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2.
Int J Mol Sci ; 25(14)2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-39062874

RESUMO

To analyze the mechanism of copper accumulation in the marine alga Ulva compressa, it was cultivated with 10 µM of copper, with 10 µM of copper and increasing concentrations of a sulfide donor (NaHS) for 0 to 7 days, and with 10 µM of copper and a concentration of the sulfide acceptor (hypotaurine) for 5 days. The level of intracellular copper was determined as well as the level of glutathione (GSH) and phytochelatins (PCs) and the expression of metallothioneins (UcMTs). The level of intracellular copper in the algae treated with copper increased at day 1, slightly increased until day 5 and remained unchanged until day 7. The level of copper in the algae cultivated with copper and 100 or 200 µM of NaHS continuously increased until day 7 and the copper level was higher in the algae cultivated with 200 µM of NaHS compared to 100 µM of NaHS. In contrast, the level of intracellular copper decreased in the algae treated with copper and hypotaurine. The level of intracellular copper did not correlate with the level of GSH or with the expression of UcMTs, and PCs were not detected in response to copper, or copper and NaHS. Algae treated with copper and with copper and 200 µM of NaHS for 5 days were visualized by TEM and the elemental composition of electrondense particles was analyzed by EDXS. The algae treated with copper showed electrondense particles containing copper and sulfur, but not nitrogen, and they were mainly located in the chloroplast, but also in the cytoplasm. The algae treated with copper and NaHS showed a higher level of electrondense particles containing copper and sulfur, but not nitrogen, and they were located in the chloroplast, and in the cytoplasm. Thus, copper is accumulated as copper sulfide insoluble particles, and not bound to GSH, PCs or UcMTs, in the marine alga U. compressa.


Assuntos
Cobre , Glutationa , Metalotioneína , Fitoquelatinas , Sulfetos , Ulva , Cobre/metabolismo , Ulva/metabolismo , Ulva/efeitos dos fármacos , Fitoquelatinas/metabolismo , Glutationa/metabolismo , Metalotioneína/metabolismo , Sulfetos/metabolismo , Taurina/análogos & derivados
4.
RECIIS (Online) ; 18(2)abr.-jun. 2024.
Artigo em Português | LILACS, Coleciona SUS | ID: biblio-1561671

RESUMO

Este artigo, por meio de aproximação genealógica, buscou investigar o que chamaremos de pistas genealó-gicas do equipamento Consultório na Rua em município de médio porte no Sul do Brasil. Para o percurso da pesquisa, junto a uma vivência em um Consultório na Rua, nesse município do país, foram realizados entrevistas e levantamentos de documentos. Na investigação foi possível encontrar pistas que apontam para uma produção de criminalização e assimilação histórica dos viventes da rua pelo Estado brasileiro, de maneira que esses pontos precisam ser discutidos e problematizados para que tais regimes de verdade não sejam norteadores das políticas públicas para tais pessoas.


This article, employing a genealogical approach, aimed to examine the genealogical traces of the Street Clinic equipment in a medium-sized city in Brazil's southern region. In order to follow the path of the research, along with an experience in a Street Clinic in a Brazilian city, interviews and document surveys were conducted. In the investigation, it was possible to find elements of the production of criminalization and historical assimilation by the Brazilian State that need to be discussed and problematized so that such regimes of truth are not guiding the production of health care for people experiencing homelessness.


Este artículo, a través de un abordaje genealógico, buscó investigar pistas genealógicas del Consultorio en la Calle en una ciudad de tamaño medio en el sur de Brasil. Para el transcurso de la investigación, junto con una experiencia en un Consultorio en la Calle en un municipio de tamaño medio en el sur de Brasil, se efectuaron entrevistas y encuestas documentales. En la investigación, fue posible encontrar pistas que apuntan a una producción de criminalización y asimilación histórica de las personas en situación de calle por parte del Estado brasileño, por lo que estos puntos necesitan ser discutidos y problematizados para que tales regímenes de verdad no guíen políticas públicas para dicha población.


Assuntos
Atenção Primária à Saúde , Apoio Social , Pessoas Mal Alojadas , Serviços de Saúde Comunitária , Política de Saúde , Classe Social , Sistema Único de Saúde , Colaboração Intersetorial , Comportamento Criminoso , Aculturação
5.
J Pediatr Nurs ; 77: e132-e138, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38594165

RESUMO

PURPOSE: The objective was analysed the patterns use of healthcare services of this population and the influence of their clinical and sociodemographic characteristics. DESIGN AND METHODS: A six-year longitudinal follow-up study was performed to evaluate the annual healthcare resources use and clinical data among children with complex chronic diseases in Spain between 2015 and 2021. The sample trends in healthcare usage and the associated factors were analysed using ANCOVA and multivariable linear regression models. RESULTS: Patients had high attendance during the follow-up period, with >15 episodes year. This trend decreased over time, especially in children with oncological diseases compared with other diseases (F (16.75; 825.4) = 32.457; p < 0.001). A multivariable model showed that children with a greater number of comorbidities (ß = 0.17), shorter survival time (ß = -0.23), who had contact with the palliative care unit (ß = 0.16), and whose mothers had a higher professional occupation (ß = 0.14), had a greater use of the healthcare system. CONCLUSIONS: Children with a higher number of comorbidities and the use of medical devices made a greater frequentation of health services, showing a trend of decreasing use over time. Socioeconomic factors such as mothers' occupational status determine healthcare frequentation. These results suggest the existence of persistent gaps in care coordination sustained over time. PRACTICAL IMPLICATIONS: Systematized and coordinated models of care for this population should consider the presence of inequalities in health care use.


Assuntos
Aceitação pelo Paciente de Cuidados de Saúde , Humanos , Feminino , Masculino , Criança , Estudos Longitudinais , Doença Crônica , Espanha , Seguimentos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Adolescente , Pré-Escolar , Fatores Socioeconômicos
6.
Int Orthop ; 48(5): 1285-1294, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38478022

RESUMO

PURPOSE: Prevalence of axillary (AN) and/or suprascapular (SSN) neuropathy in rotator cuff tear arthropathy (RCTA) is unknown. We aimed to prospectively evaluate for preoperative neurodiagnostic abnormalities in order to determine their prevalence, location, and influence on reverse shoulder arthroplasty (RSA) outcomes. METHODS: Patients who underwent RSA for RCTA were prospectively included. An electromyography and nerve conduction study were performed pre and post-surgery. Clinical situation: VAS, Relative Constant-Murley Score (rCMS) and ROM over a minimum of two years follow-up. RESULTS: Forty patients met the inclusion criteria; mean follow-up was 28.4 months (SD 4.4). Injuries in RCTA were present in 83.9% (77.4% in AN and 45.2% in SSN). There were no differences on preoperative VAS, ROM, and rCMS between patients with and without preoperative nerve injuries. Four acute postoperative neurological injuries were registered under chronic preoperative injuries. Six months after RSA, 69% of preoperative neuropathies had improved (82.14% chronic injuries and 77.7% disuse injuries). No differences in improvement between disuse and chronic injuries were found, but patients with preoperative neuropathy that had not improved at the postoperative electromyographic study at six months, scored worse on the VAS (1.44 vs 2.66; p .14) and rCMS (91.6 vs 89.04; p .27). CONCLUSIONS: The frequency of axillary and suprascapular neuropathies in RCTA is much higher than expected. Most of these injuries improve after surgery, with almost complete neurophysiological recovery and little functional impact on RSA. However, those patients with preoperative neuropathies and absence of neurophysiological improvement six months after surgery have lower functional results.


Assuntos
Artroplastia do Ombro , Lesões do Manguito Rotador , Artropatia de Ruptura do Manguito Rotador , Articulação do Ombro , Humanos , Manguito Rotador/cirurgia , Lesões do Manguito Rotador/complicações , Lesões do Manguito Rotador/diagnóstico , Lesões do Manguito Rotador/cirurgia , Estudos Prospectivos , Ombro/cirurgia , Articulação do Ombro/cirurgia , Articulação do Ombro/inervação , Artroplastia do Ombro/efeitos adversos , Artroplastia do Ombro/métodos , Resultado do Tratamento , Estudos Retrospectivos , Amplitude de Movimento Articular
7.
Obes Surg ; 34(4): 1316-1323, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38429485

RESUMO

INTRODUCTION: Laparoscopic sleeve gastrectomy (LSG) is associated with postoperative nausea and vomiting (PONV). We aimed to compare the effects of aprepitant on the incidence of PONV after LSG. METHODS: In this double-blind, randomized controlled trial, the case group received the standard care regimen for PONV (dexamethasone 10 mg, ondansetron 4 mg, and metoclopramide 10 mg) plus prophylactic oral aprepitant 80 mg 1 h preoperatively. The control group received standard care plus a placebo. Comparative analyses using the Rhodes index were performed at 0, 6, 12, and 24 h postoperatively. RESULTS: A total of 400 patients (201 in the aprepitant group and 199 in the placebo group) underwent LSG. The groups were homogeneous. The aprepitant group experienced less PONV: early, 69 (34.3%) vs. 103 (51.7%), p ≤ 0.001; 6 h, 67 (33.3%) vs. 131 (65.8%), p ≤ 0.001; 12 h, 41 (20.4%) vs. 115 (57.8%), p ≤ 0.001; and 24 h, 22 (10.9%) vs. 67 (33.7%), p ≤ 0.001. Fewer patients in the aprepitant group vomited: early, 3 (1.5%) vs. 5 (2.5%), p = 0.020; 6 h, 6 (3%) vs. 18 (9%), p = 0.020; 12 h, 2 (1%) vs. 17 (8.5%), p = 0.006; and 24 h, 1 (0.5%) vs. 6 (3%), p = 0.040. Patients in the aprepitant group required less additional PONV medication: early, 61 (30.3%) vs. 86 (43.2), p = 0.008; 6 h, 7 (3.5%) vs. 34 (17%), p = 0.001; 12 h, 6 (3%) vs. 31 (15.6%), p ≤ 0.001; and 24 h, 5 (2.5%) vs. 11 (5.5%), p ≤ 0.001. CONCLUSIONS: Prophylactic aprepitant improved PONV between 0 h (early) and 24 h postoperatively in patients undergoing LSG.


Assuntos
Antieméticos , Laparoscopia , Obesidade Mórbida , Humanos , Aprepitanto , Antieméticos/uso terapêutico , Náusea e Vômito Pós-Operatórios/tratamento farmacológico , Obesidade Mórbida/cirurgia , Gastrectomia , Método Duplo-Cego
8.
Int J Mol Sci ; 25(3)2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38339195

RESUMO

The consensus molecular subtypes (CMSs) classification of colorectal cancer (CRC) is a system for patient stratification that can be potentially applied to therapeutic decisions. Hakai (CBLL1) is an E3 ubiquitin-ligase that induces the ubiquitination and degradation of E-cadherin, inducing epithelial-to-mesenchymal transition (EMT), tumour progression and metastasis. Using bioinformatic methods, we have analysed CBLL1 expression on a large integrated cohort of primary tumour samples from CRC patients. The cohort included survival data and was divided into consensus molecular subtypes. Colon cancer tumourspheres were used to analyse the expression of stem cancer cells markers via RT-PCR and Western blotting. We show that CBLL1 gene expression is specifically associated with canonical subtype CMS2. WNT target genes LGR5 and c-MYC show a similar association with CMS2 as CBLL1. These mRNA levels are highly upregulated in cancer tumourspheres, while CBLL1 silencing shows a clear reduction in tumoursphere size and in stem cell biomarkers. Importantly, CMS2 patients with high CBLL1 expression displayed worse overall survival (OS), which is similar to that associated with CMS4 tumours. Our findings reveal CBLL1 as a specific biomarker for CMS2 and the potential of using CMS2 with high CBLL1 expression to stratify patients with poor OS.


Assuntos
Neoplasias Colorretais , Humanos , Biomarcadores , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/genética , Genes myc , Análise de Sobrevida , Ubiquitina-Proteína Ligases/metabolismo
9.
Rev. cuba. med ; 62(4)dic. 2023.
Artigo em Espanhol | CUMED, LILACS | ID: biblio-1550894

RESUMO

Introducción: El neumoencéfalo (sinonimia: aerocele o neumatocele intracerebral), se define como la presencia de gas dentro de cualquiera de los compartimentos intracraneales (intraventricular, intraparenquimatosa, subaracnoidea, subdural y epidural). Objetivo: Describir los hallazgos clínicos, estudios complementarios, conducta terapéutica y evolución de un caso con neumoencéfalo como complicación de bloqueo regional epidural por radiculopatía lumbosacra. Presentación de caso: Se presentó un paciente masculino de 57 años de edad que comenzó con un cuadro súbito de desorientación, excitabilidad psicomotriz y convulsiones tónico-clónicas, a partir de una inyección epidural de metilprednisolona como método analgésico. Conclusiones: El caso presentado exhibió manifestaciones neurológicas inespecíficas, la aparición súbita posterior al proceder invasivo hizo sospechar en un evento neurológico agudo o fenómeno tromboembólico. Los estudios complementarios como la tomografía axial computarizada craneal simple, permitió su diagnóstico para tener una conducta consecuente. El manejo conservador del neumoencéfalo como complicación del uso de anestesia epidural, constituyó una conducta terapéutica eficaz y repercutió en la satisfactoria evolución del paciente(AU)


Introduction: Pneumocephalus (synonym: aerocele or intracerebral pneumatocele), is defined as the presence of gas within any of the intracranial compartments (intraventricular, intraparenchymal, subarachnoid, subdural and epidural). Objective: To describe the clinical findings, complementary studies, therapeutic conduct and evolution of a case with pneumocephalus as a complication of regional epidural block due to lumbosacral radiculopathy Case presentation: A 57-year-old male patient was presented who began with a sudden episode of disorientation, psychomotor excitability and tonic-clonic seizures, following an epidural injection of methylprednisolone as an analgesic method. Conclusions: The case presented exhibited non-specific neurological manifestations, the sudden appearance after the invasive procedure raised suspicion of an acute neurological event or thromboembolic phenomenon. Complementary studies such as simple cranial computed axial tomography, allowed its diagnosis to have a consistent conduct. The conservative management of pneumocephalus as a complication of the use of epidural anesthesia constituted an effective therapeutic approach and had an impact on the patient's satisfactory evolution(AU)


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Radiculopatia/complicações , Metilprednisolona/uso terapêutico , Pneumoencefalografia/métodos , Tomografia Computadorizada Espiral/métodos , Anestesia Epidural/métodos
10.
Int J Mol Sci ; 24(13)2023 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-37445946

RESUMO

In the last two decades, many detailed full transcriptomic studies on complex biological samples have been published and included in large gene expression repositories. These studies primarily provide a bulk expression signal for each sample, including multiple cell-types mixed within the global signal. The cellular heterogeneity in these mixtures does not allow the activity of specific genes in specific cell types to be identified. Therefore, inferring relative cellular composition is a very powerful tool to achieve a more accurate molecular profiling of complex biological samples. In recent decades, computational techniques have been developed to solve this problem by applying deconvolution methods, designed to decompose cell mixtures into their cellular components and calculate the relative proportions of these elements. Some of them only calculate the cell proportions (supervised methods), while other deconvolution algorithms can also identify the gene signatures specific for each cell type (unsupervised methods). In these work, five deconvolution methods (CIBERSORT, FARDEEP, DECONICA, LINSEED and ABIS) were implemented and used to analyze blood and immune cells, and also cancer cells, in complex mixture samples (using three bulk expression datasets). Our study provides three analytical tools (corrplots, cell-signature plots and bar-mixture plots) that allow a thorough comparative analysis of the cell mixture data. The work indicates that CIBERSORT is a robust method optimized for the identification of immune cell-types, but not as efficient in the identification of cancer cells. We also found that LINSEED is a very powerful unsupervised method that provides precise and specific gene signatures for each of the main immune cell types tested: neutrophils and monocytes (of the myeloid lineage), B-cells, NK cells and T-cells (of the lymphoid lineage), and also for cancer cells.


Assuntos
Perfilação da Expressão Gênica , Neoplasias , Perfilação da Expressão Gênica/métodos , Transcriptoma , Monócitos , Neutrófilos , Linfócitos T , Neoplasias/genética
11.
Sci Rep ; 13(1): 11983, 2023 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-37491547

RESUMO

Green sea turtles (Chelonia mydas) can swim up to 50 km per day while only consuming seagrass or microalgae. How the animal accomplishes this vast journey on such low energy intake points to the effectiveness of their swimming technique and is a testament to the power of evolution. Understanding the green sea turtle's ability to accomplish these journeys requires insight into their propulsive strategies. Conducting animal testing to uncover their propulsive strategies brings significant challenges: firstly, the ethical issues of conducting experiments on an endangered animal, and secondly, the animal may not even swim with its regular routine during the experiments. In this work, we develop a new soft-robotic sea turtle that reproduces the real animal's form and function to provide biomechanical insights without the need for invasive experimentation. We found that the green sea turtle may only produce propulsion for approximately 30% of the limb beat cycle, with the remaining 70% exploiting a power-preserving low-drag glide. Due to the animal's large mass and relatively low drag coefficient, losses in swim speed are minimal during the gliding stage. These findings may lead to the creation of a new generation of robotic systems for ocean exploration that use an optimised derivative of the sea turtle propulsive strategy.


Assuntos
Experimentação Animal , Procedimentos Cirúrgicos Robóticos , Tartarugas , Animais , Tartarugas/anatomia & histologia , Natação
12.
J Shoulder Elbow Surg ; 32(12): 2421-2429, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37499787

RESUMO

BACKGROUND: Baseplate screws have been suggested as a possible cause of suprascapular neuropathy after reverse total shoulder arthroplasty. This study aims to investigate the association between screw penetration out of the vault, electromyographic study, and the clinical outcomes. METHODS: A total of 31 patients who underwent reverse total shoulder arthroplasty for cuff tear arthropathy were prospectively enrolled. They were followed up for a minimum of 24 months. All patients underwent computed tomography 6 months postoperatively to determine the extraosseous position of the screws (perforation of the second bone cortex and protrusion into the supra- or infraspinatus fossa). Electrodiagnostic evaluation was performed preoperatively and postoperatively to stablish any relation between cortex perforation of the screw and suprascapular nerve (SSN) injury. Clinical outcomes pre- and postoperatively (Constant score, ranges of motion, and visual analog scale) of patients with and without documented injury were recorded. RESULTS: A total of 14 patients (45.2%) had an abnormal preoperative SSN electrodiagnostic study (chronic or disuse injuries), and 6 patients (19.4%) had an abnormal postoperative study (acute injury). Of the 6 patients, 2 cases appeared over the pre-existing lesion and 4 appeared over an intact preoperative nerve, all of them affecting the infraspinatus branch of the SSN. Perforation of the second cortex was detected for 60% of superior screws and 40% of posterior screws. The mean lengths of the superior and posterior screws were 30 and 18.2 mm, respectively. Patients with screw perforation of the second cortex were assessed as having a high risk of nerve injury (40% vs. 9.5%). CONCLUSIONS: Preoperative SSN injuries do not have a significant clinical impact and do not predispose to an acute postoperative SSN lesion. The Constant score and visual analog scale score for patients with acute SSN injuries were not statistically different from those without SSN injury. The extraosseous position of the screw increases the probability of an SSN injury to 31%. This risk is higher with the posterior screw, which leads us to question whether it is really necessary to use it.


Assuntos
Artroplastia do Ombro , Traumatismos dos Nervos Periféricos , Lesões do Ombro , Articulação do Ombro , Humanos , Artroplastia do Ombro/efeitos adversos , Artroplastia do Ombro/métodos , Estudos Prospectivos , Traumatismos dos Nervos Periféricos/etiologia , Manguito Rotador/cirurgia , Lesões do Ombro/cirurgia , Parafusos Ósseos/efeitos adversos , Articulação do Ombro/cirurgia , Articulação do Ombro/inervação
13.
Urol Oncol ; 41(9): 391.e13-391.e21, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37331822

RESUMO

INTRODUCTION: While surgical management of renal cell carcinoma (RCC) is curative for many patients, others may relapse and could benefit from adjuvant treatments. Immune checkpoint inhibitors (ICI) have been proposed as a potential adjuvant therapy for improving survival in these patients, but the benefit/risk ratio of ICI in the perioperative setting remains unclear. METHODS: A systematic review and a meta-analysis of phase III trials of perioperative ICI (anti PD1/PD-L1 alone or in combination with anti-CTLA4 agents) in RCC was conducted. RESULTS: The analysis included results from 4 phase III trials, comprising 3,407 patients. ICI did not show a significant increase in disease-free survival (Hazard Ratio [HR] 0.85; 95% confidence interval [CI] 0.69-1.04; p: 0.11) or overall survival [OS] (HR 0.73; 95% CI 0.40-1.34; p: 0.31). High-grade adverse events were more frequent in the immunotherapy arm (OR 2.65; 95% CI 1.53-4.59; p: <0.001), and high-grade treatment-related adverse events were 8 times more frequent in the experimental arm (OR: 8.07; 95% CI: 3.14-20.75; p: <0.001). Subgroup analyses showed statistically significant differences favoring the experimental arm in females (HR: 0.71; 95 CI 0.55-0.92; p: 0.009), in sarcomatoid differentiation (HR: 0.60 95% CI 0.41-0.89; p: 0.01), and PD-L1 positive tumors (HR HR: 0.74; 95% CI 0.61-0.90; p: 0.003). No significant effect was found in patients according to age, type of nephrectomy (radical vs. partial), and stage (M1 without evidence of disease vs. M0 patients). CONCLUSION: Our comprehensive meta-analysis generally suggests that immunotherapy does not confer a survival advantage in the perioperative setting for RCC, with the exception of one positive study. While the overall results are not statistically significant, individual patient factors and other variables may play a role in determining who benefits from immunotherapy. Therefore, despite the mixed findings, immunotherapy may still be a viable treatment option for certain patients, and further studies are needed to determine which patient subgroups would be most likely to benefit.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Feminino , Humanos , Carcinoma de Células Renais/cirurgia , Antígeno B7-H1 , Recidiva Local de Neoplasia , Imunoterapia/métodos , Neoplasias Renais/cirurgia
14.
World J Stem Cells ; 15(5): 421-437, 2023 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-37342223

RESUMO

Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of immunoglobulin-secreting clonal plasma cells at the bone marrow (BM). The interaction between MM cells and the BM microenvironment, and specifically BM mesenchymal stem cells (BM-MSCs), has a key role in the pathophysiology of this disease. Multiple data support the idea that BM-MSCs not only enhance the proliferation and survival of MM cells but are also involved in the resistance of MM cells to certain drugs, aiding the progression of this hematological tumor. The relation of MM cells with the resident BM-MSCs is a two-way interaction. MM modulate the behavior of BM-MSCs altering their expression profile, proliferation rate, osteogenic potential, and expression of senescence markers. In turn, modified BM-MSCs can produce a set of cytokines that would modulate the BM microenvironment to favor disease progression. The interaction between MM cells and BM-MSCs can be mediated by the secretion of a variety of soluble factors and extracellular vesicles carrying microRNAs, long non-coding RNAs or other molecules. However, the communication between these two types of cells could also involve a direct physical interaction through adhesion molecules or tunneling nanotubes. Thus, understanding the way this communication works and developing strategies to interfere in the process, would preclude the expansion of the MM cells and might offer alternative treatments for this incurable disease.

15.
Bioinform Adv ; 3(1): vbad037, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37096121

RESUMO

Motivation: Modern genomic technologies allow us to perform genome-wide analysis to find gene markers associated with the risk and survival in cancer patients. Accurate risk prediction and patient stratification based on robust gene signatures is a key path forward in personalized treatment and precision medicine. Several authors have proposed the identification of gene signatures to assign risk in patients with breast cancer (BRCA), and some of these signatures have been implemented within commercial platforms in the clinic, such as Oncotype and Prosigna. However, these platforms are black boxes in which the influence of selected genes as survival markers is unclear and where the risk scores provided cannot be clearly related to the standard clinicopathological tumor markers obtained by immunohistochemistry (IHC), which guide clinical and therapeutic decisions in breast cancer. Results: Here, we present a framework to discover a robust list of gene expression markers associated with survival that can be biologically interpreted in terms of the three main biomolecular factors (IHC clinical markers: ER, PR and HER2) that define clinical outcome in BRCA. To test and ensure the reproducibility of the results, we compiled and analyzed two independent datasets with a large number of tumor samples (1024 and 879) that include full genome-wide expression profiles and survival data. Using these two cohorts, we obtained a robust subset of gene survival markers that correlate well with the major IHC clinical markers used in breast cancer. The geneset of survival markers that we identify (which includes 34 genes) significantly improves the risk prediction provided by the genesets included in the commercial platforms: Oncotype (16 genes) and Prosigna (50 genes, i.e. PAM50). Furthermore, some of the genes identified have recently been proposed in the literature as new prognostic markers and may deserve more attention in current clinical trials to improve breast cancer risk prediction. Availability and implementation: All data integrated and analyzed in this research will be available on GitHub (https://github.com/jdelasrivas-lab/breastcancersurvsign), including the R scripts and protocols used for the analyses. Supplementary information: Supplementary data are available at Bioinformatics Advances online.

16.
Nat Methods ; 20(5): 706-713, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37024653

RESUMO

Discovery of off-target CRISPR-Cas activity in patient-derived cells and animal models is crucial for genome editing applications, but currently exhibits low sensitivity. We demonstrate that inhibition of DNA-dependent protein kinase catalytic subunit accumulates the repair protein MRE11 at CRISPR-Cas-targeted sites, enabling high-sensitivity mapping of off-target sites to positions of MRE11 binding using chromatin immunoprecipitation followed by sequencing. This technique, termed DISCOVER-Seq+, discovered up to fivefold more CRISPR off-target sites in immortalized cell lines, primary human cells and mice compared with previous methods. We demonstrate applicability to ex vivo knock-in of a cancer-directed transgenic T cell receptor in primary human T cells and in vivo adenovirus knock-out of cardiovascular risk gene PCSK9 in mice. Thus, DISCOVER-Seq+ is, to our knowledge, the most sensitive method to-date for discovering off-target genome editing in vivo.


Assuntos
Sistemas CRISPR-Cas , Pró-Proteína Convertase 9 , Humanos , Animais , Camundongos , Pró-Proteína Convertase 9/genética , Edição de Genes/métodos , Genoma
17.
Rev. cuba. med ; 62(1)mar. 2023.
Artigo em Espanhol | LILACS-Express | LILACS | ID: biblio-1449994

RESUMO

Introducción: Las malformaciones de Arnold-Chiari, son un grupo heterogéneo de desórdenes neurológicos caracterizados por alteraciones dentro de las regiones del cerebelo, tallo cerebral y unión cráneo-cervical; todas resultan en un desplazamiento inferior del cerebelo hacia el canal espinal por el foramen magno, sea en conjunto con la médula inferior o no. Objetivo: Describir los hallazgos clínicos, estudios complementarios, criterios diagnósticos, conducta terapéutica y evolución, en un caso con malformación de Chiari tipo I con siringomielia. Presentación de caso: Se presenta a una paciente con cefalea de curso insidioso a la que se le diagnostica malformación de Chiari tipo I con siringomielia, que requirió tratamiento neuroquirúrgico. La evolución posoperatoria fue favorable. Conclusiones: La malformación de Arnold-Chiari es una entidad rara; la aparición de la resonancia magnética nuclear ha permitido que su diagnóstico aumente y por tanto, su incidencia. El caso presentado tuvo un curso clínico clásico.


Introduction: Arnold-Chiari malformations are a heterogeneous group of neurological disorders characterized by alterations within the regions of the cerebellum, brain stem and craniocervical junction; all result in inferior displacement of the cerebellum into the spinal canal through the foramen magnum, whether in conjunction with the inferior cord or not. Objective: To describe the clinical findings, complementary studies, diagnostic criteria, therapeutic approach and evolution, in a case with type I Chiari malformation with syringomyelia. Case report: A patient with an insidious course of headache is reported. She was diagnosed with type I Chiari malformation with syringomyelia, which required neurosurgical treatment. The postoperative evolution was favorable. Conclusions: Conclusions: Arnold-Chiari malformation is a rare entity. the appearance of nuclear magnetic resonance has allowed it to be diagnosed and therefore its incidence has increased. The reported case had a classic clinical course.

18.
Biotechnol Biofuels Bioprod ; 16(1): 21, 2023 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-36759921

RESUMO

BACKGROUND: Horticultural intensive type systems dedicated in producing greenhouse vegetables are one of the primary industries generating organic waste. Towards the implementation of a zero-waste strategy, this work aims to use discarded vegetables (tomato, pepper and watermelon) as feedstock for producing microbial oil using the oleaginous yeast Cryptococcus curvatus. RESULTS: The soluble fraction, resulting after crushing and centrifuging these residues, showed C/N ratios of about 15, with a total carbohydrate content (mainly glucose, fructose and sucrose) ranging from 30 g/L to 65 g/L. Using these liquid fractions as substrate under a pulse-feeding strategy with a concentrated glucose solution resulted in an intracellular total lipid accumulation of about 30% (w/w) of the total dry cell weight (DCW). To increase this intracellular lipid content, the initial C/N content was increased from 15 to 30 and 50. Under these conditions, the process performance of the pulse-feeding strategy increased by 20-36%, resulting in a total intracellular lipid concentration of 35-40% DCW (w/w). CONCLUSION: These results demonstrate the potential of discarded vegetables as a substrate for producing bio-based products such as microbial oil when proper cultivation strategies are available.

19.
Arch Orthop Trauma Surg ; 143(8): 4951-4959, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36752833

RESUMO

BACKGROUND: Femoroacetabular impingement syndrome (FAIS) is a common hip pathology that causes pain and functional limitation in young patients. subspine femoroacetabular impingement (SFAI) is an increasingly diagnosed extra-articular subtype that occurs from mechanical conflict of the anteroinferior iliac spine (AIIS) with the cervico-diaphyseal junction during hip flexion, which is poorly described in the literature. QUESTIONS/PURPOSES: We aimed to describe the clinical, functional, and radiological results of the arthroscopic treatment of a group of patients with SFAI treated in our Hip Unit. STUDY DESIGN: Case series. METHODS: We present a retrospective study of ten patients with SFAI treated between 2013 and 2020 with arthroscopic resection. Clinical results were assessed with scales such as visual analog scale (VAS); modified Harris Hip Score (mHHS), and Hip disability and Osteoarthritis Outcome Score (HOOS). Radiological results were assessed with radiological measurements, magnetic resonance imaging (MRI), and computed tomography (CT) reconstructions. RESULTS: Six patients had a Type III AIIS and four of them had Type II. Two patients had previously been surgically treated for FAIS. The range of motion improved in flexion from 107 ± 11 degrees before surgery to 127.5 ± 6 degrees (p = 0.005). MHHS improved from 48.1 (38-75.3) before surgery to 83.1 (57-91) (p = 0.007) and HOOS improved from 65.2 (58-75) to 89 (68.1-100) (p = 0.007). VAS improved from 7.3 (5-9) pre-surgical to 2.5 (0-8) post-surgical (p = 0.005). We did not have significant complications except for an asymptomatic case of heterotopic ossification (Brooker I). CONCLUSION: Arthroscopic decompression of AIIS in SFAI patients is a safe procedure that provides satisfactory short-term functional results, improving clinical symptoms, function, sports performance, and range of motion in our study.


Assuntos
Impacto Femoroacetabular , Humanos , Impacto Femoroacetabular/diagnóstico por imagem , Impacto Femoroacetabular/cirurgia , Articulação do Quadril/diagnóstico por imagem , Articulação do Quadril/cirurgia , Articulação do Quadril/patologia , Estudos Retrospectivos , Radiografia , Tomografia Computadorizada por Raios X , Artroscopia/métodos , Resultado do Tratamento
20.
Clin Cancer Res ; 29(7): 1232-1242, 2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-36648492

RESUMO

PURPOSE: Despite recent approvals for checkpoint inhibitors and antibody-drug conjugates targeting NECTIN4 or TROP2, metastatic bladder cancer remains incurable and new treatment strategies are urgently needed. CUB domain-containing protein 1 (CDCP1) is a cell surface protein and promising drug target for many cancers. This study aimed to determine whether CDCP1 is expressed in bladder cancer and whether CDCP1 can be targeted for treatment with radiolabeled antibodies. EXPERIMENTAL DESIGN: CDCP1 expression was evaluated in four bladder cancer datasets (n = 1,047 biopsies). A tissue microarray of primary bladder cancer biopsies was probed for CDCP1 by IHC. CDCP1 expression was evaluated in patient-derived xenografts and cell lysates by immunoblot, flow cytometry, and saturation binding assays. Tumor detection in mouse bladder cancer models was tested using 89Zr-labeled 4A06, a monoclonal antibody targeting the ectodomain of CDCP1. 177Lu-4A06 was applied to mice bearing UMUC3 or HT-1376 xenografts to evaluate antitumor effects (CDCP1 expression in UMUC3 is 10-fold higher than HT-1376). RESULTS: CDCP1 was highest in the basal/squamous subtype, and CDCP1 was expressed in 53% of primary biopsies. CDCP1 was not correlated with pathologic or tumor stage, metastatic site, or NECTIN4 and TROP2 at the mRNA or protein level. CDCP1 ranged from 105 to 106 receptors per cell. Mechanism studies showed that RAS signaling induced CDCP1 expression. 89Zr-4A06 PET detected five human bladder cancer xenografts. 177Lu-4A06 inhibited the growth of UMUC3 and HT-1376 xenografts, models with high and moderate CDCP1 expression, respectively. CONCLUSIONS: These data establish that CDCP1 is expressed in bladder cancer, including TROP2 and NECTIN4-null disease, and suggest that bladder cancer can be treated with CDCP1-targeted radiotherapy.


Assuntos
Radioisótopos , Neoplasias da Bexiga Urinária , Humanos , Animais , Camundongos , Zircônio , Proteínas de Neoplasias/genética , Medicina de Precisão , Antígenos CD/metabolismo , Antígenos de Neoplasias/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Linhagem Celular Tumoral , Moléculas de Adesão Celular/genética
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