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We present here the K9 lymphoma assay, a novel 31-gene targeted next-generation sequencing panel designed for genomic profiling of canine lymphoid neoplasms. Addressing the growing demand for advanced diagnostics in veterinary oncology, this assay enables sensitive identification of known and actionable mutations specific to canine lymphomas, while evaluating its prognostic potential to facilitate diagnosis and prognosis. Our analysis, spanning several B- and T-cell lymphoma histotypes, unveiled distinct mutational landscapes distinguishing tumors derived from immature versus mature lymphocytes. Clustering analysis revealed a shared genetic origin between diffuse large B-cell lymphoma and marginal zone lymphoma, aligning with findings in human lymphomas, with TRAF3 emerging as the most frequently mutated gene across B-cell lymphoma subtypes. Significantly, TP53 mutations demonstrated universal adverse prognostic implications across B-cell lymphomas. Additionally, SETD2 mutations contributed to shorter time-to-progression, underscoring the role of epigenetic dysregulation in B-cell tumors. In T-cell lymphomas, SATB1 and FBXW7 were frequently mutated, warranting further investigation in larger cohorts. Our findings advocate for tailored therapeutic approaches based on the genetic profile, impacting treatment decisions and outcomes in canine lymphoma management. This study provides pivotal insights bridging veterinary and human oncology, paving the way for comprehensive genomic diagnostics and therapeutic strategies in comparative oncology.
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Enfermedades de los Perros , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Perros , Animales , Enfermedades de los Perros/genética , Enfermedades de los Perros/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Pronóstico , Linfoma/genética , Linfoma/veterinaria , Linfoma/diagnóstico , Linfoma/patología , Linfoma de Células T/genética , Linfoma de Células T/veterinaria , Linfoma de Células T/patología , Linfoma de Células T/diagnósticoRESUMEN
Graves disease is the most common cause of hyperthyroidism in iodine-sufficient areas. The main responsible mechanism is related to autoantibodies that bind and activate the thyrotropin receptor (TSHR). Although Graves hyperthyroidism is relatively common, no causal treatment options are available. Established treatment modalities are antithyroid drugs, which reduce thyroid hormone synthesis, radioactive iodine and surgery. However, emerging drugs that target the main autoantigen (monoclonal antibodies, small molecules, peptides) or block the immune pathway have been recently tested in clinical trials. Graves disease can involve the thyroid exclusively or it can be associated with extrathyroidal manifestations, among which Graves orbitopathy is the most common. The presence of Graves orbitopathy can change the management of the disease. An established treatment for moderate-to-severe Graves orbitopathy is intravenous glucocorticoids. However, recent advances in understanding the pathogenesis of Graves orbitopathy have allowed the development of new target-based therapies by blocking pro-inflammatory cytokine receptors, lymphocytic infiltration or the insulin-like growth factor 1 receptor (IGF1R), with several clinical trials providing promising results. This article reviews the new discoveries in the pathogenesis of Graves hyperthyroidism and Graves orbitopathy that offer several important tools in disease management.
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AIM: Ensuring an adequate distal resection margin (DRM) is a key factor in achieving the gold standard in surgical treatment for rectal surgery. The aim of this article is to describe our surgical technique and the usefulness of intraoperative ultrasonography (IOUS) for evaluating the DRM during robotic rectal surgery (RRS). METHOD: Prospective data on five consecutive patients with rectal cancer who underwent RRS between January 2023 and December 2023 were collected. IOUS was utilized to evaluate the DRM in all patients. RESULTS: The mean time for the IOUS examination ranged from 5 to 10 min. There were no intraoperative complications or conversions to open surgery. The median length of hospital stay was 6.4 days (±1.67 days). During hospitalization, one patient experienced a Grade II complication according to the Clavien-Dindo classification, specifically postoperative ileus. Furthermore, one patient experienced a delayed anastomotic fistula, which was conservatively treated without readmission. At definitive pathology, the median distance of the tumour from the DRM was 29 mm (±1.41 mm) and all patients had an R0 resection. CONCLUSION: IOUS is a reproducible and helpful modality for identifying the distal margin of the cutting line during robotic resection of rectal cancers. It does not affect the operating time compared with other methods and could be an alternative method for assessment of the DRM during RRS.
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BACKGROUND: Regional lymph nodes are frequently sampled in cats with suspected intestinal lymphoma; however, their diagnostic value has not been explored. OBJECTIVES: To investigate whether histologic and immunohistochemical analysis of mesenteric lymph nodes correlates with the diagnosis of intestinal lymphoma in cats. ANIMALS: One hundred 2 client-owned cats diagnosed with intestinal lymphoma. METHODS: Retrospective study. The inclusion criteria required a full-thickness biopsy of the small intestine and concurrent excision of mesenteric lymph nodes. Histologic and immunophenotypic analyses were performed on intestinal biopsies and corresponding lymph nodes. Selected nodal samples diagnosed with reactive lymph nodes underwent clonality testing. RESULTS: Transmural T-cell lymphomas, encompassing small and large cell types, were predominant (64 cases, 62.7%), with large B-cell lymphomas being more frequently transmural (68.8%) than mucosal (31.2%). Among all lymph nodes examined, 44 (43.1%; 95% CI: 33.9%-52.8%) exhibited neoplastic infiltration. Among cases of small cell lymphoma, 51 out of 72 (70.8%; 95% CI: 59.4%-80.1%) showed no nodal involvement. Clonality results correctly identified 19/30 (63.3%; 95% CI: 45.5%-78.2%) reactive lymph nodes. Concerns were raised regarding clonal identification in the remaining cases and potential misdiagnoses based on phenotypic characteristics. CONCLUSION AND CLINICAL IMPORTANCE: The study underscores the potential drawbacks of relying solely on mesenteric lymph nodes for diagnosing intestinal lymphomas in cats, particularly small cell subtypes. It emphasizes the importance of full-thickness biopsies for assessing transmural infiltration and recommends caution when utilizing mesenteric lymph nodes for histologic, immunohistochemical and clonality evaluations in mucosal lymphomas. Despite limitations, this research highlights the need for comprehensive diagnostic strategies in cats with intestinal lymphoma.
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Enfermedades de los Gatos , Neoplasias Intestinales , Ganglios Linfáticos , Linfoma , Animales , Gatos , Enfermedades de los Gatos/patología , Enfermedades de los Gatos/diagnóstico , Estudios Retrospectivos , Neoplasias Intestinales/veterinaria , Neoplasias Intestinales/patología , Neoplasias Intestinales/diagnóstico , Ganglios Linfáticos/patología , Masculino , Femenino , Linfoma/veterinaria , Linfoma/patología , Linfoma/diagnóstico , Biopsia/veterinaria , Intestino Delgado/patología , Mesenterio/patología , Linfoma de Células T/veterinaria , Linfoma de Células T/patología , Linfoma de Células T/diagnósticoRESUMEN
Central pancreatectomy (CP) is indicated for benign or low-grade pancreatic tumors located in the neck or proximal pancreatic body. This procedure is demanding and has a high rate of postoperative complications. Minimally invasive surgery is now commonly used for CP but it is still unclear whether the robotic approach offers any advantages over conventional pancreatic minimally invasive surgery. Most studies on robotic CP are limited to case reports or case series; however, there are two important studies on this topic. Currently, the evidence on robotic CP remains limited, making it challenging to draw definitive conclusions in favor of one technique over the other. The use of a robotic platform, with its integrated tools such as intraoperative ultrasound, can guide the surgeon in performing this technically demanding procedure in a safer manner. The controversy regarding the best minimally invasive surgery approach for CP is still ongoing and requires further research.
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Pancreatectomía , Neoplasias Pancreáticas , Procedimientos Quirúrgicos Robotizados , Humanos , Pancreatectomía/métodos , Procedimientos Quirúrgicos Robotizados/métodos , Neoplasias Pancreáticas/cirugía , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Complicaciones Posoperatorias/prevención & control , PronósticoRESUMEN
Vascular tone regulation is a crucial aspect of cardiovascular physiology, with significant implications for overall cardiovascular health. However, the precise physiological mechanisms governing smooth muscle cell contraction and relaxation remain uncertain. The complexity of vascular tone regulation stems from its multiscale and multifactorial nature, involving global hemodynamics, local flow conditions, tissue mechanics, and biochemical pathways. Bridging this knowledge gap and translating it into clinical practice presents a challenge. In this paper, a computational model is presented to integrate chemo-mechano-biological pathways with cardiovascular biomechanics, aiming to unravel the intricacies of vascular tone regulation. The computational framework combines an algebraic description of global hemodynamics with detailed finite element analyses at the scale of vascular segments for describing their passive and active mechanical response, as well as the molecular transport problem linked with chemo-biological pathways triggered by wall shear stresses. Their coupling is accounted for by considering a two-way interaction. Specifically, the focus is on the role of nitric oxide-related molecular pathways, which play a critical role in modulating smooth muscle contraction and relaxation to maintain vascular tone. The computational framework is employed to examine the interplay between localized alterations in the biomechanical response of a specific vessel segment-such as those induced by calcifications or endothelial dysfunction-and the broader global hemodynamic conditions-both under basal and altered states. The proposed approach aims to advance our understanding of vascular tone regulation and its impact on cardiovascular health. By incorporating chemo-mechano-biological mechanisms into in silico models, this study allows us to investigate cardiovascular responses to multifactorial stimuli and incorporate the role of adaptive homeostasis in computational biomechanics frameworks.
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Simulación por Computador , Análisis de Elementos Finitos , Modelos Cardiovasculares , Fenómenos Biomecánicos , Humanos , Estrés Mecánico , Hemodinámica/fisiología , Óxido Nítrico/metabolismo , Mecanotransducción Celular/fisiología , Vasos Sanguíneos/fisiologíaRESUMEN
BACKGROUND: Central pancreatectomy (CP) is a parenchymal-sparing technique indicated for the resection of selected lesions of the neck or proximal body of the pancreas.1,2 The risk of postoperative complications is theoretically doubled because the surgeon has to manage two cut surfaces of the pancreas. The video shows a fully robotic CP to treat a 62-year-old male patient with a mixed-type intraductal papillary mucinous neoplasm (IPMN) of the pancreatic neck, using ultrasound (US) and Wirsung endoscopic evaluation to guide the pancreatic resection and ensure optimal resection margins. MATERIALS AND METHODS: A US-guided robotic CP was carried out, and an intraoperative endoscopic evaluation of the MPD was performed to determine the distal transection level. A transmesocolic, end-to-side, robot-sewn Wirsung-jejunostomy with internal MPD stenting was then created. The procedure was completed with a side-to-side jejunojejunostomy. RESULTS: The operative time was 290 min, with negligible blood loss. During the postoperative course, the patient experienced bleeding from a branch of the gastroduodenal artery with subsequent fluid collection, which was successfully treated with angioembolization and percutaneous drainage. He was discharged home on postoperative day 22. Final pathology revealed a non-invasive IPMN with low-grade dysplasia and free surgical margins. At 12 months of follow-up, the patient was doing well, with no evidence of local recurrence and endocrine or exocrine pancreatic insufficiency. CONCLUSIONS: The combination of robotic surgery with intraoperative US and Wirsungoscopy may offer distinct technical advantages for challenging pancreatectomies that follow the principles of parenchymal-sparing surgery.
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Pancreatectomía , Conductos Pancreáticos , Neoplasias Pancreáticas , Procedimientos Quirúrgicos Robotizados , Humanos , Masculino , Pancreatectomía/métodos , Persona de Mediana Edad , Procedimientos Quirúrgicos Robotizados/métodos , Conductos Pancreáticos/cirugía , Conductos Pancreáticos/patología , Conductos Pancreáticos/diagnóstico por imagen , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Intraductales Pancreáticas/cirugía , Neoplasias Intraductales Pancreáticas/patología , Neoplasias Intraductales Pancreáticas/diagnóstico por imagen , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/diagnóstico por imagen , Carcinoma Ductal Pancreático/patología , Adenocarcinoma Mucinoso/cirugía , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/diagnóstico por imagen , PronósticoRESUMEN
This work presents the application of a chemo-mechano-biological constitutive model of soft tissues for describing tissue inflammatory response to damage in collagen constituents. The material model is implemented into a nonlinear finite element formulation to follow up a coronary standard balloon angioplasty for one year. Numerical results, compared with available in vivo clinical data, show that the model reproduces the temporal dynamics of vessel remodeling associated with subintimal damage. Such dynamics are bimodular, being characterized by an early tissue resorption and lumen enlargement, followed by late tissue growth and vessel constriction. Applicability of the modeling framework in retrospective studies is demonstrated, and future extension towards prospective applications is discussed.
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Angioplastia Coronaria con Balón , Angioplastia de Balón , Vasos Coronarios , Estudios Retrospectivos , Colágeno , Simulación por ComputadorRESUMEN
The identification of carotid atherosclerotic lesion at risk for plaque rupture, eventually resulting in cerebral embolism and stroke, is of paramount clinical importance. High stress in the fibrous plaque cap has been proposed as risk factor. However, among others, residual strains influence said stress predictions, but quantitative and qualitative implications of residual strains in this context are not well explored. We therefore propose a multiplicative kinematics-based Growth and Remodeling (G&R) framework to predict residual strains from homogenizing tissue stress and then investigate its implication on plaque stress. Carotid vessel morphology of four patients was reconstructed from clinical Computed Tomography-Angiography (CT-A) images and equipped with heterogeneous tissue constitutive properties assigned through a histology-based artificial intelligence image segmentation tool. As compared to a purely elastic analysis and depending on patient-specific morphology and tissue distributions, the incorporation of residual strains reduced the maximum wall stress by up to 30 % and resulted in a fundamentally different distribution of stress across the atherosclerotic wall. Regardless residual strains homogenized tissue stresses, the fibrous plaque cap may persistently be exposed to spots of high stress. In conclusion, the incorporation of residual strains in biomechanical studies of atherosclerotic carotids may be important for a reliable assessment of fibrous plaque cap stress.
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Aterosclerosis , Placa Aterosclerótica , Accidente Cerebrovascular , Humanos , Inteligencia Artificial , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/patología , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/patología , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/patología , Accidente Cerebrovascular/patología , Fibrosis , Estrés MecánicoRESUMEN
BACKGROUND: Graves' orbitopathy (GO) is subject to epidemiological and care-related changes. Aim of the survey was to identify trends in presentation of GO to the European Group On Graves' Orbitopathy (EUGOGO) tertiary referral centres and initial management over time. METHODS: Prospective observational multicentre study. All new referrals with diagnosis of GO within September-December 2019 were included. Clinical and demographic characteristics, referral timelines and initial therapeutic decisions were recorded. Data were compared with a similar EUGOGO survey performed in 2012. RESULTS: Besides age (mean age: 50.5±13 years vs 47.7±14 years; p 0.007), demographic characteristics of 432 patients studied in 2019 were similar to those in 2012. In 2019, there was a decrease of severe cases (9.8% vs 14.9; p<0.001), but no significant change in proportion of active cases (41.3% vs 36.6%; p 0.217). After first diagnosis of GO, median referral time to an EUGOGO tertiary centre was shorter (2 (0-350) vs 6 (0-552) months; p<0.001) in 2019. At the time of first visit, more patients were already on antithyroid medications (80.2% vs 45.0%; p<0.001) or selenium (22.3% vs 3.0%; p<0.001). In 2019, the initial management plans for GO were similar to 2012, except for lid surgery (2.4% vs 13.9%; p<0.001) and prescription of selenium (28.5% vs 21.0%; p 0.027). CONCLUSION: GO patients are referred to tertiary EUGOGO centres in a less severe stage of the disease than before. We speculate that this might be linked to a broader awareness of the disease and faster and adequate delivered treatment.
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Oftalmopatía de Graves , Selenio , Humanos , Adulto , Persona de Mediana Edad , Oftalmopatía de Graves/diagnóstico , Oftalmopatía de Graves/epidemiología , Oftalmopatía de Graves/terapia , Estudios Prospectivos , Derivación y Consulta , Centros de Atención TerciariaRESUMEN
PURPOSE: Graves orbitopathy (GO) is the most common extrathyroidal manifestation of Graves disease. Although its pathogenesis is not fully elucidated, GO is commonly considered an autoimmune disease due to loss of self-tolerance against autoantigens shared by thyroid epithelial cells and orbital fibroblasts. High-dose intravenous glucocorticoids (ivGCs) are the most used treatment for moderate-to-severe, active GO, but the addition of other immunomodulating treatments can improve the efficacy of ivGCs. Among the various risk factors that can affect the occurrence of GO, cholesterol may be worthy of interest. Since 2015 the role of cholesterol and cholesterol-lowering medications has been investigated. The purpose of this review is to discuss this topic, thereby offering new therapeutic opportunities for patients with GO. METHODS: We searched PubMed for studies published between January 1, 1980 and June 1, 2023, using the search terms "Graves orbitopathy," "thyroid eye disease," "Graves ophthalmopathy," "thyroid ophthalmopathy," "thyroid-associated ophthalmopathy," "endocrine ophthalmopathy," "cholesterol," "lipids," "statins," "low-density lipoprotein," "atorvastatin," and "cholesterol-lowering drugs." Only English-language articles were included. RESULTS: A correlation between low-density lipoprotein cholesterol and the risk of GO development has been reported. Furthermore, low-density lipoprotein cholesterol has been proposed as a risk factor that can affect the course of GO and the response to ivGCs. The protective role of cholesterol-lowering medications in preventing GO has been also investigated. Statin treatment was found to have potential benefits in reducing the risk of GO in patients with Graves disease. Given these findings, measurement of low-density lipoprotein cholesterol and treatment of hypercholesterolemia in patients with moderate-to-severe, active GO may be considered before starting ivGCs administration. Recently, a randomized clinical trial aimed at investigating the effects of statins in GO suggested that the addition of oral atorvastatin to ivGCs improves the overall outcome of moderate-to-severe, active GO in hypercholesterolemic patients given ivGCs. CONCLUSIONS: Overall, statins seem to have a preventive and therapeutic role in moderate-to-severe active GO. Their efficacy can be related to cholesterol-lowering activity, pleiotropic actions, and interaction with methylprednisolone.
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Enfermedad de Graves , Oftalmopatía de Graves , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Oftalmopatía de Graves/tratamiento farmacológico , Atorvastatina , Glucocorticoides/uso terapéutico , Lipoproteínas LDL , Colesterol , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
The advantages of using the robotic platform may not be clearly evident in left colectomies, where the surgeon operates in an "open field" and does not routinely require intraoperative suturing. Current evidences are based on limited cohorts reporting conflicting outcomes regarding robotic left colectomies (RLC). The aim of this study is to report a bi-centric experience with robotic left colectomy in order to help in defining the role of the robotic approach for these procedures. This is a bi-centric propensity score matched study including patients who underwent RLC or laparoscopic left colectomy (LLC) between January 1, 2012 and May 1, 2022. RLC patients were matched to LLC patients in a 1:1 ratio. Main outcomes were conversion to open surgery and 30-day morbidity. In total, 300 patients were included. Of 143 (47.7%) RLC patients, 119 could be matched. After matching, conversion rate (4.2 vs. 7.6%, p = 0.265), 30-day morbidity (16.1 vs. 13.7%, p = 0.736), Clavien-Dindo grade ≥ 3 complications (2.4 vs 3.2%, p = 0.572), transfusions (0.8 vs. 4.0%, p = 0.219), and 30-day mortality (0.8 vs 0.8%, p = 1.000) were comparable for RLC and LLC, respectively. Median operative time was longer for RLC (296 min 260-340 vs. 245, 195-296, p < 0.0001). Early oral feeding, time to first flatus, and hospital stay were similar between groups. RLC has safety parameters as well as conversion to open surgery comparable with standard laparoscopy. Operative time is longer with the robotic approach.
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Laparoscopía , Procedimientos Quirúrgicos Robotizados , Humanos , Procedimientos Quirúrgicos Robotizados/métodos , Puntaje de Propensión , Laparoscopía/métodos , Colectomía/efectos adversos , Colectomía/métodos , Tempo Operativo , Tiempo de Internación , Estudios Retrospectivos , Resultado del Tratamiento , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiologíaRESUMEN
BACKGROUND: The adoption of robotic surgery for esophageal cancer has been expanding rapidly over the recent years. In the setting of two-field esophagectomy, different techniques exist for intrathoracic esophagogastric anastomosis, although the superiority of one over another has not been clearly demonstrated. Potential benefits in terms of anastomotic leakage and stenosis have been reported in association with a linear-stapled anastomosis as compared to the more widespread techniques of circular mechanical and hand-sewn reconstructions, however, there is still limited reported evidence on its application to robotic surgery. We here report our fully robotic technique of side-to-side, semi-mechanical anastomosis. METHODS: All consecutive patients undergoing fully robotic esophagectomy featuring intrathoracic side-to-side stapled anastomosis by a single surgical team were included in this analysis. Operative technique is detailed, and perioperative data are assessed. RESULTS: A total of 49 patients were included. There were no intraoperative complications and no conversion occurred. The rate of overall postoperative morbidity was 25, 14% being the relative rate of major complications. With anastomotic-related morbidity in particular, one patient developed minor anastomotic leakage. CONCLUSIONS: Our experience demonstrates that a linear, side-to-side fully robotic stapled anastomosis can be created with a high technical success and minimal incidence of anastomosis-related morbidity.
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Neoplasias Esofágicas , Procedimientos Quirúrgicos Robotizados , Humanos , Esofagectomía/efectos adversos , Fuga Anastomótica/epidemiología , Fuga Anastomótica/etiología , Fuga Anastomótica/prevención & control , Procedimientos Quirúrgicos Robotizados/métodos , Resultado del Tratamiento , Anastomosis Quirúrgica/efectos adversos , Neoplasias Esofágicas/complicaciones , Estudios Retrospectivos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugíaRESUMEN
Damage in soft biological tissues causes an inflammatory reaction that initiates a chain of events to repair the tissue. This work presents a continuum model and its in silico implementation that describe the cascade of mechanisms leading to tissue healing, coupling mechanical as well as chemo-biological processes. The mechanics is described by means of a Lagrangian nonlinear continuum mechanics framework and follows the homogenized constrained mixtures theory. Plastic-like damage, growth and remodeling as well as homeostasis are taken into account. The chemo-biological pathways account for two molecular and four cellular species, and are activated by damage of collagen molecules in fibers. To consider proliferation, differentiation, diffusion and chemotaxis of species, diffusion-advection-reaction equations are employed. To the best of authors' knowledge, the proposed model combines for the first time such high number of chemo-mechano-biological mechanisms in a consistent continuum biomechanical framework. The resulting set of coupled differential equations describe balance of linear momentum, evolution of kinematic variables as well as mass balance equations. They are discretized in time according to a backward Euler finite difference scheme, and in space through a finite element Galerkin discretization. The features of the model are firstly demonstrated presenting the species dynamics and highlighting the influence of damage intensities on the growth outcome. In terms of a biaxial test, the chemo-mechano-biological coupling and the model's applicability to reproduce normal as well as pathological healing are shown. A last numerical example underlines the model's applicability to complex loading scenarios and inhomogeneous damage distributions. Concluding, the present work contributes towards comprehensive in silico models in biomechanics and mechanobiology.
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Colágeno , Modelos Biológicos , Arterias , Fenómenos Biomecánicos , Simulación por Computador , Estrés Mecánico , Análisis de Elementos FinitosRESUMEN
CONTEXT: Gut bacteria can influence host immune responses but little is known about their role in tolerance-loss mechanisms in Graves disease (GD; hyperthyroidism caused by autoantibodies, TRAb, to the thyrotropin receptor, TSHR) and its progression to Graves orbitopathy (GO). OBJECTIVE: This work aimed to compare the fecal microbiota in GD patients, with GO of varying severity, and healthy controls (HCs). METHODS: Patients were recruited from 4 European countries (105 GD patients, 41 HCs) for an observational study with cross-sectional and longitudinal components. RESULTS: At recruitment, when patients were hyperthyroid and TRAb positive, Actinobacteria were significantly increased and Bacteroidetes significantly decreased in GD/GO compared with HCs. The Firmicutes to Bacteroidetes (F:B) ratio was significantly higher in GD/GO than in HCs. Differential abundance of 15 genera was observed in patients, being most skewed in mild GO. Bacteroides displayed positive and negative correlations with TSH and free thyroxine, respectively, and was also significantly associated with smoking in GO; smoking is a risk factor for GO but not GD. Longitudinal analyses revealed that the presence of certain bacteria (Clostridiales) at diagnosis correlated with the persistence of TRAb more than 200 days after commencing antithyroid drug treatment. CONCLUSION: The increased F:B ratio observed in GD/GO mirrors our finding in a murine model comparing TSHR-immunized with control mice. We defined a microbiome signature and identified changes associated with autoimmunity as distinct from those due to hyperthyroidism. Persistence of TRAb is predictive of relapse; identification of these patients at diagnosis, via their microbiome, could improve management with potential to eradicate Clostridiales.
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Microbioma Gastrointestinal , Enfermedad de Graves , Oftalmopatía de Graves , Hipertiroidismo , Humanos , Ratones , Animales , Carmin de Índigo/uso terapéutico , Estudios Transversales , Autoanticuerpos , Receptores de Tirotropina , Hipertiroidismo/complicacionesRESUMEN
In cancer microenvironment, aberrant glycosylation events of ECM proteins and cell surface receptors occur. We developed a protocol to generate 3D bioprinted models of colorectal cancer (CRC) crosslinking hyaluronic acid and gelatin functionalized with three signalling glycans characterized in CRC, 3'-Sialylgalactose, 6'-Sialylgalactose and 2'-Fucosylgalactose. The crosslinking, performed exploiting azide functionalized gelatin and hyaluronic acid and 4arm-PEG-dibenzocyclooctyne, resulted in biocompatible hydrogels that were 3D bioprinted with commercial CRC cells HT-29 and patient derived CRC tumoroids. The glycosylated hydrogels showed good 3D printability, biocompatibility and stability over the time. SEM and synchrotron radiation SAXS/WAXS analysis revealed the influence of glycosylation in the construct morphology, whereas MALDI-MS imaging showed that protein profiles of tumoroid cells vary with glycosylation, indicating that sialylation and fucosylation of ECM proteins induce diverse alterations to the proteome of the tumoroid and surrounding cells.
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Neoplasias Colorrectales , Ácido Hialurónico , Humanos , Gelatina/farmacología , Dispersión del Ángulo Pequeño , Difracción de Rayos X , Polisacáridos , Hidrogeles/farmacología , Ingeniería de Tejidos/métodos , Andamios del Tejido , Microambiente TumoralRESUMEN
CONTEXT: A role of DNA methylation in Graves orbitopathy (GO) has been proposed. OBJECTIVE: This work aimed to investigate DNA methylation and gene expression in orbital fibroblasts from control and GO patients, under basal conditions or following challenge with an anti- thyrotropin (TSH) receptor antibody (M22) or cytokines involved in GO; to investigate the relationship between DNA methylation and cell function (proliferation); and to perform a methylome analysis. METHODS: Orbital fibroblasts from 6 GO and 6 control patients from a referral center underwent methylome analysis of the whole genome. RESULTS: Global DNA methylation increased significantly both in control and GO fibroblasts on incubation with M22. Expression of 2 selected genes (CYP19A1 and AIFM2) was variably affected by M22 and interleukin-6. M22 increased cell proliferation in control and GO fibroblasts, which correlated with global DNA methylation. Methylome analysis revealed 19 869 DNA regions differently methylated in GO fibroblasts, encompassing 3957 genes and involving CpG islands, shores, and shelves. A total of 119 gene families and subfamilies, 89 protein groups, 402 biological processes, and 7 pathways were involved. Three genes found to be differentially expressed were concordantly hypermethylated or hypomethylated. Among the differently methylated genes, insulin-like growth factor-1 receptor and several fibroblast growth factors and receptors were included. CONCLUSION: We propose that, when exposed to an autoimmune environment, orbital fibroblasts undergo hypermethylation or hypomethylation of certain genes, involving CpG promoters, which results in differential gene expression, which may be responsible for functional alterations, in particular higher proliferation, and ultimately for the GO phenotype in vivo.
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Oftalmopatía de Graves , Humanos , Oftalmopatía de Graves/metabolismo , Metilación de ADN , Tirotropina/metabolismo , Receptores de Tirotropina , Expresión Génica , Fibroblastos/metabolismoRESUMEN
Prompt and stable control of hyperthyroidism is fundamental to avoid the detrimental effects of thyroid hormone excess, and antithyroid drugs, mainly methimazole (MMI), represent the first-line treatment for Graves' disease (GD) hyperthyroidism. Decreased serum concentrations of selenium (Se) and calcifediol (25(OH)D, VitD) have been reported in newly diagnosed GD patients in observational studies. Low Se levels might exacerbate oxidative stress by compromising the antioxidant machinery's response to reactive oxygen species, and low VitD levels might hamper the anti-inflammatory immune response. We performed a randomized controlled clinical trial (EudraCT 2017-00505011) to investigate whether Se and cholecalciferol (VitD) addition to MMI is associated with a prompter control of hyperthyroidism. Forty-two consecutive patients with newly-onset GD and marginal/insufficient Se and VitD levels were randomly assigned to treatment with either MMI monotherapy or MMI combined with Se and VitD. Se treatment was withdrawn after 180 days, while the other treatments were continued. Combination therapy resulted in a significantly greater reduction in serum FT4 concentration at 45 days (-37.9 pg/ml, CI 95%, -43.7 to -32.2 pg/ml) and 180 days (-36.5 pg/ml, CI 95%, -42 to -30.9 pg/ml) compared to MMI monotherapy (respectively: -25.7 pg/ml, CI 95%, -31.6 to -19.7 pg/ml and -22.9 pg/ml, CI 95%, -28 to -17.3 pg/ml, p 0.002). Data at 270 days confirmed this trend (-37.8 pg/ml, CI 95%, -43.6 to -32.1 pg/ml vs -24.4 pg/ml, CI 95%, -30.3 to -18.4 pg/ml). The quality of life (QoL) score was investigated by the validated "Thyroid-related Patient-Reported Outcome" questionnaire (ThyPRO). ThyPRO composite score showed a greater improvement in the intervention group at 45 days (-14.6, CI 95%, -18.8 to -10.4), 180 (-9, CI 95%, -13.9 to -4.2) and 270 days (-14.3, CI 95%, -19.5 to -9.1) compared to MMI group (respectively, -5.2, CI 95%, -9.5 to -1; -5.4, CI 95%, -10.6 to -0.2 and -3.5, CI 95%, -9 to -2.1, p 0-6 months and 6-9 months <0.05). Our results suggest that reaching optimal Se and VitD levels increases the early efficacy of MMI treatment when Se and VitD levels are suboptimal.
Asunto(s)
Enfermedad de Graves , Hipertiroidismo , Selenio , Suplementos Dietéticos , Humanos , Metimazol/uso terapéutico , Calidad de Vida , Selenio/uso terapéutico , Vitamina D/uso terapéutico , Vitaminas/uso terapéuticoAsunto(s)
Diverticulitis del Colon , Diverticulitis , Laparoscopía , Procedimientos Quirúrgicos Robotizados , Humanos , Constricción Patológica/etiología , Constricción Patológica/cirugía , Diverticulitis/cirugía , Colon Sigmoide/cirugía , Biopsia , Diverticulitis del Colon/complicaciones , Diverticulitis del Colon/cirugíaRESUMEN
INTRODUCTION: Dysthyroid optic neuropathy (DON) is the most severe complication of Graves' orbitopathy (GO) and its management may require decompression surgery. Clear recommendations do not exist about which surgery should be performed and how extended the decompression should be. In this paper we present our experience regarding the management of DON via 3 different surgical protocols: a modified extended orbital apex decompression, a 2 walls decompression (inferior and lateral) and a 3 walls decompression (inferior, lateral and medial) and evaluate the functional outcomes. METHODS: Retrospective evaluation of subjects affected by DON not responding to medical therapy has been performed. All patients were submitted to pre- and post-operative ophthalmologic evaluations and orbital and sinuses CT scan in order to evaluate functional and surgical outcomes. RESULTS: 27 patients were enrolled in the study. Surgical procedures were performed on 42 orbits. A statistically significant post-operative improvement was recorded in visual acuity, proptosis, color vision and fundus oculi evaluation for all groups. No patient developed major or minor complications after surgery. CONCLUSIONS: Extended endonasal approach and 3 walls decompression have been proved effective in the management of DON. The choice between them is done according to degree of proptosis, general status and eye-surface damages.