazolium chloride monomer was synthesized. Then, the surface modification of zirconia substrates was performed with this monomer via surface-initiated photo atom transfer radical polymerization for antibacterial activity. X-ray photoelectron spectroscopy, ellipsometry, static contact angle measurements, and an atomic force microscope were used to characterize the films for each step of the surface modification. The results revealed that cationic polymers could be successfully deposited on the zirconia surfaces, and the thickness of the grafted layer steadily increased with polymerization time. Finally, the antibacterial adhesion test was used to evaluate the antibacterial activity of the modified zirconia substrates, and we successfully showed the antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa strains.

4.
Front Microbiol ; 15: 1332448, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38505547

RESUMO

Previously, we pointed out in P. aeruginosa PAO1 biofilm cells the accumulation of a hypothetical protein named PA3731 and showed that the deletion of the corresponding gene impacted its biofilm formation capacity. PA3731 belongs to a cluster of 4 genes (pa3732 to pa3729) that we named bac for "Biofilm Associated Cluster." The present study focuses on the PA14_16140 protein, i.e., the PA3732 (BacA) homolog in the PA14 strain. The role of BacA in rhamnolipid secretion, biofilm formation and virulence, was confirmed by phenotypic experiments with a bacA mutant. Additional investigations allow to advance that the bac system involves in fact 6 genes organized in operon, i.e., bacA to bacF. At a molecular level, quantitative proteomic studies revealed an accumulation of the BAC cognate partners by the bacA sessile mutant, suggesting a negative control of BacA toward the bac operon. Finally, a first crystallographic structure of BacA was obtained revealing a structure homologous to chaperones or/and regulatory proteins.

5.
World Neurosurg ; 185: e461-e466, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38369107

RESUMO

BACKGROUND: Intraoperative neuroelectrophysiology monitoring (IONM) has been used to decrease complications and to increase the successful rate of microvascular decompression (MVD) MVD for hemifacial spasm (HFS). Still, it is not available at limited resource centers. We report the outcome of patients undergoing MVD for HFS without using IONM. METHODS: The variables concerning the patients' demographics (age and gender), clinical characteristics, offending vessels (vertebral artery type and non-vertebral artery type), postoperative grade of HFS, and postoperative complications of HFS patients undergoing MVD were retrospectively reviewed and collected. The scoring system provided by the Japan Society for MVD was used to evaluate the postoperative outcome of HFS. Postoperative hearing ability was evaluated according to a subjective assessment of the patients. RESULTS: A total of 228 patients were recruited. Their median age was 51.0 (44.0-57.0) years old. The total cure effect was observed in 207 (90.8%) patients within the first week after the surgery and in 200 (96.1%) patients in a 2-year follow-up. Permanent hearing disturbance happened in 2 patients (0.9%). No patient had permanent unilateral deafness (0%). No postoperative permanent facial paralysis was reported. CONCLUSIONS: MVD without IONM may be performed safely and effectively to treat patients with HFS.


Assuntos
Espasmo Hemifacial , Cirurgia de Descompressão Microvascular , Humanos , Espasmo Hemifacial/cirurgia , Cirurgia de Descompressão Microvascular/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Resultado do Tratamento , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Monitorização Neurofisiológica Intraoperatória/métodos , Monitorização Intraoperatória/métodos
6.
Clin Cancer Res ; 30(10): 2121-2139, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38416404

RESUMO

PURPOSE: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed. EXPERIMENTAL DESIGN: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF biomarker approach in retrospective clinical data sets of patients treated with platinum-based chemotherapy or ATR inhibition. RESULTS: ART0380 had potent, selective antitumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10,609 ATM variants in 8,587 patient tumors. Cancer lineage-specific differences were seen in the prevalence of deleterious (Tier 1) versus unknown/benign (Tier 2) variants, selective pressure for loss of heterozygosity, and concordance between a deleterious variant and ATM loss of protein (LOP). A novel ATM LOF biomarker approach that accounts for variant classification, relationship to ATM LOP, and tissue-specific penetrance significantly enriched for patients who benefited from platinum-based chemotherapy or ATR inhibition. CONCLUSIONS: These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia , Neoplasias , Humanos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Animais , Neoplasias/genética , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Camundongos , Mutação com Perda de Função , Linhagem Celular Tumoral , Biomarcadores Tumorais/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Especificidade de Órgãos/genética
7.
Jpn J Infect Dis ; 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38296537

RESUMO

This cross-sectional study investigated the antimicrobial resistance (AMR) patterns of Gram-negative pathogens isolated from 4,789 hospitalized patients with lower respiratory tract infections (LRTIs). Of the collected specimens, 1,325 (27.7%) specimens tested positive for Gram-negative bacteria. The most prevalent isolates were Acinetobacter baumannii (38.6%), Pseudomonas aeruginosa (33.5%), Klebsiella pneumoniae (18.7%), Escherichia coli (5.6%), and Klebsiella aerogenes (3.5%). Antimicrobial resistance analysis revealed high resistance rates among A. baumannii isolates, showing resistance (79.9%-100%) to multiple classes of antibiotics, except amikacin, trimethoprim/sulfamethoxazole, and colistin. P. aeruginosa displayed lower resistance to colistin (<10%), but resistance to other antibiotics was high. K. pneumoniae displayed elevated resistance rates against most penicillins, ranging from 90.0% to 100.0%. In contrast, the resistance rates were notably lower for colistin (7.1%) and amikacin (16.7%). K. aerogenes showed high resistance to various antibiotics, while sensitivity was observed for amikacin (95.1%), ampicillin (100.0%), and colistin (100.0%). E. coli exhibited resistance to ampicillin (96.9%) but showed maximum sensitivity to several antibiotics. The study identified significant antimicrobial resistance trends and highlighted the prevalence of multidrug-resistant strains (93.6% for K. aerogenes and 69.1%-92.4% for other isolates). These findings emphasize the urgent need for appropriate antibiotic stewardship practices to combat antimicrobial resistance in Gram-negative pathogens associated with LRTIs.

8.
Skeletal Radiol ; 53(7): 1287-1293, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38217703

RESUMO

OBJECTIVE: To describe femoroacetabular posterior translation (FAPT) using dynamic hip ultrasonography (DHUS), and to determine the inter- and intra-rater reliability of hip ultrasound measurements of FAPT. MATERIALS AND METHODS: The study design was a feasibility study of 13 healthy young adults (26 hips) using test-retest analysis. The data was collected prospectively over a 2-week time period. Three DHUS measurements (posterior neutral (PN), flexion, adduction, and internal rotation (PFADIR), and stand and load (PStand) were measured by four independent raters (2 senior who divided the cohort, 1 intermediate, 1 junior) at two time points for bilateral hips of each participant. Reliability was assessed by calculating the intraclass correlation coefficient (ICC) along with 95% confidence intervals (CIs) for each rater and across all raters. RESULTS: A total of 468 US scans were completed. The mean age of the cohort was 25.7 years (SD 5.1 years) and 54% were female. The inter-rater reliability was excellent for PFADIR (ICC 0.85 95% CI 0.76-0.91), good for PN (ICC 0.69 95% CI 0.5-0.81), and good for PStand (ICC 0.72 95% CI 0.55-0.83). The intra-rater reliability for all raters was good for PFADIR (ICC 0.60 95% CI 0.44-0.73), fair for PN (ICC 0.42 95% CI 0.21-0.59), and fair for PStand (ICC 0.42 95% CI 0.22-0.59). CONCLUSION: This is the first study to present a protocol using dynamic ultrasonography to measure FAPT. DHUS measure for FAPT was shown to be reliable across raters with varying levels of ultrasound experience.


Assuntos
Estudos de Viabilidade , Ultrassonografia , Humanos , Feminino , Masculino , Reprodutibilidade dos Testes , Ultrassonografia/métodos , Adulto , Estudos Prospectivos , Articulação do Quadril/diagnóstico por imagem , Amplitude de Movimento Articular/fisiologia
9.
Nat Plants ; 9(10): 1598-1606, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37735255

RESUMO

Nitrogen is an essential macronutrient that is absorbed by roots and stored in leaves, mainly as ribulose-1,5-bisphosphate carboxylase/oxygenase1,2. During nitrogen deficiency (-N), plants activate leaf senescence for source-to-sink nitrogen remobilization for adaptative growth3-6. However, how -N signals perceived by roots are propagated to shoots remains underexplored. We found that ELF18-INDUCED LONG NONCODING RNA 1 (ELENA1) is -N inducible and attenuates -N-induced leaf senescence in Arabidopsis. Analysis of plants expressing the ELENA1 promoter ß-glucuronidase fusion gene showed that ELENA1 is transcribed specifically in roots under -N. Reciprocal grafting of the wild type and elena1 demonstrated that ELENA1 functions systemically. ELENA1 dissociates the MEDIATOR SUBUNIT 19a-ORESARA1 transcriptional complex, thereby calibrating senescence progression. Our observations establish the systemic regulation of leaf senescence by a root-derived long non-coding RNA under -N in Arabidopsis.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , RNA Longo não Codificante , Nitrogênio/metabolismo , Arabidopsis/metabolismo , RNA Longo não Codificante/genética , Senescência Vegetal , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Folhas de Planta/metabolismo , Regulação da Expressão Gênica de Plantas
10.
Int J Pharm ; 643: 123263, 2023 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-37482230

RESUMO

Most nanoparticles produced for drug delivery purposes are spherical. However, the literature suggests that elongated particles are advantageous, notably in terms of cellular uptake. Thus, we synthesized biocompatible polylactide-b-poly(ethylene glycol) (PLA-PEG) polymers bearing carboxylate moieties, and used them to formulate worm-like nanoparticles by a simple emulsion-evaporation process. Worm-like nanoparticles with variable aspect ratio were obtained by simply adjusting the molar mass of the PLA block: the shorter the molar mass of the PLA block, the more elongated the particles. As PLA molar mass decreased from 80,000 g/mol to 13,000 g/mol, the proportion of worm-like nanoparticles increased from 0 to 46%, in contradiction with the usual behavior of block polymers based on their packing parameter. To explain this unusual phenomenon, we hypothesized the shape arises from a combination of steric and electrostatic repulsions between PEG chains bearing a carboxylate moiety present at the dichloromethane-water interface during the evaporation process. Worm-like particles turned out to be unstable when incubated at 37 °C, above polymer glass transition temperature. Indeed, above Tg, a Plateau-Rayleigh instability occurs, leading to the division of the worm-like particles into spheres. However, this instability was slow enough to assess worm-like particles uptake by murine macrophages. A slight but significant increase of internalization was observed for worm-like particles, compared to their spherical counterparts, confirming the interest of developing biocompatible anisotropic nanoparticles for pharmaceutical applications such as drug delivery.


Assuntos
Nanopartículas , Polímeros , Camundongos , Animais , Polietilenoglicóis , Poliésteres , Sistemas de Liberação de Medicamentos , Tamanho da Partícula
11.
Antibiotics (Basel) ; 12(6)2023 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-37370385

RESUMO

The poor bioavailability of antibiotics at infection sites is one of the leading causes of treatment failure and increased bacterial resistance. Therefore, developing novel, non-conventional antibiotic delivery strategies to deal with bacterial pathogens is essential. Here, we investigated the encapsulation of two fluoroquinolones, ciprofloxacin and levofloxacin, into polymer-based nano-carriers (nano-antibiotics), with the goal of increasing their local bioavailability at bacterial infection sites. The formulations were optimized to achieve maximal drug loading. The surfaces of nano-antibiotics were modified with anti-staphylococcal antibodies as ligand molecules to target S. aureus pathogens. The interaction of nano-antibiotics with the bacterial cells was investigated via fluorescent confocal microscopy. Conventional tests (MIC and MBC) were used to examine the antibacterial properties of nano-antibiotic formulations. Simultaneously, a bioluminescence assay model was employed, revealing the rapid and efficient assessment of the antibacterial potency of colloidal systems. In comparison to the free-form antibiotic, the targeted nano-antibiotic exhibited enhanced antimicrobial activity against both the planktonic and biofilm forms of S. aureus. Furthermore, our data suggested that the efficacy of a targeted nano-antibiotic treatment can be influenced by its antibiotic release profile.

12.
Data Brief ; 49: 109305, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37346928

RESUMO

This paper presents a dataset from a survey of student perceptions and experiences of quality assurance in Vietnamese higher education institutions. Data were collected from July to September 2020 using the online survey via Google Forms. The survey was sent to students via their email and social media, and there were 1323 valid responses. The data collection instrument was developed based on an international survey administered by UNESCO. The survey was designed to elicit data with respect to students' views on institutional quality policy and model, quality assurance procedures and tools, and student survey. The dataset serves as an insightful reference for institutional practitioners and policymakers in quality assurance to revise internal quality assurance policies and instruments to enhance the quality of teaching and learning. Moreover, the dataset could be of interest to other educational researchers who can use it to investigate students' understanding and viewpoints on quality assurance.

13.
Biomed Phys Eng Express ; 9(4)2023 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-37137289

RESUMO

Ozone depletion has always been a hot crisis around the globe. Its consequence is the increase in ultraviolet radiation at the surface in many regions and countries, which then causes danger to the human immune system, eyes, and especially skin - the part that is directly exposed most to the sunlight. According to the World Health Organization, the number of cases of skin cancer is higher than that of breast, prostate, and lung cancer combined. Therefore, there has been a lot of research to apply deep learning models in solving the problem of skin cancer classification. This paper proposes a novel approach, named MetaAttention, aimed at improving the performance of transfer learning models for skin lesion classification. The method combines image features with patients' metadata features using the attention mechanism, incorporating clinical knowledge related to ABCD signals to better distinguish melanoma cell carcinoma disease, which has long been a significant challenge for researchers. The experimental results indicate that the proposed approach outperforms the state-of-the-art method, EfficientNet-B4, achieving an accuracy of 89.9% with Scale-dot product MetaAttention and 90.63% with Additive MetaAttention. The method has the potential to support dermatologists in diagnosing skin lesions effectively and efficiently. Furthermore, with larger datasets, our method could be further fine-tuned to achieve even better performance on a broader range of labels.


Assuntos
Melanoma , Dermatopatias , Neoplasias Cutâneas , Masculino , Humanos , Melanoma/diagnóstico , Raios Ultravioleta , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Pele/patologia
14.
Materials (Basel) ; 16(5)2023 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-36903179

RESUMO

Urbanization processes in Asia are still ongoing; thus, aggregate demand is expected to increase in following years. Even though construction and demolition waste is a source for secondary building materials in industrialized countries, it is not yet an alternative construction material source in Vietnam as the urbanization process is still ongoing. Thus, there is a need for river sand and aggregates alternatives in concrete, namely manufactured sand (m-sand) from primary solid rock materials and secondary waste materials. The focus in the present study for Vietnam was on m-sand sand as alternative for river sand, and different ashes as alternatives for cement in concrete. The investigations comprised concrete lab tests according to the formulations of concrete strength class C 25/30 in accordance with DIN EN 206, followed by a lifecycle assessment study in order to identify the environmental impact of the alternatives. In total 84 samples were investigated, consisting of 3 reference samples, 18 samples with primary substitutes, 18 samples with secondary substitutes, and 45 samples with cement substitutes. This kind of holistic investigation approach comprising material alternatives and accompanying LCA was the first study for Vietnam, and even for Asia, and represents a substantial added value for future policy development in order to cope with resource scarcity. The results show that with the exception of metamorphic rocks, all m-sands meet the requirements for quality concrete. In terms of cement replacement, the mixes showed that a higher percentage of ash reduces the compressive strength. The compressive strength values of the mixes with up to 10% coal filter ash or rice husk ash were equivalent to the C25/30 standard concrete formulation. Higher ash contents up to 30% lead to the reduction of the concrete quality. The LCA study's results highlighted the better environmental footprints across environmental impact categories in the 10% substitution material in comparison to the use of primary materials. The LCA analysis results showed that cement as a component in concrete holds the highest footprint. The use of secondary waste as alternative for cement provides significant environmental advantage.

15.
J Infect Dis ; 227(7): 917-925, 2023 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-36735316

RESUMO

BACKGROUND: Neisseria gonorrhoeae is a major public health problem due to increasing incidence and antimicrobial resistance. Genetic markers of reduced susceptibility have been identified; the extent to which those are representative of global antimicrobial resistance is unknown. We evaluated the performance of whole-genome sequencing (WGS) used to predict susceptibility to ciprofloxacin and other antimicrobials using a global collection of N. gonorrhoeae isolates. METHODS: Susceptibility testing of common antimicrobials and the recently developed zolifodacin was performed using agar dilution to determine minimum inhibitory concentrations (MICs). We identified resistance alleles at loci known to contribute to antimicrobial resistance in N. gonorrhoeae from WGS data. We tested the ability of each locus to predict antimicrobial susceptibility. RESULTS: A total of 481 N. gonorrhoeae isolates, collected between 2004 and 2019 and making up 457 unique genomes, were sourced from 5 countries. All isolates with demonstrated susceptibility to ciprofloxacin (MIC ≤0.06 µg/mL) had a wild-type gyrA codon 91. Multilocus approaches were needed to predict susceptibility to other antimicrobials. All isolates were susceptible to zoliflodacin, defined by an MIC ≤0.25 µg/mL. CONCLUSIONS: Single marker prediction can be used to inform ciprofloxacin treatment of N. gonorrhoeae infection. A combination of molecular markers may be needed to determine susceptibility for other antimicrobials.


Assuntos
Anti-Infecciosos , Gonorreia , Humanos , Neisseria gonorrhoeae , Antibacterianos/farmacologia , Gonorreia/tratamento farmacológico , Gonorreia/epidemiologia , Ciprofloxacina/farmacologia , Anti-Infecciosos/farmacologia , Testes de Sensibilidade Microbiana , Farmacorresistência Bacteriana/genética , Azitromicina/farmacologia
16.
Antibiotics (Basel) ; 13(1)2023 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-38275318

RESUMO

The emergence of multi-drug resistant pathogens is a major public health problem, leading us to rethink and innovate our bacterial control strategies. Here, we explore the antibiofilm and antivirulence activities of nineteen 6-polyaminosterol derivatives (squalamine-based), presenting a modulation of their polyamine side chain on four major pathogens, i.e., carbapenem-resistant A. baumannii (CRAB) and P. aeruginosa (CRPA), methicillin-resistant S. aureus (MRSA), and vancomycin-resistant E. faecium (VRE) strains. We screened the effect of these derivatives on biofilm formation and eradication. Derivatives 4e (for CRAB, VRE, and MRSA) and 4f (for all the strains) were the most potent ones and displayed activities as good as those of conventional antibiotics. We also identified 11 compounds able to decrease by more than 40% the production of pyocyanin, a major virulence factor of P. aeruginosa. We demonstrated that 4f treatment acts against bacterial infections in Galleria mellonella and significantly prolonged larvae survival (from 50% to 80%) after 24 h of CRAB, VRE, and MRSA infections. As shown by proteomic studies, 4f triggered distinct cellular responses depending on the bacterial species but essentially linked to cell envelope. Its interesting antibiofilm and antivirulence properties make it a promising a candidate for use in therapeutics.

17.
Genes (Basel) ; 13(11)2022 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-36360175

RESUMO

Morinda officinalis How is well-known as a valuable medicinal plant found in some regions of Vietnam. This species is mainly used for treating male impotence, irregular menstruation, and rheumatoid arthritis. This study aimed to identify the species of and genetic diversity in three M. officinalis populations: one each in Quang Binh (QB), Thua Thien Hue (TTH), and Quang Nam (QN). In this study, four DNA barcoding markers (ITS1, ITS2, matK, and rbcL) were used to identify the species and 22 microsatellite markers were applied for population structure and diversity analyses. The results showed that the sequences of gene regions studied in M. officinalis had a high similarity (>95%) to the ITS1, ITS2, matK, and rbcL sequences of M. officinalis on BLAST. Of the four DNA barcoding markers used, ITS1 and ITS2 showed higher efficiency in DNA amplification of M. officinalis. From this study, 27 GenBank codes were published on BLAST. The results also revealed high levels of genetic diversity in populations. The average observed and expected heterozygosity values were HO = 0.513 and HE = 0.612, respectively. The average FST value was 0.206. Analysis of molecular variance (AMOVA) showed 70% variation within populations and 30% among populations. The population structure of M. officinalis inferred in STRUCTURE revealed that the optimum number of genetic groups for the admixture model was K = 2. These findings provided vital background information for future studies in the conservation of M. officinalis in both ex situ and in situ plans.


Assuntos
Código de Barras de DNA Taxonômico , Morinda , Filogenia , Código de Barras de DNA Taxonômico/métodos , DNA de Plantas/genética , Análise de Sequência de DNA , Vietnã , Marcadores Genéticos , Repetições de Microssatélites/genética , Variação Genética/genética
18.
J Adv Pract Oncol ; 13(7): 664-672, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36199491

RESUMO

Background: Advanced practice providers (APPs) play important roles in enrolling, educating, and caring for patients in clinical trials. However, much remains unknown about the role of APPs in managing adverse events (AEs) in early (phase I to II) clinical trials. In this study, we assessed the outpatient management of grade 3 to 4 AEs by APPs in early trials and characterized the workflow of our APP Phase I to II Fast Track (FT) Clinic. Patients and Methods: We retrospectively reviewed records of patients with advanced or metastatic solid tumors enrolled in phase I to II clinical trials who were seen by APPs from September 2017 to August 2018 in the APP phase I to II FT clinic in the Department of Investigational Cancer Therapeutics. Results: A total of 808 patients enrolled in 159 clinical trials were seen in 2,697 visits (median 3 visits per patient; range 1-28) by 10 APPs. Treatment was interrupted in 6.9% of visits, and grade 3 to 4 AEs were seen in 5.4% of visits; however, patients from 1.4% of visits were sent to the emergency center (EC) and/or admitted. Patients referred to the EC and/or admitted were more likely to have baseline hypoalbuminemia, high lactate dehydrogenase, and poor Eastern Cooperative Oncology Group performance status (i.e., ECOG > 1; p < .001). There were no associations between EC referral and gender, APP years of experience, or type of treatment. Conclusions: The APP Phase I to II FT Clinic has an important role in the management of AEs by APPs in early clinical trials in the outpatient setting, potentially avoiding EC visits and admissions.

19.
New Phytol ; 236(5): 1779-1795, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36093737

RESUMO

The mediator complex is highly conserved in eukgaryotes and is integral for transcriptional responses. Mediator subunits associate with signal-responsive transcription factors (TF) to activate expression of specific signal-responsive genes. As the key TF of Arabidopsis thaliana senescence, ORESARA1 (ORE1) is required for nitrogen deficiency (-N) induced senescence; however, the mediator subunit that associates with ORE1 remains unknown. Here, we show that Arabidopsis MED19a associates with ORE1 to activate -N senescence-responsive genes. Disordered MED19a forms inducible nuclear condensates under -N that is regulated by decreasing MED19a lysine acetylation. MED19a carboxyl terminus (cMED19a) harbors a mixed-charged intrinsically disordered region (MC-IDR) required for ORE1 interaction and liquid-liquid phase separation (LLPS). Plant and human cMED19 are sufficient to form heterotypic condensates with ORE1. Human cMED19 MC-IDR, but not yeast cMED19 IDR, partially complements med19a suggesting functional conservation in evolutionarily distant eukaryotes. Phylogenetic analysis of eukaryotic cMED19 revealed that the MC-IDR could arise through convergent evolution. Our result of MED19 MC-IDR suggests that plant MED19 is regulated by phase separation during stress responses.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Complexo Mediador , Humanos , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas , Complexo Mediador/genética , Complexo Mediador/metabolismo , Nutrientes , Filogenia , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
20.
JCI Insight ; 7(16)2022 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-35862204

RESUMO

Accumulation of activated natural killer (NK) cells in tissues during Ebola virus infection contributes to Ebola virus disease (EVD) pathogenesis. Yet, immunization with Ebola virus-like particles (VLPs) comprising glycoprotein and matrix protein VP40 provides rapid, NK cell-mediated protection against Ebola challenge. We used Ebola VLPs as the viral surrogates to elucidate the molecular mechanism by which Ebola virus triggers heightened NK cell activity. Incubation of human peripheral blood mononuclear cells with Ebola VLPs or VP40 protein led to increased expression of IFN-γ, TNF-α, granzyme B, and perforin by CD3-CD56+ NK cells, along with increases in degranulation and cytotoxic activity of these cells. Optimal activation required accessory cells like CD14+ myeloid and CD14- cells and triggered increased secretion of numerous inflammatory cytokines. VP40-induced IFN-γ and TNF-α secretion by NK cells was dependent on IL-12 and IL-18 and suppressed by IL-10. In contrast, their increased degranulation was dependent on IL-12 with little influence of IL-18 or IL-10. These results demonstrate that Ebola VP40 stimulates NK cell functions in an IL-12- and IL-18-dependent manner that involves CD14+ and CD14- accessory cells. These potentially novel findings may help in designing improved intervention strategies required to control viral transmission during Ebola outbreaks.


Assuntos
Ebolavirus , Doença pelo Vírus Ebola , Doença pelo Vírus Ebola/prevenção & controle , Humanos , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Interleucina-18 , Células Matadoras Naturais , Leucócitos Mononucleares , Fator de Necrose Tumoral alfa/metabolismo
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