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2.
Nat Commun ; 14(1): 5335, 2023 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-37660077

RESUMO

The role of the immune microenvironment in maintaining disease remission in patients with multiple myeloma (MM) is not well understood. In this study, we comprehensively profile the immune system in patients with newly diagnosed MM receiving continuous lenalidomide maintenance therapy with the aim of discovering correlates of long-term treatment response. Leveraging single-cell RNA sequencing and T cell receptor ß sequencing of the peripheral blood and CyTOF mass cytometry of the bone marrow, we longitudinally characterize the immune landscape in 23 patients before and one year after lenalidomide exposure. We compare patients achieving sustained minimal residual disease (MRD) negativity to patients who never achieved or were unable to maintain MRD negativity. We observe that the composition of the immune microenvironment in both the blood and the marrow varied substantially according to both MRD negative status and history of autologous stem cell transplant, supporting the hypothesis that the immune microenvironment influences the depth and duration of treatment response.


Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Lenalidomida , Imunofenotipagem , Pacientes , Receptores de Antígenos de Linfócitos T alfa-beta , Microambiente Tumoral
3.
Opt Express ; 31(15): 23746-23753, 2023 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-37475218

RESUMO

This paper presents a novel target positioner system that exhibits high sensitivity and accuracy. Specifically, the system is capable of precisely locating rough target surfaces within a micron-scale in the focal plane. The high sensitivity comes from the nonlinear detection scheme which uses the two-photon-absorption process in a Si-photodiode and a CMOS sensor at 1550 [nm]. The setup employs a confocal configuration that is easy to align and does not require a conjugated focal plane selective aperture (pinhole), thus demonstrating its feasibility and tilt tolerance of the target. Moreover, the system offers high accuracy up to 5 [µm], which corresponds to the step size of the focus scanning. The presented positioner system has potential applications in microfabrication with lasers and laser-driven plasma accelerators even at high repetition rates, limited by the detection bandwidth of the photodiode. Additionally, the principle can be extended to cameras if spatial information is needed and the system design can be extended to other spectral ranges with minimal changes.

4.
Commun Biol ; 6(1): 770, 2023 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-37481629

RESUMO

Low blood flow through the fetal left heart is often conjectured as an etiology for hypoplastic left heart syndrome (HLHS). To investigate if a decrease in left heart flow results in growth failure, we generate left ventricular inflow obstruction (LVIO) in mid-gestation fetal lambs by implanting coils in their left atrium using an ultrasound-guided percutaneous technique. Significant LVIO recapitulates important clinical features of HLHS: decreased antegrade aortic valve flow, compensatory retrograde perfusion of the brain and ascending aorta (AAo) from the arterial duct, severe left heart hypoplasia, a non-apex forming LV, and a thickened endocardial layer. The hypoplastic AAo have miRNA-gene pairs annotating to cell proliferation that are inversely differentially expressed by bulk RNA-seq. Single-nucleus RNA-seq of the hypoplastic LV myocardium shows an increase in fibroblasts with a reciprocal decrease in cardiomyocyte nuclei proportions. Fibroblasts, cardiomyocytes and endothelial cells from hypoplastic myocardium have increased expression of extracellular matrix component or fibrosis genes with dysregulated fibroblast growth factor signaling. Hence, a severe sustained ( ~ 1/3 gestation) reduction in fetal left heart flow is sufficient to cause left heart hypoplasia. This is accompanied by changes in cellular composition and gene expression consistent with a pro-fibrotic environment and aberrant induction of mesenchymal programs.


Assuntos
Células Endoteliais , Carneiro Doméstico , Ovinos , Animais , Feto , Miocárdio , Ventrículos do Coração
5.
J Intellect Disabil Res ; 67(7): 630-639, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37042218

RESUMO

BACKGROUND: Alterations in oral health have a negative impact on the quality of life of persons with intellectual disabilities (PwIDs). Chewing is a process that influences and determines optimal oral health. However, little is known about how intellectual disability (ID) affects masticatory performance. This study aimed to analyse the differences in masticatory performance between young adults with IDs, young adults without IDs and older adults without IDs. METHODS: A cross-sectional analytical design was used. The masticatory performance was evaluated with a chewing gum validated instrument. In addition, the labial and tongue strength was assessed with the Iowa Oral Performance Instrument. We compared the masticatory performance between groups using one-way analysis of covariance. Body mass index, muscle mass, missing teeth, lip strength and tongue strength were included as separate covariates. A multivariate regression analysis was performed to identify which independent variables could explain masticatory performance in each group. RESULTS: Thirty-two PwIDs, 31 young adults without IDs and 32 older adults without IDs were recruited. PwIDs showed poorer masticatory performance compared with older adults (mean difference: -3.06, 95% confidence interval: -3.87 to -2.26) and healthy controls (mean difference: -2.38, 95% confidence interval: -3.19 to -1.57). The analysis of covariance showed significant difference between groups in the masticatory performance (F = 47.35, P < 0.001, ηp 2  = 0.507). Missing teeth (P < 0.001), right lip strength (P = 0.025) and tongue strength (P = 0.007) as covariables showed a significant interaction with the model. In the PwID group, lip strength and lack of teeth explained 58% of the variance in masticatory performance (R2  = 0.580, standard error = 1.12, P < 0.001). CONCLUSIONS: Persons with intellectual disabilities have a poorer masticatory performance than adults without IDs. Our findings indicate that the primary determinants of optimal masticatory function in PwIDs are the strength of the lip seal and the number of missing teeth.


Assuntos
Deficiência Intelectual , Humanos , Adulto Jovem , Idoso , Estudos Transversais , Lábio , Qualidade de Vida , Língua/fisiologia
6.
Arch. Soc. Esp. Oftalmol ; 98(3): 142-149, mar. 2023. tab
Artigo em Espanhol | IBECS | ID: ibc-216821

RESUMO

Antecedentes El estrabismo genera un impacto psicosocial negativo en los pacientes adultos, afectando aspectos como la autopercepción y la calidad de vida. No existe en Colombia una escala que permita medir dicho impacto. Objetivo Realizar la traducción y adaptación transcultural del instrumento AS-20 al español colombiano, para medición de la calidad de vida en pacientes adultos con estrabismo en Colombia. Materiales y métodos Prueba piloto de un estudio de corte transversal de traducción, traducción inversa y adaptación del instrumento de medición tipo escala de calidad de vida AS-20 de su idioma original en pacientes adultos con estrabismo en Bogotá, Colombia. Resultados Dieciséis pacientes fueron evaluados. El rango de edad fue entre 18 y 68 años, con un promedio de 41 años. La escala fue respondida en una media de tiempo de 10,62min. Se reportó dificultad en 3 individuos para la comprensión de 2 ítems (preguntas 8 y 14), los cuales se ajustaron, resolviendo la dificultad. Conclusión Se realizó la traducción y prueba piloto de la escala AS-20 a español colombiano identificando y corrigiendo los problemas de traducción en la prueba. Este es el primer paso del proceso de adaptación transcultural. Con base en los resultados, la validación y adaptación transcultural se puede finalizar en un próximo estudio (AU)


Background Strabismus generates a negative psychosocial impact on adult patients, affecting aspects such as self-perception and quality of life. There is no scale in Colombian Spanish that measures these impacts. Objective To carry out the translation and cross-cultural adaptation of the AS-20 instrument into Colombian Spanish, for measuring the quality of life in adult patients with strabismus in Colombia. Materials and methods Pilot test of a cross-sectional study for the translation, reverse translation, and cross-cultural adaptation of the AS-20 instrument from its original language, English, to Colombian Spanish, in adult patients with strabismus in Bogotá, Colombia. Results Sixteen patients were assessed. The age range was between 18 and 68 years with a mean age of 41 years. The scale was answered in an average time of 10.62min. Difficulty was reported in 3 individuals for understanding 2 items (questions 8 and 14), which were resolved. Conclusion The translation and pilot test of AS-20 scale into Colombian Spanish was carried out, identifying and solving translational difficulties. It is the first step in the cross-cultural adaptation process. Based on the results, the validation and cross-cultural adaptation can be completed in a future study (AU)


Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Inquéritos e Questionários , Traduções , Comparação Transcultural , Qualidade de Vida , Estrabismo/psicologia , Colômbia , Pilotos , Reprodutibilidade dos Testes , Estudos Transversais
7.
Anaesthesia ; 78(2): 188-196, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36351436

RESUMO

Genicular nerves block is a promising technique to treat acute postoperative pain in total knee arthroplasty. Similar to surgeon-administered local infiltration analgesia, it targets sensory branches from the knee capsule, but through a selective ultrasound-guided injection that reduces local anaesthetic dose (150 ml ropivacaine 0.2% with local infiltration analgesia vs. 20 ml with genicular nerves block). This randomised non-inferiority trial compared the analgesic efficacy of genicular nerves block vs. local infiltration analgesia in the first 24 h following total knee arthroplasty. Sixty patients were randomly allocated to receive either ultrasound-guided block of five genicular nerves or local infiltration analgesia. The primary outcome was rest pain numeric rating scale (0-10) at 24 h. Secondary outcomes included pain numeric rating scale (rest and movement) and cumulative opioid consumption during the first 24 h. We analysed 29 patients in the genicular nerves block group and 30 in the local infiltration analgesia group. We found that the median difference (95%CI) in postoperative rest pain at 24 h (non-inferiority criteria, Δ = 1) was -1.0 (-2.0 to 1.0, p < 0.001). Median difference in cumulative opioid consumption was 0.0 mg (-3.0-5.0, p < 0.001) meeting the non-inferiority criteria, Δ = 23 mg. We conclude that genicular nerves block of five nerves provides non-inferior analgesia in the first 24 h following surgery compared with local infiltration analgesia, but with a considerable reduction in the local anaesthetic dose.


Assuntos
Analgesia , Artroplastia do Joelho , Bloqueio Nervoso , Humanos , Anestésicos Locais , Analgésicos Opioides/uso terapêutico , Bloqueio Nervoso/métodos , Analgesia/métodos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Analgésicos/uso terapêutico , Ultrassonografia de Intervenção
8.
Arch Soc Esp Oftalmol (Engl Ed) ; 98(3): 142-149, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36577464

RESUMO

BACKGROUND: Strabismus generates a negative psychosocial impact on adult patients, affecting aspects such as self-perception and quality of life. There is no scale in Colombian Spanish that measures these impacts. OBJECTIVE: To carry out the translation and cross-cultural adaptation of the AS-20 instrument into Colombian Spanish. MATERIALS AND METHODS: Pilot test of a cross-sectional Study for the translation, reverse translation, and cross-cultural the AS-20 instrument from its original language, English, to Colombian Spanish, in adult patients with strabismus in Bogotá, Colombia. RESULTS: 16 patients were assessed. The age range was between 18 and 68 years with a mean age of 41 years. The scale was answered in an average time of 10.62min. Difficulty was reported in three individuals for understanding two items (questions 8 and 14), which were resolved. CONCLUSION: The translation and pilot test of AS-20 scale into Colombian Spanish was carried out, identifying and solving translational difficulties. Is the first step in the cross-cultural adaptation process. Based on the results, the validation and cross-cultural adaptation can be completed in a future study.


Assuntos
Qualidade de Vida , Estrabismo , Humanos , Adulto , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Colômbia , Projetos Piloto , Inquéritos e Questionários , Estudos Transversais
10.
Appl Opt ; 61(26): 7539-7546, 2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-36256350

RESUMO

An accurate location of the focal position with respect to a solid target is a key task for different applications, for instance, in laser driven plasma acceleration for x-ray generation where minimum required intensities are above 1014W/cm2. For such practical applications, new approaches for focus location and target delivery techniques are needed to achieve the required intensity, repeatability, and stability. There are different techniques to accomplish the focusing and target positioning task such as interferometry-, microscopy-, astigmatism-, and nonlinear-optics-based techniques, with their respective advantages and limitations. We present improvements of a focusing technique based on an astigmatic method with potential applications where maximum intensity at the target position is necessary. The presented technique demonstrates high accuracy up to 5 µm, below the Rayleigh range, and also its capability to work in rough surfaces targets and tilt tolerance of the target, with respect to the normal of the target surface.

11.
Nature ; 609(7929): 1021-1028, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36131014

RESUMO

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.


Assuntos
Diferenciação Celular , Neoplasias Cerebelares , Meduloblastoma , Metencéfalo , Diferenciação Celular/genética , Linhagem da Célula , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Cerebelo/embriologia , Cerebelo/patologia , Subunidades alfa de Fatores de Ligação ao Core/genética , Proteínas Hedgehog/metabolismo , Histona Desmetilases , Humanos , Antígeno Ki-67/metabolismo , Meduloblastoma/classificação , Meduloblastoma/genética , Meduloblastoma/patologia , Metencéfalo/embriologia , Metencéfalo/patologia , Proteínas Musculares , Mutação , Fatores de Transcrição Otx/deficiência , Fatores de Transcrição Otx/genética , Proteínas Repressoras , Proteínas com Domínio T/metabolismo , Fatores de Transcrição
12.
J Food Prot ; 85(9): 1265-1272, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35687746

RESUMO

ABSTRACT: In Mexico, the prevalence of Salmonella enterica in low-water-activity foods and its link to outbreaks are unknown. The aim of this study was to determine the microbiological profile and the prevalence of S. enterica in several low-water-activity foods, including peanuts, pecans, raisins, sun-dried tomatoes, and chocolate sprinkles, purchased in retail establishments in Querétaro, Mexico. Seventy samples of each food item sold in bulk were purchased. Aerobic plate count, molds, yeasts, total coliforms, Escherichia coli, and Staphylococcus aureus were quantified in 10-g samples. The prevalence of S. enterica in 25-g samples was determined. From positive samples, S. enterica isolates (60) were characterized based on their antimicrobial susceptibility to 14 antibiotics, the presence-absence of 13 virulence genes, and serotype. The concentration of aerobic plate count, molds, yeasts, total coliforms, and E. coli ranged from 3.1 to 5.2 log CFU g-1, from 2.0 to 2.4 log CFU g-1, from 2.0 to 3.0 log CFU g-1, from 0.6 to 1.1 log most probable number (MPN) g-1, and from 0.5 to 0.9 log MPN g-1, respectively. S. aureus was not detected in any sample (<10 CFU g-1). The prevalence of S. enterica in chocolate sprinkles, raisins, peanuts, pecans, and sun-dried tomatoes was 26, 29, 31, 40, and 52%, respectively. Most isolates (68.3%) were resistant to at least one antibiotic. Chromosome-associated virulence genes were found in all isolates, and only one strain had sopE, and 98.3% of the isolates were grouped in the same virulotype. Among the isolates, the most frequent serotype was Tennessee (51 of 60). According to the characteristics evaluated, we grouped the isolates into 24 clusters. The elevated prevalence of S. enterica highlights the role of low-water-activity food items sold in bulk at markets as potential vehicles for pathogen transmission. Regardless of the low variability among S. enterica isolates, their characterization could be helpful to elucidate which strains are circulating in these foods for improving epidemiological surveillance.


Assuntos
Carya , Chocolate , Salmonella enterica , Solanum lycopersicum , Vitis , Antibacterianos , Arachis , Carya/microbiologia , Contagem de Colônia Microbiana , Escherichia coli , Microbiologia de Alimentos , Solanum lycopersicum/microbiologia , México , Prevalência , Salmonella , Água
13.
Nutr. hosp ; 39(3): 663-677, may. - jun. 2022. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-209949

RESUMO

Antecedentes: los trastornos gastrointestinales (TGI) son comorbilidades comunes en los pacientes con trastornos del espectro autista (TEA); los tratamientos con dietas libres de gluten y caseína (LGLC) o suplementos de prebióticos/probióticos podrían reducir la severidad de los TGI. Objetivo: integrar y discutir la evidencia sobre la efectividad de las terapias con dietas LGLC y suplementos de prebióticos/probióticos sobre los TGI en pacientes con TEA. Metodología: se utilizaron las guías para la publicación de revisiones sistemáticas y metaanálisis (PRISMA). Se analizaron las características de los participantes, las intervenciones dietéticas, la administración de suplementos de prebióticos/prebióticos, los efectos de las intervenciones sobre los TGI, el riesgo de sesgo de los estudios y la seguridad de los tratamientos. Resultados: se analizaron quince investigaciones; la prevalencia de los TGI entre los pacientes con TEA fue alta (58 %; rango, 27-83 %). En más del 20 % de los pacientes intervenidos con dietas LGLC o suplementos disminuyó la severidad de los TGI (principalmente estreñimiento, diarrea y dolor abdominal). Se reportaron aumentos en los conteos de bacterias benéficas y una disminución de la proporción de bacterias patógenas tras el uso de los suplementos. Sin embargo, todas estas investigaciones presentaron sesgos metodológicos importantes. Conclusiones: aunque se han encontrado reducciones en la frecuencia y severidad de algunos TGI, la efectividad de estos tratamientos aún no se ha comprobado. Dadas las diferencias metodológicas de las investigaciones, se justifica el diseño de estudios rigurosos para evaluar los efectos terapéuticos de estos tratamientos sobre la salud gastrointestinal en pacientes con TEA (AU)


Background: gastrointestinal disorders (GIDs) are common comorbidities in patients with autism spectrum disorders (ASD); treatments with gluten- and casein-free (LGLC) diets or prebiotic/probiotic supplements may reduce the severity of GIDs. Objective: to integrate and discuss the evidence on the effectiveness of LGLC diet therapies and prebiotic/probiotic supplements on GIDs in patients with ASD. Methodology: the guidelines for the publication of systematic reviews and meta-analyses (PRISMA) were used. Participant characteristics, dietary interventions, prebiotic/prebiotic supplementation, effects of interventions on GIDs, risk of bias, and safety of treatments were analyzed. Results: fifteen investigations were analyzed; the prevalence of GIDs among patients with ASD was high (58 %; range, 27-83 %). In more than 20 % of the patients managed with LGLC diets or supplements GID severity decreased (mainly constipation, diarrhea, and abdominal pain). Increases in the counts of beneficial bacteria and a decrease in the proportion of pathogenic bacteria were reported after supplement use. However, all these investigations had significant methodological biases. Conclusions: although reductions in the frequency and severity of some GIDs have been found, the effectiveness of these treatments has not been proven yet. Given the methodological differences in the investigations, the design of rigorous studies to evaluate the therapeutic effects of these treatments on gastrointestinal health in patients with ASD is warranted (AU)


Assuntos
Humanos , Transtorno do Espectro Autista/complicações , Gastroenteropatias/dietoterapia , Gastroenteropatias/etiologia , Alimento Funcional , Prebióticos/administração & dosagem , Probióticos/administração & dosagem
14.
Prog Neurobiol ; 209: 102208, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34923049

RESUMO

Sleep disorders have been linked to alterations of gut microbiota composition in adult humans and animal models, but it is unclear how this link develops. With longitudinal assessments in 162 healthy infants, we present a so far unrecognized sleep-brain-gut interrelationship. First, we report a link between sleep habits and gut microbiota: daytime sleep is associated with bacterial diversity, and nighttime sleep fragmentation and variability are linked with bacterial maturity and enterotype. Second, we demonstrate a sleep-brain-gut link: bacterial diversity and enterotype are associated with sleep neurophysiology. Third, we show that the sleep-brain-gut link is relevant in development: sleep habits and bacterial markers predict behavioral-developmental outcomes. Our results demonstrate the dynamic interplay between sleep, gut microbiota, and the maturation of brain and behavior during infancy, which aligns with the newly emerging concept of a sleep-brain-gut axis. Importantly, sleep and gut microbiota represent promising health targets since both can be modified non-invasively. As many adult diseases root in early childhood, leveraging protective factors of adequate sleep and age-appropriate gut microbiota in infancy could constitute a health promoting factor across the entire human lifespan.


Assuntos
Microbioma Gastrointestinal , Animais , Encéfalo , Pré-Escolar , Humanos , Sono
15.
Encephale ; 48(6): 668-673, 2022 Dec.
Artigo em Francês | MEDLINE | ID: mdl-34802708

RESUMO

INTRODUCTION: The coronavirus disease (COVID-19) pandemic has caused a major health crisis and the quarantine of most of the planet's population. During confinement, anxiety symptoms may appear. The pandemic dramatically changes the lives of individuals by becoming a concrete manifestation of the threat. Constant exposure to information about the virus can increase anxiety, especially since the information may be erroneous or contradictory. This article examines the factors that predict student anxiety in the context of a pandemic. METHOD: The quantitative study involves a sample of 445 students from the University of Quebec in Abitibi-Témiscamingue. Anxiety was measured using the Beck Anxiety Inventory, and several sociodemographic variables were tested. RESULTS: The results demonstrated the effects of certain variables on anxiety, especially for women and non-binary people, were more marked than for men. Having dependent children has proven to be a protective factor. CONCLUSION: The study suggests that this variability is now considered when proposing intervention measures in a containment context. The limitations and perspectives of the study are presented and analyzed.


Assuntos
COVID-19 , Pandemias , Criança , Masculino , Feminino , Humanos , SARS-CoV-2 , Ansiedade/etiologia , Estudantes
16.
F1000Res ; 102021.
Artigo em Inglês | MEDLINE | ID: mdl-34912541

RESUMO

Single-cell RNA-sequencing (scRNA-seq) has revolutionized molecular biology and medicine by enabling high-throughput studies of cellular heterogeneity in diverse tissues. Applying network biology approaches to scRNA-seq data can provide useful insights into genes driving heterogeneous cell-type compositions of tissues. Here, we present scNetViz-  a Cytoscape app to aid biological interpretation of cell clusters in scRNA-seq data using network analysis. scNetViz calculates the differential expression of each gene across clusters and then creates a cluster-specific gene functional interaction network between the significantly differentially expressed genes for further analysis, such as pathway enrichment analysis. To automate a complete data analysis workflow, scNetViz integrates parts of the Scanpy software, which is a popular Python package for scRNA-seq data analysis, with Cytoscape apps such as stringApp, cyPlot, and enhancedGraphics. We describe our implementation of methods for accessing data from public single cell atlas projects, differential expression analysis, visualization, and automation. scNetViz enables users to analyze data from public atlases or their own experiments, which we illustrate with two use cases. Analysis can be performed via the Cytoscape GUI or CyREST programming interface using R (RCy3) or Python (py4cytoscape).


Assuntos
Redes Reguladoras de Genes , Software , Automação , Análise de Dados , Fluxo de Trabalho
17.
J Immunother Cancer ; 9(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34599023

RESUMO

BACKGROUND: Sitravatinib, a tyrosine kinase inhibitor that targets TYRO3, AXL, MERTK and the VEGF receptor family, is predicted to increase the M1 to M2-polarized tumor-associated macrophages ratio in the tumor microenvironment and have synergistic antitumor activity in combination with anti-programmed death-1/ligand-1 agents. SNOW is a window-of-opportunity study designed to evaluate the immune and molecular effects of preoperative sitravatinib and nivolumab in patients with oral cavity squamous cell carcinoma. METHODS: Patients with newly-diagnosed untreated T2-4a, N0-2 or T1 >1 cm-N2 oral cavity carcinomas were eligible. All patients received sitravatinib 120 mg daily from day 1 up to 48 hours pre-surgery and one dose of nivolumab 240 mg on day 15. Surgery was planned between day 23 and 30. Standard of care adjuvant radiotherapy was given based on clinical stage. Tumor photographs, fresh tumor biopsies and blood samples were collected at baseline, at day 15 after sitravatinib alone, and at surgery after sitravatinib-nivolumab combination. Tumor flow cytometry, multiplex immunofluorescence staining and single-cell RNA sequencing (scRNAseq) were performed on tumor biopsies to study changes in immune-cell populations. Tumor whole-exome sequencing and circulating tumor DNA and cell-free DNA were evaluated at each time point. RESULTS: Ten patients were included. Grade 3 toxicity occurred in one patient (hypertension); one patient required sitravatinib dose reduction, and one patient required discontinuation and surgery delay due to G2 thrombocytopenia. Nine patients had clinical-to-pathological downstaging, with one complete response. Independent pathological treatment response (PTR) assessment confirmed a complete PTR and two major PTRs. With a median follow-up of 21 months, all patients are alive with no recurrence. Circulating tumor DNA and cell-free DNA dynamics correlated with clinical and pathological response and distinguished two patient groups with different tumor biological behavior after sitravatinib alone (1A) versus sitravatinib-nivolumab (1B). Tumor immunophenotyping and scRNAseq analyses revealed differential changes in the expression of immune cell populations and sitravatinib-targeted and hypoxia-related genes in group 1A vs 1B patients. CONCLUSIONS: The SNOW study shows sitravatinib plus nivolumab is safe and leads to deep clinical and pathological responses in oral cavity carcinomas. Multi-omic biomarker analyses dissect the differential molecular effects of sitravatinib versus the sitravatinib-nivolumab and revealed patients with distinct tumor biology behavior. TRIAL REGISTRATION NUMBER: NCT03575598.


Assuntos
Anilidas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Bucais/tratamento farmacológico , Nivolumabe/uso terapêutico , Piridinas/uso terapêutico , Idoso , Anilidas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Período Pré-Operatório , Piridinas/farmacologia
18.
Opt Lett ; 46(17): 4248-4251, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34469986

RESUMO

Plasmonic photothermal therapy (PPTT), as an increasingly studied treatment alternative, has been widely regarded mostly as a surface tissue treatment choice. Although some techniques have been implemented for interstitial tumors, these involve some grade of invasiveness, as the outer skin is usually broken to introduce light-delivering optical fibers or even catheters. In this work, we present a potential non-invasive strategy using the stereotactic approach, long employed in radiosurgery, by converging multiple near infrared laser beams for PPTT in tissue-equivalent optical phantoms that enclose small gel spheres and simulate interstitial tissue impregnated with plasmonic nanoparticles. The real-time in-depth monitoring of temperature increase is realized by an infrared camera face-on mounted over the phantom. Our results show that a significant reduction in the surface heating can be achieved with this configuration while remarkably increasing the interstitial reach of PPTT, assuring a ∼6∘C temperature increase for the simulated tumors at 10 mm depth and ∼4∘C at 15 mm depth and opening up new possibilities for future clinical applications.


Assuntos
Nanopartículas , Neoplasias , Ouro , Humanos , Lasers , Imagens de Fantasmas
19.
Environ Pollut ; 285: 117664, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34380230

RESUMO

The impacts of COVID-19 lockdown restrictions have provided a valuable global experiment into the extent of improvements in air quality possible with reductions in vehicle movements. Mexico City, London and Delhi all share the problem of air quality failing WHO guideline limits, each with unique situations and influencing factors. We determine, discuss and compare the air quality changes across these cities during the COVID-19, to understand how the findings may support future improvements in their air quality and associated health of citizens. We analysed ground-level PM10, PM2.5, NO2, O3 and CO changes in each city for the period 1st January to August 31, 2020 under different phases of lockdown, with respect to daily average concentrations over the same period for 2017 to 2019. We found major reductions in PM10, PM2.5, NO2 and CO across the three cities for the lockdown phases and increases in O3 in London and Mexico City but not Delhi. The differences were due to the O3 production criteria across the cities, for Delhi production depends on the VOC-limited photochemical regime. Levels of reductions were commensurate with the degree of lockdown. In Mexico City, the greatest reduction in measured concentration was in CO in the initial lockdown phase (40%), in London the greatest decrease was for NO2 in the later part of the lockdown (49%), and in Delhi the greatest decrease was in PM10, and PM2.5 in the initial lockdown phase (61% and 50%, respectively). Reduction in pollutant concentrations agreed with reductions in vehicle movements. In the initial lockdown phase vehicle movements reduced by up to 59% in Mexico City and 63% in London. The cities demonstrated a range of air quality changes in their differing geographical areas and land use types. Local meteorology and pollution events, such as forest fires, also impacted the results.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , COVID-19 , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Cidades , Controle de Doenças Transmissíveis , Monitoramento Ambiental , Humanos , Índia , Londres , México , Pandemias , Material Particulado/análise , SARS-CoV-2
20.
Appl Opt ; 59(33): 10591-10598, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33361994

RESUMO

We present a new method to calculate the complex refractive index of spherical scatterers in a novel optical phantom developed by using homemade monodisperse silica nanospheres embedded into a polyester resin matrix and an ethanol-water mixture for applications in diffuse imaging. The spherical geometry of these nanoparticles makes them suitable for direct comparison between the values of the absorption and reduced scattering coefficients (µa and µs', respectively) obtained by the diffusion approximation solution to the transport equation from scattering measurements and those obtained by the Mie solution to Maxwell's equations. The values of the optical properties can be obtained by measuring, using an ultrafast detector, the time-resolved intensity distribution profiles of diffuse light transmitted through a thick slab of the silica nanosphere phantom, and by fitting them to the time-dependent diffusion approximation solution to the transport equation. These values can also be obtained by Mie solutions for spherical particles when their physical properties and size are known. By using scanning electron microscopy, we measured the size of these nanospheres, and the numerical results of µa and µs' can then be inferred by calculating the absorption and scattering efficiencies. Then we propose a numerical interval for the imaginary part of the complex refractive index of SiO2 nanospheres, ns, which is estimated by fixing the fitted values of µa and µs', using the known value of the real part of ns, and finding the corresponding value of Im(ns) that matches the optical parameters obtained by both methods finding values close to those reported for silica glass. This opens the possibility of producing optical phantoms with scattering and absorption properties that can be predicted and designed from precise knowledge of the physical characteristics of their constituents from a microscopic point of view.

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