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1.
Clin Infect Dis ; 78(2): 476-483, 2024 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-37864849

RESUMO

BACKGROUND: With more than 7500 cases reported since April 2022, Spain has experienced the highest incidence of mpox in Europe. From 12 July onward, the modified vaccinia Ankara-Bavaria Nordic (MVA-BN) smallpox vaccine was offered as pre-exposure prophylaxis for those receiving pre-exposure prophylaxis for human immunodeficiency virus (HIV-PrEP). Our aim was to assess the effectiveness of 1 dose of MVA-BN vaccine as pre-exposure prophylaxis against mpox virus (MPXV) infection in persons on HIV-PrEP. METHODS: National retrospective cohort study between 12 July and 12 December 2022. Individuals aged ≥18 years receiving HIV-PrEP as of 12 July with no previous MPXV infection or vaccination were eligible. Each day, we matched individuals receiving a first dose of vaccine and unvaccinated controls of the same age and region. We used a Kaplan-Meier estimator, calculated risk ratios (RR) and vaccine effectiveness (VE = [1 - RR]x100). RESULTS: We included 5660 matched pairs, with a median follow-up of 62 days (interquartile range, 24-97). Mpox cumulative incidence was 5.6 per 1000 (25 cases) in unvaccinated and 3.5 per 1000 (18 cases) in vaccinated. No effect was found during days 0-6 post-vaccination (VE, -38.3; 95% confidence interval [CI], -332.7 to 46.4), but VE was 65% at ≥7 days (95% CI, 22.9 to 88.0) and 79% at ≥14 days (95% CI, 33.3 to 100.0) post-vaccination. CONCLUSIONS: One dose of MVA-BN vaccine offered protection against mpox in most-at-risk population shortly after the vaccination. Further studies need to assess the VE of a second dose and the duration of protection over time.


Assuntos
Infecções por HIV , Mpox , Vacinas , Vacínia , Humanos , Adolescente , Adulto , Vacínia/prevenção & controle , Estudos de Coortes , Estudos Retrospectivos , Vaccinia virus , Vacinação , Monkeypox virus , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle
2.
FEMS Yeast Res ; 242024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38604750

RESUMO

Major progress in developing Saccharomyces cerevisiae strains that utilize the pentose sugar xylose has been achieved. However, the high inhibitor content of lignocellulose hydrolysates still hinders efficient xylose fermentation, which remains a major obstacle for commercially viable second-generation bioethanol production. Further improvement of xylose utilization in inhibitor-rich lignocellulose hydrolysates remains highly challenging. In this work, we have developed a robust industrial S. cerevisiae strain able to efficiently ferment xylose in concentrated undetoxified lignocellulose hydrolysates. This was accomplished with novel multistep evolutionary engineering. First, a tetraploid strain was generated and evolved in xylose-enriched pretreated spruce biomass. The best evolved strain was sporulated to obtain a genetically diverse diploid population. The diploid strains were then screened in industrially relevant conditions. The best performing strain, MDS130, showed superior fermentation performance in three different lignocellulose hydrolysates. In concentrated corncob hydrolysate, with initial cell density of 1 g DW/l, at 35°C, MDS130 completely coconsumed glucose and xylose, producing ± 7% v/v ethanol with a yield of 91% of the maximum theoretical value and an overall productivity of 1.22 g/l/h. MDS130 has been developed from previous industrial yeast strains without applying external mutagenesis, minimizing the risk of negative side-effects on other commercially important properties and maximizing its potential for industrial application.


Assuntos
Etanol , Fermentação , Lignina , Engenharia Metabólica , Saccharomyces cerevisiae , Xilose , Lignina/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Xilose/metabolismo , Etanol/metabolismo , Microbiologia Industrial
3.
Anticancer Drugs ; 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38941120

RESUMO

Patients with recurrent/metastatic (R/M) platinum-refractory squamous cell carcinoma of the head and neck (SCCHN) have fewer treatment options and harbor an especially poor prognosis. Maintaining treatment with anti-PD1 agents beyond response evaluation criteria in solid tumors-defined disease progression (TBP) has been shown to be efficacious in several solid tumors, including head and neck cancer. We present the case of a platinum-refractory locally recurrent, PD-L1-negative hypopharyngeal carcinoma, that received second-line nivolumab which was then maintained beyond progression under the following criteria: no Eastern Cooperative Oncology Group performance status deterioration, no rapidly progressive disease, no severe toxicity, and evidence of overall treatment benefit. The patient achieved a partial response 8 months after starting second-line nivolumab, with progressive disease at 26 months, then followed by the first TBP with nivolumab lasting for 15 months due to a new tumor progression. A second TBP with nivolumab lasting for 7 months, was followed by a third TBP with nivolumab for 12 months and achieving a major tumor response. Treatment is still ongoing 60 months after starting nivolumab, with excellent tolerance to therapy. Maintaining anti-PD1 agents beyond progression is an efficacious treatment option for patients with R/M SCCHN, that may achieve very durable disease control and even late major responses.

4.
Inorg Chem ; 63(24): 10897-10914, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38795015

RESUMO

Contrast agents are important imaging probes in clinical MRI, allowing the identification of anatomic changes that otherwise would not be possible. Intensive research on the development of new contrast agents is being made to image specific pathological markers or sense local biochemical changes. The most widely used MRI contrast agents are based on gadolinium(III) complexes. Due to their very high charge density, they have low permeability through tight biological barriers such as the blood-brain barrier, hampering their application in the diagnosis of neurological disorders. In this study, we explore the interaction between the widely used contrast agent [Gd(DOTA)]- (Dotarem) and POPC lipid bilayers by means of molecular dynamics simulations. This metal complex is a standard reference where several chemical modifications have been introduced to improve key properties such as bioavailability and targeting. The simulations unveil detailed insights into the agent's interaction with the lipid bilayer, offering perspectives beyond experimental methods. Various properties, including the impact on global and local bilayer properties, were analyzed. As expected, the results indicate a low partition coefficient (KP) and high permeation barrier for this reference compound. Nevertheless, favorable interactions are established with the membrane leading to moderately long residence times. While coordination of one inner-sphere water molecule is maintained for the membrane-associated chelate, the physical-chemical attributes of [Gd(DOTA)]- as a MRI contrast agent are affected. Namely, increases in the rotational correlation times and in the residence time of the inner-sphere water are observed, with the former expected to significantly increase the water proton relaxivity. This work establishes a reference framework for the use of simulations to guide the rational design of new contrast agents with improved relaxivity and bioavailability and for the development of liposome-based formulations for use as imaging probes or theranostic agents.


Assuntos
Meios de Contraste , Bicamadas Lipídicas , Imageamento por Ressonância Magnética , Simulação de Dinâmica Molecular , Compostos Organometálicos , Meios de Contraste/química , Imageamento por Ressonância Magnética/métodos , Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Bicamadas Lipídicas/química , Fosfatidilcolinas/química , Compostos Heterocíclicos
5.
Anal Bioanal Chem ; 416(11): 2657-2676, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38329514

RESUMO

The extensive application of metallic nanoparticles (NPs) in several fields has significantly impacted our daily lives. Nonetheless, uncertainties persist regarding the toxicity and potential risks associated with the vast number of NPs entering the environment and human bodies, so the performance of toxicological studies are highly demanded. While traditional assays focus primarily on the effects, the comprehension of the underlying processes requires innovative analytical approaches that can detect, characterize, and quantify NPs in complex biological matrices. Among the available alternatives to achieve this information, mass spectrometry, and more concretely, inductively coupled plasma mass spectrometry (ICP-MS), has emerged as an appealing option. This work critically reviews the valuable contribution of ICP-MS-based techniques to investigate NP toxicity and their transformations during in vitro and in vivo toxicological assays. Various ICP-MS modalities, such as total elemental analysis, single particle or single-cell modes, and coupling with separation techniques, as well as the potential of laser ablation as a spatially resolved sample introduction approach, are explored and discussed. Moreover, this review addresses limitations, novel trends, and perspectives in the field of nanotoxicology, particularly concerning NP internalization and pathways. These processes encompass cellular uptake and quantification, localization, translocation to other cell compartments, and biological transformations. By leveraging the capabilities of ICP-MS, researchers can gain deeper insights into the behaviour and effects of NPs, which can pave the way for safer and more responsible use of these materials.


Assuntos
Terapia a Laser , Nanopartículas Metálicas , Nanopartículas , Humanos , Análise Espectral , Nanopartículas Metálicas/química , Espectrometria de Massas/métodos , Nanopartículas/toxicidade , Nanopartículas/análise
6.
Appl Microbiol Biotechnol ; 108(1): 153, 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38240846

RESUMO

Evolutionary engineering experiments, in combination with omics technologies, revealed genetic markers underpinning the molecular mechanisms behind acetic acid stress tolerance in the probiotic yeast Saccharomyces cerevisiae var. boulardii. Here, compared to the ancestral Ent strain, evolved yeast strains could quickly adapt to high acetic acid levels (7 g/L) and displayed a shorter lag phase of growth. Bioinformatic-aided whole-genome sequencing identified genetic changes associated with enhanced strain robustness to acetic acid: a duplicated sequence in the essential endocytotic PAN1 gene, mutations in a cell wall mannoprotein (dan4Thr192del), a lipid and fatty acid transcription factor (oaf1Ser57Pro) and a thiamine biosynthetic enzyme (thi13Thr332Ala). Induction of PAN1 and its associated endocytic complex SLA1 and END3 genes was observed following acetic acid treatment in the evolved-resistant strain when compared to the ancestral strain. Genome-wide transcriptomic analysis of the evolved Ent acid-resistant strain (Ent ev16) also revealed a dramatic rewiring of gene expression among genes associated with cellular transport, metabolism, oxidative stress response, biosynthesis/organization of the cell wall, and cell membrane. Some evolved strains also displayed better growth at high acetic acid concentrations and exhibited adaptive metabolic profiles with altered levels of secreted ethanol (4.0-6.4% decrease), glycerol (31.4-78.5% increase), and acetic acid (53.0-60.3% increase) when compared to the ancestral strain. Overall, duplication/mutations and transcriptional alterations are key mechanisms driving improved acetic acid tolerance in probiotic strains. We successfully used adaptive evolutionary engineering to rapidly and effectively elucidate the molecular mechanisms behind important industrial traits to obtain robust probiotic yeast strains for myriad biotechnological applications. KEY POINTS: •Acetic acid adaptation of evolutionary engineered robust probiotic yeast S. boulardii •Enterol ev16 with altered genetic and transcriptomic profiles survives in up to 7 g/L acetic acid •Improved acetic acid tolerance of S. boulardii ev16 with mutated PAN1, DAN4, OAF1, and THI13 genes.


Assuntos
Probióticos , Saccharomyces boulardii , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Ácido Acético/metabolismo , Saccharomyces boulardii/genética , Saccharomyces boulardii/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Probióticos/metabolismo , Biomarcadores/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/metabolismo
7.
J Med Genet ; 60(7): 644-654, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36446582

RESUMO

BACKGROUND: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported. METHODS: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature. RESULTS: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. CONCLUSION: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.


Assuntos
Anormalidades Múltiplas , Transtorno do Espectro Autista , Doenças do Desenvolvimento Ósseo , Deficiência Intelectual , Anormalidades Dentárias , Masculino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Anormalidades Múltiplas/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Dentárias/genética , Fácies , Transtorno do Espectro Autista/genética , Variações do Número de Cópias de DNA , Proteínas Repressoras/genética , Deleção Cromossômica , Fenótipo , Fatores de Transcrição/genética
8.
Scand J Med Sci Sports ; 34(1): e14526, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37858294

RESUMO

BACKGROUND: Ethylene and vinyl acetate (EVA) and polyether block amide (PEBA) are recently the most widely used materials for advanced footwear technology (AFT) that has been shown to improve running economy (RE). This study investigated the effects of these midsole materials on RE and biomechanics, in both fresh and worn state (after 450 km). METHODS: Twenty-two male trained runners participated in this study. Subjects ran four 4-min trials at 13 km‧h-1 with both fresh EVA and PEBA AFT and with the same models with 450 km of wear using a randomized crossover experimental design. We measured energy cost of running (W/kg), spatiotemporal, and neuromuscular parameters. RESULTS: There were significant differences in RE between conditions (p = 0.01; n2 = 0.17). There was a significant increase in energy cost in the worn PEBA condition compared with new (15.21 ± 1.01 and 14.87 ± 0.99 W/kg; p < 0.05; ES = 0.54), without differences between worn EVA (15.13 ± 1.14 W/kg; p > 0.05), and new EVA (15.15 ± 1.13 w/kg; ES = 0.02). The increase in energy cost between new and worn was significantly higher for the PEBA shoes (0.32 ± 0.38 W/kg) but without significant increase for the EVA shoes (0.06 ± 0.58 W/kg) (p < 0.01; ES = 0.51) with changes in step frequency and step length. The new PEBA shoes had lower energy cost than the new EVA shoes (p < 0.05; ES = 0.27) with significant differences between conditions in contact time. CONCLUSION: There is a clear RE advantage of incorporating PEBA versus EVA in an AFT when the models are new. However, after 450 km of use, the PEBA and EVA shoes had similar RE.


Assuntos
Ácidos Borônicos , Corrida , Humanos , Masculino , Fenômenos Biomecânicos , Estudos Cross-Over , Sapatos
9.
Eur Spine J ; 33(4): 1624-1636, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38372794

RESUMO

PURPOSE: The objective of this meta-analysis was to determine the incidence of disc degeneration in patients with surgically treated adolescent idiopathic scoliosis (AIS) and identify the associated risk factors. METHODS: PubMed, EMBASE, Scopus, and Cochrane Collaboration Library databases were searched. The outcomes of interest were the incidence of disc degeneration, SRS-22, and radiological risk factors. The lower instrumented vertebra (LIV) was also evaluated. Fixed effects were used if there was no evidence of heterogeneity. Statistical analysis was performed using Review Manager. RESULTS: A meta-analysis was conducted including nine studies with a total of 565 patients. The analysis revealed that the global incidence of intervertebral disc degeneration in patients with surgically treated AIS patients was 24.78% (95% CI 16.59-32.98%) 10 years after surgery, which significantly increased to 32.32% (95% CI 21.16-43.47% at an average of 13.8 years after surgery. Among patients with significant degenerative disc changes, the SRS-22 functional, self-image, and satisfaction domains showed significantly worse results (MD - 0.25, 95% CI - 0.44 to - 0.05; MD - 0.50, 95% CI - 0.75 to - 0.25; and MD - 0.34, 95% CI - 0.66 to - 0.03, respectively). Furthermore, instrumentation at or above the L3 level was associated with a lower incidence of intervertebral disc degeneration compared to instrumentation below the L3 level (OR 0.25, 95% CI 0.10-0.64). It was also found that the preoperative and final follow-up lumbar curve magnitudes (MD 8.11, 95% CI 3.82-12.41) as well as preoperative and final follow-up lumbar lordosis (MD 0.42, 95% CI - 3.81 to 4.65) were associated with adjacent disc degeneration. CONCLUSIONS: This meta-analysis demonstrated that the incidence of intervertebral disc degeneration significantly increased with long-term follow-up using fusion techniques, reaching up to 32% when patients were 28 years of age. Incomplete correction of deformity and fusion of levels below L3, were identified as negative prognostic factors. Furthermore, patients with disc degeneration showed worse functional outcomes.


Assuntos
Degeneração do Disco Intervertebral , Escoliose , Fusão Vertebral , Adolescente , Humanos , Incidência , Degeneração do Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/epidemiologia , Degeneração do Disco Intervertebral/cirurgia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Fatores de Risco , Escoliose/diagnóstico por imagem , Escoliose/epidemiologia , Escoliose/cirurgia , Fusão Vertebral/métodos , Resultado do Tratamento
10.
PLoS Genet ; 17(10): e1009826, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34624020

RESUMO

Development of cell factories for conversion of lignocellulosic biomass hydrolysates into biofuels or bio-based chemicals faces major challenges, including the presence of inhibitory chemicals derived from biomass hydrolysis or pretreatment. Extensive screening of 2526 Saccharomyces cerevisiae strains and 17 non-conventional yeast species identified a Candida glabrata strain as the most 5-hydroxymethylfurfural (HMF) tolerant. Whole-genome (WG) transformation of the second-generation industrial S. cerevisiae strain MD4 with genomic DNA from C. glabrata, but not from non-tolerant strains, allowed selection of stable transformants in the presence of HMF. Transformant GVM0 showed the highest HMF tolerance for growth on plates and in small-scale fermentations. Comparison of the WG sequence of MD4 and GVM1, a diploid segregant of GVM0 with similarly high HMF tolerance, surprisingly revealed only nine non-synonymous SNPs, of which none were present in the C. glabrata genome. Reciprocal hemizygosity analysis in diploid strain GVM1 revealed AST2N406I as the only causative mutation. This novel SNP improved tolerance to HMF, furfural and other inhibitors, when introduced in different yeast genetic backgrounds and both in synthetic media and lignocellulose hydrolysates. It stimulated disappearance of HMF and furfural from the medium and enhanced in vitro furfural NADH-dependent reducing activity. The corresponding mutation present in AST1 (i.e. AST1D405I) the paralog gene of AST2, also improved inhibitor tolerance but only in combination with AST2N406I and in presence of high inhibitor concentrations. Our work provides a powerful genetic tool to improve yeast inhibitor tolerance in lignocellulosic biomass hydrolysates and other inhibitor-rich industrial media, and it has revealed for the first time a clear function for Ast2 and Ast1 in inhibitor tolerance.


Assuntos
Antifúngicos/farmacologia , Farmacorresistência Fúngica/genética , Tolerância a Medicamentos/genética , Furaldeído/análogos & derivados , Mutação/genética , Saccharomyces cerevisiae/genética , Transformação Genética/genética , Biomassa , Fermentação/genética , Furaldeído/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , Proteínas de Saccharomyces cerevisiae/genética
11.
Proc Natl Acad Sci U S A ; 118(33)2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34389674

RESUMO

Astrocytes have emerged as a potential source for new neurons in the adult mammalian brain. In mice, adult striatal neurogenesis can be stimulated by local damage, which recruits striatal astrocytes into a neurogenic program by suppression of active Notch signaling (J. P. Magnusson et al., Science 346, 237-241 [2014]). Here, we induced adult striatal neurogenesis in the intact mouse brain by the inhibition of Notch signaling in astrocytes. We show that most striatal astrocyte-derived neurons are confined to the anterior medial striatum, do not express established striatal neuronal markers, and exhibit dendritic spines, which are atypical for striatal interneurons. In contrast to striatal neurons generated during development, which are GABAergic or cholinergic, most adult astrocyte-derived striatal neurons possess distinct electrophysiological properties, constituting the only glutamatergic striatal population. Astrocyte-derived neurons integrate into the adult striatal microcircuitry, both receiving and providing synaptic input. The glutamatergic nature of these neurons has the potential to provide excitatory input to the striatal circuitry and may represent an efficient strategy to compensate for reduced neuronal activity caused by aging or lesion-induced neuronal loss.


Assuntos
Astrócitos/fisiologia , Conexina 30/metabolismo , Ácido Glutâmico/metabolismo , Neurônios/fisiologia , Animais , Diferenciação Celular , Conexina 30/genética , Desoxiuridina/análogos & derivados , Desoxiuridina/farmacologia , Fenômenos Eletrofisiológicos , Neurônios GABAérgicos/enzimologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Interneurônios/enzimologia , Proteínas Luminescentes , Camundongos , Camundongos Transgênicos , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Recombinação Genética , Tamoxifeno/farmacologia
12.
Sensors (Basel) ; 24(9)2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38732857

RESUMO

This study presents a pioneering approach that leverages advanced sensing technologies and data processing techniques to enhance the process of clinical documentation generation during medical consultations. By employing sophisticated sensors to capture and interpret various cues such as speech patterns, intonations, or pauses, the system aims to accurately perceive and understand patient-doctor interactions in real time. This sensing capability allows for the automation of transcription and summarization tasks, facilitating the creation of concise and informative clinical documents. Through the integration of automatic speech recognition sensors, spoken dialogue is seamlessly converted into text, enabling efficient data capture. Additionally, deep models such as Transformer models are utilized to extract and analyze crucial information from the dialogue, ensuring that the generated summaries encapsulate the essence of the consultations accurately. Despite encountering challenges during development, experimentation with these sensing technologies has yielded promising results. The system achieved a maximum ROUGE-1 metric score of 0.57, demonstrating its effectiveness in summarizing complex medical discussions. This sensor-based approach aims to alleviate the administrative burden on healthcare professionals by automating documentation tasks and safeguarding important patient information. Ultimately, by enhancing the efficiency and reliability of clinical documentation, this innovative method contributes to improving overall healthcare outcomes.


Assuntos
Aprendizado Profundo , Humanos , Interface para o Reconhecimento da Fala
13.
Int J Mol Sci ; 25(1)2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38203790

RESUMO

This Special Issue presents five contributions covering various topics, as it would be expected for an area as comprehensive and multidisciplinary as Macromolecules [...].


Assuntos
Estudos Interdisciplinares , Portugal , Substâncias Macromoleculares
14.
Int J Mol Sci ; 25(4)2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38396713

RESUMO

Carcinoid heart disease (CHD) is a frequent and life-threatening complication in patients with carcinoid tumors. Its clinical management is challenging is some cases since serotonin-induced valve fibrosis leads to heart failure. Telotristat is an inhibitor of tryptophan-hydroxylase (TPH), a key enzyme in serotonin production. Telotristat use in patients with carcinoid syndrome and uncontrollable diarrhea under somatostatin analogs is approved, but its specific role in patients with CHD is still not clear. IN this context, we aimed to explore the effect of telotristat in heart fibrosis using a mouse model of serotonin-secreting metastasized neuroendocrine neoplasm (NEN). To this aim, four treatment groups (n = 10/group) were evaluated: control, monthly octreotide, telotristat alone, and telotristat combined with octreotide. Plasma serotonin and NT-proBNP levels were determined. Heart fibrosis was histologically evaluated after 6 weeks of treatment or when an individual mouse's condition was close to being terminal. Heart fibrosis was observed in all groups. Non-significant reductions in primary tumor growth were observed in all of the treated groups. Feces volume was increased in all groups. A non-significant decrease in feces volume was observed in the octreotide or telotristat-treated groups, while it was significantly reduced with the combined treatment at the end of the study compared with octreotide (52 g reduction; p < 0.01) and the control (44.5 g reduction; p = 0.05). Additionally, plasma NT-proBNP decreased in a non-significant, but clinically relevant, manner in the octreotide (28.2% reduction), telotristat (45.9% reduction), and the octreotide + telotristat (54.1% reduction) treatment groups. No significant changes were observed in plasma serotonin levels. A similar non-significant decrease in heart valve fibrosis was observed in the three treated groups. In conclusion, Telotristat alone and especially in combination with octreotide decreases NT-proBNP levels in a mouse model of serotonin-secreting metastasized NEN, when compared with the control and octreotide, but its effect on heart valve fibrosis (alone and in combination) was not superior to octreotide in monotherapy.


Assuntos
Doença Cardíaca Carcinoide , Tumores Neuroendócrinos , Fenilalanina/análogos & derivados , Pirimidinas , Humanos , Octreotida/farmacologia , Octreotida/uso terapêutico , Doença Cardíaca Carcinoide/tratamento farmacológico , Serotonina , Tumores Neuroendócrinos/tratamento farmacológico , Fibrose
15.
Int J Mol Sci ; 25(11)2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38892006

RESUMO

There is increasing evidence about the role of inflammation in sarcopenia and tumor progression; thus, its modulation would represent a valuable strategy for improving clinical outcomes in patients with cancer. Several studies have reported that whey protein has significant anti-inflammatory and antioxidant characteristics in humans. We aimed to evaluate the effects of whey protein-based oral nutritional support on circulating cytokines in patients with solid tumors undergoing systemic treatment. Forty-six patients with solid tumors of different origin and undergoing systemic treatment were evaluated. Nutritional support with two daily whey protein-based oral supplements was administered. Circulating levels of IL-6, IL-8, IL-10, MCP-1 and IP-10 were determined. Nutritional evaluation included anthropometric, instrumental and biochemical parameters. Over 63% of the evaluated patients underwent surgery, 56.5% required chemotherapy and almost 50% received combined treatment. Patients with resected primary tumor presented with lower baseline IL-6 (p < 0.05) and IP-10 (p < 0.001); after three months of nutritional support, they presented with lower IL-8 (p < 0.05) and tended to present lower IL-6 and IP-10 (p = 0.053 and 0.067, respectively). Significant positive correlations between circulating cytokines, C-reactive protein and ferritin were observed; similarly, negative correlations with anthropometric and biochemical nutritional parameters were noticed (p < 0.05). We did not observe significant changes in circulating cytokine levels (IL-6, IL-8, IL-10, MCP-1 and IP-10) in patients with cancer undergoing systemic treatment after three months of nutritional support with whey protein-based oral supplements. According to a univariate analysis in our cohort, circulating IL-8 was associated with mortality in these patients, additionally, MCP-1 and IP-10 tended to correlate; but an age- and sex-adjusted multivariate analysis revealed that only baseline MCP-1 was significantly associated with mortality (OR 1.03 (95% CI: 1.00-1.05)). In conclusion, surgery of the primary solid tumor and combination treatment allow significant reduction in circulating cytokine levels, which remained stable while patients received nutritional support with whey protein-based oral supplements over three months. The role of MCP-1 as an independent factor for mortality in these patients should be further evaluated.


Assuntos
Citocinas , Inflamação , Neoplasias , Apoio Nutricional , Proteínas do Soro do Leite , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Inflamação/sangue , Apoio Nutricional/métodos , Citocinas/sangue , Adulto , Suplementos Nutricionais , Quimiocina CCL2/sangue
16.
Int J Mol Sci ; 25(11)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38892306

RESUMO

The development of specific antiviral therapies targeting SARS-CoV-2 remains fundamental because of the continued high incidence of COVID-19 and limited accessibility to antivirals in some countries. In this context, dark chemical matter (DCM), a set of drug-like compounds with outstanding selectivity profiles that have never shown bioactivity despite being extensively assayed, appears to be an excellent starting point for drug development. Accordingly, in this study, we performed a high-throughput screening to identify inhibitors of the SARS-CoV-2 main protease (Mpro) using DCM compounds as ligands. Multiple receptors and two different docking scoring functions were employed to identify the best molecular docking poses. The selected structures were subjected to extensive conventional and Gaussian accelerated molecular dynamics. From the results, four compounds with the best molecular behavior and binding energy were selected for experimental testing, one of which presented inhibitory activity with a Ki value of 48 ± 5 µM. Through virtual screening, we identified a significant starting point for drug development, shedding new light on DCM compounds.


Assuntos
Antivirais , Proteases 3C de Coronavírus , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases , SARS-CoV-2 , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Antivirais/farmacologia , Antivirais/química , Humanos , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , COVID-19/virologia , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Ligação Proteica , Ligantes
17.
J Sci Food Agric ; 2024 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-38520251

RESUMO

BACKGROUND: Aquaponic systems are sustainable processes of managing water and nutrients for food production. An innovate nutrient-efficient catfish-based (Clarias gariepinus) aquaponics system was implemented for producing two cultivars of two leafy vegetables largely consumed worldwide: lamb's lettuce (Valerianella locusta var. Favor and Valerianella locusta var. de Hollande) and arugula (Eruca vesicaria var. sativa and Eruca sativa). Different growing treatments (4 × 2 factorial design) were applied to plants of each cultivar, grown at two light intensities (120 and 400 µmol m-2 s-1). During growth, several morphological characteristics (root length, plant height, leaf number, foliage diameter and biggest leaf length) were measured. At harvest, plants were weighed and examined qualitatively in terms of greenness and health status. Additionally, leaf extracts were obtained and used to determine total phenolic contents, antioxidant capacities, and levels of cytotoxicity to Caco-2 intestinal model cells. RESULTS: After a 5-week growth period, both lamb's lettuce cultivars presented high levels of greenness and health status, at both light intensities, particularly the var. de Hollande that also showed higher average performance in terms of plant morphology. In turn, arugula cultivars showed lower levels of greenness and health status, especially the cultivar E. vesicaria var. sativa submitted to direct sunlight during growth. In addition, plant specimens submitted to higher levels of light intensity showed higher contents in antioxidants/polyphenols. Cultivars with a higher content in antioxidants/polyphenols led to higher Caco-2 cell viability. CONCLUSION: For successful industrial implementation of the aquaponics technology, different and optimized acclimatizing conditions must be applied to different plant species and cultivars. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

18.
BMC Nurs ; 23(1): 86, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38308260

RESUMO

BACKGROUND: During the COVID-19 pandemic, decentralised clinical trials incorporated self-monitoring, self-reporting, and telenursing tools to address health literacy and health empowerment of patients enrolled in clinical trials. We aimed to determine the impact of an educational intervention using telenursing consultations on health literacy, health empowerment, and health-related quality of life in cancer patients enrolled in clinical trials by measuring the level of satisfaction with the care received and assessing the views of healthcare professionals concerning the advanced practice nurse (APN) role in oncology clinical trials. METHODS: In this pilot analytical, descriptive, longitudinal, quasi-experimental, and pre-post test study, an educational intervention was conducted by 5 visits with an APN using synchronous teleconsultation in patients starting cancer treatment for the first time in a clinical trial (n = 60), and health professionals working with the APN (n = 31). A descriptive analysis of the samples and questionnaires were utilised along with statistical comparisons. RESULTS: After the intervention, patients' health literacy (31.7%), health empowerment (18.3%), and health-related quality of life (33.3%) increased (p < 0.05), with a decrease and trend towards resolution of care needs (p < 0.05). Satisfaction with the quality and care received in terms of perceived convenience, transition, and continuity of care showed positive results in 64.9 ± 20.7, 77.6 ± 19.5, and 72.1 ± 20.4 of respondents, respectively. On the overall assessment of the APN role, healthcare professionals expressed a high level of agreement with the statements related to their work performance. CONCLUSIONS: The data indicates that a clinical trial APN-led telenursing educational intervention results in an overall increase in health literacy, an improvement in health empowerment and health-related quality of life, and a decrease in care needs of oncology clinical trials patients. Patients stated that they received a high quality of care and health professionals indicated high levels of acceptance with APNs. Based on these results, we suggest that the APN role should gain more recognition in the Spanish healthcare system and their professional competencies should be aligned with those of other countries.

19.
Rev Esp Enferm Dig ; 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38685899

RESUMO

We present the case of a 29-year-old patient with multiple allergies, mild asthma and rhinoconjunctivitis who reported a history of esophageal impactions after ingestion of solid foods. These episodes resolved spontaneously at home and by self-induced vomiting and never required endoscopic removal. The patient presented to the emergency department due to a sensation of food impaction lasting more than 12 hours after eating meat the night before, which did not subside with the intake of liquids or self-induced vomiting. Endoscopic evaluation was requested for foreign body extraction. A meat bolus impacted in the distal esophagus was easily removed using a Roth basket, revealing a severe esophageal stricture that prevented passage of the endoscope into the gastric cavity. Furthermore, in the same area where the foreign body was previously located, a deep esophageal tear was seen. Given the high suspicion of perforation, the patient was examined, and thoracic and cervical crepitation was observed. It was decided to immediately insert, with only endoscopic control, a partially covered Ultraflex® esophageal stent measuring 18 mm in diameter and 15 cm in length. After insertion, clinical improvement and cessation of crepitation were observed.

20.
Rev Esp Enferm Dig ; 116(4): 229-230, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37204096

RESUMO

Acute pancreatitis (AP) is the leading hospital admission in Gastroenterology and has a variable clinical course. Identifying severity of AP patients in its early stages is of foremost importance to improve prognosis. The revised Atlanta Classification grades AP severity by the presence of organ failure and local complications.


Assuntos
Anemia , Pancreatite , Humanos , Pancreatite/complicações , Pancreatite/diagnóstico , Doença Aguda , Índice de Gravidade de Doença , Estudos Retrospectivos , Prognóstico , Anemia/complicações
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