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Glioblastoma (GBM) is the most common malignant central nervous system tumor. The emerging field of epigenetics stands out as particularly promising. Notably, the discovery of micro RNAs (miRNAs) has paved the way for advancements in diagnosing, treating, and prognosticating patients with brain tumors. We aim to provide an overview of the emergence of miRNAs in GBM and their potential role in the multifaceted management of this disease. We discuss the current state of the art regarding miRNAs and GBM. We performed a narrative review using the MEDLINE/PUBMED database to retrieve peer-reviewed articles related to the use of miRNA approaches for the treatment of GBMs. MiRNAs are intrinsic non-coding RNA molecules that regulate gene expression mainly through post-transcriptional mechanisms. The deregulation of some of these molecules is related to the pathogenesis of GBM. The inclusion of molecular characterization for the diagnosis of brain tumors and the advent of less-invasive diagnostic methods such as liquid biopsies, highlights the potential of these molecules as biomarkers for guiding the management of brain tumors such as GBM. Importantly, there is a need for more studies to better examine the application of these novel molecules. The constantly changing characterization and approach to the diagnosis and management of brain tumors broaden the possibilities for the molecular inclusion of novel epigenetic molecules, such as miRNAs, for a better understanding of this disease.
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The incidence of human papilloma virus-mediated oropharyngeal squamous cell carcinoma (OPSCC) has increased over the past 40 years, particularly among young individuals with a favorable prognosis; however, current therapy often leads to unfortunate side effects, such as dysphagia. Despite the emphasis on dysphagia in previous studies, there is an important research gap in understanding the correlation between neuronal changes and patient-reported and functional outcomes in patients with OPSCC. To address this issue, we examined pathologic tissue samples from patients with OPSCC using multiplex immunofluorescence staining and machine learning to correlate tumor-associated neuronal changes with prospectively collected patient-reported and functional outcomes. We found that tumor enrichment of adrenergic (TH+) and CGRP+ sensory-afferent nerves correlated with poorer swallowing outcomes. Functional electromyography recordings showed correlations between growing (GAP43+) and immature cholinergic (ChAT+DCX+) nerves and denervation patterns in survivors of OPSCC. A murine model of radiation-induced dysphagia further confirmed that immature cholinergic and CGRP+ nerves were correlated with impaired swallowing. Preclinical interventional studies also supported the independent contributions of CGRP+ and cholinergic (ChAT+) nerves to dysphagia in treated mouse models of OPSCC. Our results suggest that CGRP+ and ChAT+ neuronal signaling play distinct roles in tumor- and radiation-induced dysphagia in OPSCC and offer a comprehensive dataset on the neural landscape of OPSCC. These insights may guide early interventions for swallow preservation and the repurposing of neurology-related drugs, such as CGRP blockers, in clinical oncology and survivorship.
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Carcinoma de Células Escamosas , Transtornos de Deglutição , Neoplasias Orofaríngeas , Humanos , Neoplasias Orofaríngeas/radioterapia , Neoplasias Orofaríngeas/patologia , Animais , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/fisiopatologia , Masculino , Camundongos , Deglutição/efeitos da radiação , Feminino , Pessoa de Meia-Idade , Resultado do Tratamento , Peptídeo Relacionado com Gene de Calcitonina/metabolismoRESUMO
Squamous cell carcinoma (SCC) is a common tumor of the uterine cervix, usually related to human papillomavirus (HPV). While osteoclast-like giant cells (OGCs) have been reported to be associated with tumors at various locations, to the best of our knowledge, only six cases have been reported in the cervix to date. The present study describes the case of a 38-year-old woman with a medical history of ectopic pregnancy and vaginal childbirth, who presented with coitorrhagia. On physical examination, a mass of ~4 cm was found in the uterine cervix. A biopsy of this lesion revealed infiltrating SCC, leading to a radical hysterectomy 2 months later. The surgical specimen displayed an exophytic lesion with a maximum diameter of 3.5 cm confined to the uterine cervix, histologically consistent with an infiltrating non-keratinizing SCC. There was a prominent intra- and peritumoral chronic inflammatory reaction, and a high number of OGCs. Immunohistochemically, tumoral cells were positive for cytokeratin ßE12, epithelial membrane antigen, p40, p63 and p16, and negative for CD68, vimentin and CD163. OGCs exhibited an inverted expression pattern, with positivity only for histiocytic markers. PCR for HPV detection revealed a HPV 34 genotype (probable high oncogenic risk). This profile suggests the non-neoplastic nature of OGCs, i.e. they should be considered as part of the immune response to the tumor. To the best of our knowledge, this case is the seventh instance of SCC with OGCs in the uterine cervix. Similar findings in other organs, such as the breast, pancreas or stomach, have been associated with a favorable prognosis. While two of the three reported cases with poor outcomes in the uterine cervix had an associated sarcomatoid component, the limited number of cases described to date in this location does not yet allow for an accurate prediction of behavior.
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Spinal metastasis of Glioblastoma is a rare occurrence, especially in pediatric patients, and extremely rare to become symptomatic. The pathology is poorly understood and remains with unclear dissemination mechanisms. The treatment approaches are varied and multimodal therapy (surgery, chemotherapy, and radiotherapy) can be employed to manage this type of metastasis. We report a case of a 17-year-old female who underwent a gross-total resection of a right frontal glioblastoma and had adjuvant therapy with chemo- and radiotherapy. In the sixth month of follow-up, the patient presented a paraparesis, and a distant recurrence at T7-T8 was detected. The patient was treated with gross-total resection of the tumor through a laminectomy. The histopathological results were consistent with an isocitrate dehydrogenase (IDH) wildtype GBM metastasis. The patient was treated with multimodal therapy, including surgery, radiotherapy, and chemotherapy. A complementary comprehensive review of current available literature on this topic is also presented.
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Cigarette smoking is associated with COVID-19 prevalence and severity, but the mechanistic basis for how smoking alters SARS-CoV-2 pathogenesis is unknown. A potential explanation is that smoking alters the expression of the SARS-CoV-2 cellular receptor and point of entry, angiotensin converting enzyme-2 (ACE-2), and its cofactors including transmembrane protease serine 2 (TMPRSS2). We investigated the impact of cigarette smoking on the expression of ACE-2, TMPRSS2, and other known cofactors of SARS-CoV-2 infection and the resultant effects on infection severity in vitro. Cigarette smoke extract (CSE) exposure increased ACE-2 and TMPRSS2 mRNA expression compared to air control in ferret airway cells, Calu-3 cells, and primary human bronchial epithelial (HBE) cells derived from normal and COPD donors. CSE-exposed ferret airway cells inoculated with SARS-CoV-2 had a significantly higher intracellular viral load versus vehicle-exposed cells. Likewise, CSE-exposure increased both SARS-CoV-2 intracellular viral load and viral replication in both normal and COPD HBE cells over vehicle control. Apoptosis was increased in CSE-exposed, SARS-CoV-2-infected HBE cells. Knockdown of ACE-2 via an antisense oligonucleotide (ASO) reduced SARS-CoV-2 viral load and infection in CSE-exposed ferret airway cells that was augmented by co-administration of camostat mesylate to block TMPRSS2 activity. Smoking increases SARS-CoV-2 infection via upregulation of ACE2 and TMPRSS2.
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AIM: Recent evidence challenges the current standard of offering surgery to patients with ileocaecal Crohn's disease (CD) only when they present complications of the disease. The aim of this study was to compare short-term results of patients who underwent primary ileocaecal resection for either inflammatory (luminal disease, earlier in the disease course) or complicated phenotypes, hypothesizing that the latter would be associated with worse postoperative outcomes. METHOD: A retrospective, multicentre comparative analysis was performed including patients operated on for primary ileocaecal CD at 12 referral centres. Patients were divided into two groups according to indication of surgery for inflammatory (ICD) or complicated (CCD) phenotype. Short-term results were compared. RESULTS: A total of 2013 patients were included, with 291 (14.5%) in the ICD group. No differences were found between the groups in time from diagnosis to surgery. CCD patients had higher rates of low body mass index, anaemia (40.9% vs. 27%, p < 0.001) and low albumin (11.3% vs. 2.6%, p < 0.001). CCD patients had longer operations, lower rates of laparoscopic approach (84.3% vs. 93.1%, p = 0.001) and higher conversion rates (9.3% vs. 1.9%, p < 0.001). CCD patients had a longer hospital stay and higher postoperative complication rates (26.1% vs. 21.3%, p = 0.083). Anastomotic leakage and reoperations were also more frequent in this group. More patients in the CCD group required an extended bowel resection (14.1% vs. 8.3%, p: 0.017). In multivariate analysis, CCD was associated with prolonged surgery (OR 3.44, p = 0.001) and the requirement for multiple intraoperative procedures (OR 8.39, p = 0.030). CONCLUSION: Indication for surgery in patients who present with an inflammatory phenotype of CD was associated with better outcomes compared with patients operated on for complications of the disease. There was no difference between groups in time from diagnosis to surgery.
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Doença de Crohn , Íleo , Fenótipo , Complicações Pós-Operatórias , Humanos , Doença de Crohn/cirurgia , Doença de Crohn/complicações , Feminino , Estudos Retrospectivos , Masculino , Adulto , Resultado do Tratamento , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Pessoa de Meia-Idade , Íleo/cirurgia , Adulto Jovem , Ceco/cirurgia , Laparoscopia/métodos , Laparoscopia/estatística & dados numéricos , Laparoscopia/efeitos adversos , Duração da Cirurgia , Tempo de Internação/estatística & dados numéricos , Fatores de TempoRESUMO
OBJECTIVE: This study aimed to investigate the limitations, barriers, and complications in the early transition from the microscopic transsphenoidal approach (MTA) to the endonasal endoscopic approach (EEA) to the skull base in our institution. METHODS: Technical challenges, as well as clinical features and complications, were compared between MTA, EEA, and mixed cases during the early surgical curve. RESULTS: The period from the early learning curve was 1 year until the EEA protocol was used routinely. A total of 34 patients registered a resection using a transsphenoidal approach. Eighteen patients underwent EEA, 11 underwent MTA, and five underwent a mixed endonasal and microscopic approach. Non-significant differences were found in endocrine outcomes between the three groups. Patients with unchanged or improved visual function were higher in the EEA group (p = 0.147). Non-significant differences were found in terms of the extent of resection (EOR) between groups (p = 0.369). Only 1 (2.9%) patient in the whole series developed a post-operative CSF leaking that resolved with medical management, belonging to the EEA group (5.5%). CONCLUSIONS: The early phase of the learning curve did not affect our series significantly in terms of the EOR, endocrine status, and visual outcomes.
OBJETIVO: Investigar las limitaciones, las barreras y las complicaciones en la transición del abordaje transesfenoidal microscópico (ATM) al abordaje endonasal endoscópico (AEE) para la base del cráneo en nuestra institución. MÉTODO: Se compararon las características clínicas y las complicaciones entre ATM, AEE y casos mixtos durante la curva quirúrgica temprana. RESULTADOS: El periodo desde la curva de aprendizaje inicial fue de 1 año hasta que se utilizó el protocolo AEE de forma sistemática. Un total de 34 pacientes tuvieron una resección por vía transesfenoidal. A 18 pacientes se les realizó AEE, a 11 ATM y a 5 abordaje mixto endonasal y microscópico. Se encontraron diferencias no significativas en los resultados endocrinos entre los tres grupos. Los pacientes con función visual sin cambios o mejorada fueron más en el grupo AEE (p = 0.147). No se encontraron diferencias significativas respecto a la extensión de la resección (p = 0.369). Solo 1 (2.9%) paciente desarrolló una fístula de líquido cefalorraquídeo que se resolvió con manejo médico, perteneciente al grupo AEE (5.5%). CONCLUSIONES: La fase inicial de la curva de aprendizaje no afectó significativamente a nuestra serie en términos de extensión de la resección, estado endocrino y resultados visuales.
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Curva de Aprendizado , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Neoplasias Hipofisárias/cirurgia , Idoso , Estudos Retrospectivos , Microcirurgia/métodos , Sela Túrcica/cirurgia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Cavidade Nasal/cirurgia , Cirurgia Endoscópica por Orifício Natural/métodos , Neuroendoscopia/métodos , Vazamento de Líquido Cefalorraquidiano/etiologia , Vazamento de Líquido Cefalorraquidiano/epidemiologia , Endoscopia/métodosRESUMO
Rationale: The role of MUC5B mucin expression in IPF pathogenesis is unknown. Bleomycin-exposed rodent models do not exhibit sustained fibrosis or airway remodeling. Unlike mice, ferrets have human-like distribution of MUC5B expressing cell types and natively express the risk-conferring variant that induces high MUC5B expression in humans. We hypothesized that ferrets would consequently exhibit aberrant repair to propagate fibrosis similar to human IPF. Methods: Bleomycin (5U/kg) or saline-control was micro-sprayed intratracheally then wild-type ferrets were evaluated through 22 wks. Clinical phenotype was assessed with lung function. Fibrosis was assessed with µCT imaging and comparative histology with Ashcroft scoring. Airway remodeling was assessed with histology and quantitative immunofluorescence. Results: Bleomycin ferrets exhibited sustained restrictive physiology including decreased inspiratory capacity, decreased compliance, and shifted Pressure-Volume loops through 22 wks. Volumetric µCT analysis revealed increased opacification of the lung bleomycin-ferrets. Histology showed extensive fibrotic injury that matured over time and MUC5B-positive cystic structures in the distal lung suggestive of honeycombing. Bleomycin ferrets had increased proportion of small airways that were double-positive for CCSP and alpha-tubulin compared to controls, indicating an aberrant 'proximalization' repair phenotype. Notably, this aberrant repair was associated with extent of fibrotic injury at the airway level. Conclusions: Bleomycin-exposed ferrets exhibit sustained fibrosis through 22 wks and have pathologic features of IPF not found in rodents. Ferrets exhibited proximalization of the distal airways and other pathologic features characteristic of human IPF. MUC5B expression through native cell types may play a key role in promoting airway remodeling and lung injury in IPF.
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BACKGROUND: Coxiella burnetii, the causative agent of Q fever, is a zoonotic multi-host vector-borne pathogen of major public health importance. Although the European Food Safety Authority has recently made the monitoring of this bacterium in wildlife a priority, the role of wild lagomorphs in the transmission and maintenance of C. burnetii is poorly understood. AIMS: The aims of this study were to determine the prevalence and risk factors associated with C. burnetii circulation in European wild rabbits (Oryctolagus cuniculus) and Iberian hares (Lepus granatensis) and to assess the presence of this pathogen in ticks that feed on them in Mediterranean ecosystems in Spain, the country with the highest number of reported cases of Q fever in Europe. METHODS: A total of 574 spleen samples were collected from 453 wild rabbits and 121 Iberian hares, and 513 ticks (processed in 120 pools) between the 2017/2018 and 2021/2022 hunting seasons. RESULTS: C. burnetii DNA was detected in 103 (17.9%; 95% CI: 14.8-21.1) of the 574 wild lagomorphs tested. By species, prevalence was 16.3% (74/453; 95% CI: 12.9-19.7) in the European wild rabbit and 24.0% (29/121; 95% CI: 16.4-31.6) in the Iberian hare. At least one positive lagomorph was found on 47.9% of the 96 hunting estates sampled and in every hunting season since 2018/2019. Two risk factors associated with C. burnetii infection were as follows: outbreak of myxomatosis on the hunting estate in the month prior to sampling and high tick abundance observed by gamekeepers on the hunting estate. C. burnetii DNA was also found in 33 of the 120 (27.5%; 95% CI: 19.5-35.5) tick pools tested. The pathogen was detected in 66.7% (4/6), 29.2% (26/89) and 21.4% (3/14) of Haemaphysalis hispanica, Rhipicephalus pusillus and Hyalomma lusitanicum pools respectively. CONCLUSIONS: This study provides new epidemiological data on C. burnetii in European wild rabbits and is the first survey on this zoonotic pathogen performed in Iberian hares. Our results indicate widespread endemic circulation of C. burnetii and highlight the importance of both wild lagomorph species as natural reservoirs of this zoonotic bacterium in Mediterranean ecosystems in southern Spain, which may be of public and animal health concern. The high prevalence and wide diversity of positive tick species suggest the possible role of ticks in the epidemiological cycle of C. burnetii, with the potential risk of transmission to sympatric species, including humans.
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Animais Selvagens , Coxiella burnetii , Lebres , Lagomorpha , Febre Q , Animais , Espanha/epidemiologia , Coxiella burnetii/isolamento & purificação , Febre Q/epidemiologia , Febre Q/veterinária , Animais Selvagens/microbiologia , Lagomorpha/microbiologia , Lebres/microbiologia , Coelhos , Carrapatos/microbiologia , Ecossistema , Prevalência , Fatores de RiscoRESUMO
PURPOSE: Sinonasal undifferentiated carcinoma (SNUC) is a rare, aggressive malignancy of the sinonasal cavity with poor prognosis and limited treatment options. To investigate the potential for SNUC sensitivity to combinatory immunotherapy, we performed in vitro studies with SNUC cell lines and used multi-spectral immunofluorescence to characterize the in vivo patient SNUC tumor immune microenvironment (TIME). EXPERIMENTAL DESIGN: Human-derived SNUC cell lines were used for in vitro studies of tumor cell susceptibility to natural killer (NK) cell-based immunotherapeutic strategies. Tumor samples from 14 treatment naïve SNUC patients were examined via multi-spectral immunofluorescence and clinical correlations assessed. RESULTS: Anti-PD-L1 blockade enhanced NK cell lysis of SNUC cell lines â¼5.4 fold (P ≤ 0.0001). This effect was blocked by a CD16 neutralizing antibody demonstrating activity through an antibody-dependent cellular cytotoxicity (ADCC) mediated pathway. ADCC-dependent lysis of SNUC cells was further enhanced by upregulation of PD-L1 on tumor cells by exogenous interferon-gamma (IFN-γ) administration or interleukin-15 (IL-15) stimulated IFN-γ release from NK cells. Combination treatment with anti-PD-L1 blockade and IL-15 superagonism enhanced NK-cell killing of SNUC cells 9.6-fold (P ≤ 0.0001). Untreated SNUC patient tumor samples were found to have an NK cell infiltrate and PD-L1+ tumor cells at a median of 5.4 cells per mm2. A striking 55.7-fold increase in CKlow tumor cell/NK cell interactions was observed in patients without disease recurrence after treatment (P = 0.022). Patients with higher CD3+CD8+ in the stroma had a significantly improved 5-year overall survival (P = 0.0029) and a significant increase in CKlow tumor cell/CD8+ cytotoxic T cell interactions was noted in long-term survivors (P = 0.0225). CONCLUSION: These data provide the pre-clinical rationale for ongoing investigation into combinatory immunotherapy approaches for SNUC.
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Most platforms used for the molecular reconstruction of the tumor-immune microenvironment (TIME) of a solid tumor fail to explore the spatial context of the three-dimensional (3D) space of the tumor at a single-cell resolution, and thus lack information about cell-cell or cell-extracellular matrix (ECM) interactions. To address this issue, a pipeline which integrated multiplex spatially resolved multi-omics platforms was developed to identify crosstalk signaling networks among various cell types and the ECM in the 3D TIME of two FFPE (formalin-fixed paraffin embedded) gynecologic tumor samples. These platforms include non-targeted mass spectrometry imaging (glycans, metabolites, and peptides) and Stereo-seq (spatial transcriptomics) and targeted seqIF (IHC proteomics). The spatially resolved imaging data in a two- and three-dimensional space demonstrated various cellular neighborhoods in both samples. The collection of spatially resolved analytes in a voxel (3D pixel) across serial sections of the tissue was also demonstrated. Data collected from this analytical pipeline were used to construct spatial 3D maps with single-cell resolution, which revealed cell identity, activation, and energized status. These maps will provide not only insights into the molecular basis of spatial cell heterogeneity in the TIME, but also novel predictive biomarkers and therapeutic targets, which can improve patient survival rates.
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Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While induction chemotherapy leads to remission in most patients, a significant number will experience relapse. Therefore, there is a need for novel therapies that can improve remission rates in patients with relapsed and refractory AML. CD70 is the natural ligand for CD27 (a member of the TNF superfamily) and appears to be a promising therapeutic target. Consequently, there is considerable interest in developing chimeric antigen receptor (CAR) T-cell therapy products that can specifically target CD70 in various neoplasms, including AML. In this study, we employed routine diagnostic techniques, such as immunohistochemistry and flow cytometry, to investigate the expression of CD70 in bone marrow samples from treatment-naïve and relapsed AML patients after hypomethylating agents (HMA). Also, we evaluated the impact of HMA on CD70 expression and examined CD70 expression in various leukemic cell subsets and normal hematopoietic progenitors.
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BACKGROUND AND OBJECTIVES: Recurrent isolated pancreatic metastasis from Renal Cell Carcinoma (RCC) after pancreatic resection is rare. The purpose of our study is to describe a series of cases of relapse of pancreatic metastasis from renal cancer in the pancreatic remnant and its surgical treatment with a repeated pancreatic resection, and to analyse the results of both overall and disease-free survival. METHODS: Multicenter retrospective study of patients undergoing pancreatic resection for RCC pancreatic metastases, from January 2010 to May 2020. Patients were grouped into two groups depending on whether they received a single pancreatic resection (SPS) or iterative pancreatic resection. Data on short and long-term outcome after pancreatic resection were collected. RESULTS: The study included 131 pancreatic resections performed in 116 patients. Thus, iterative pancreatic surgery (IPS) was performed in 15 patients. The mean length of time between the first pancreatic surgery and the second was 48.9 months (95 % CI: 22.2-56.9). There were no differences in the rate of postoperative complications. The DFS rates at 1, 3 and 5 years were 86 %, 78 % and 78 % vs 75 %, 50 % and 37 % in the IPS and SPS group respectively (p = 0.179). OS rates at 1, 3, 5 and 7 years were 100 %, 100 %, 100 % and 75 % in the IPS group vs 95 %, 85 %, 80 % and 68 % in the SPS group (p = 0.895). CONCLUSION: Repeated pancreatic resection in case of relapse of pancreatic metastasis of RCC in the pancreatic remnant is justified, since it achieves OS results similar to those obtained after the first resection.
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Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Pancreáticas , Humanos , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/patologia , Estudos Retrospectivos , Pancreatectomia/métodos , Neoplasias Pancreáticas/patologia , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , RecidivaRESUMO
AIM: Venous thromboembolic events (VTEs) are relatively common adverse surgical complications. Extended VTE prophylaxis for 4 weeks is recommended after colorectal cancer surgery, but its use in inflammatory bowel disease surgery lacks high-quality evidence. This retrospective study aimed to assess and characterize VTEs within the first 30 days after ileal pouch-anal anastomosis (IPAA) procedures and subtotal colectomies (STCs) for ulcerative colitis (UC). METHODS: All patients who underwent IPAA for UC between 1 January 2017 and 31 December 2021 were included. VTE rates after IPAA, in-hospital or at-home occurrences, utilization of in-hospital thromboprophylaxis, and prescribed anticoagulant treatment were evaluated. Retrospectively, the same variables were analysed if patients of the cohort underwent STC before the IPAA construction. RESULTS: In all, 204 patients underwent IPAA (61.8% men, 73% laparoscopic), with an average hospital stay of 6.8 days. Among them, 116 patients underwent STC prior to IPAA. Thirteen patients (6.3%) experienced VTEs after IPAA, with 76.9% (10/13) of cases occurring during hospitalization and under adequate thromboprophylaxis. The VTE rate after STC was 10.3% (12/116), with 58.2% (7/12) occurring in hospital and under appropriate thromboprophylaxis. No reoperations or mortality were attributed to thrombotic events. The type and duration of anticoagulant treatment varied considerably. CONCLUSION: The VTE rate after IPAA for UC was 6.3%, with the majority of events occurring in hospital and under adequate thromboprophylaxis. These findings suggest that routine use of extended VTE prophylaxis in our cohort may not be supported. Further research is needed to clarify the optimal VTE prophylaxis strategy for inflammatory bowel disease surgery.
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Anticoagulantes , Colite Ulcerativa , Complicações Pós-Operatórias , Proctocolectomia Restauradora , Tromboembolia Venosa , Humanos , Colite Ulcerativa/cirurgia , Colite Ulcerativa/complicações , Estudos Retrospectivos , Feminino , Masculino , Tromboembolia Venosa/prevenção & controle , Tromboembolia Venosa/etiologia , Adulto , Proctocolectomia Restauradora/efeitos adversos , Proctocolectomia Restauradora/métodos , Anticoagulantes/uso terapêutico , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Pessoa de Meia-Idade , Colectomia/efeitos adversos , Colectomia/métodos , Tempo de Internação/estatística & dados numéricosRESUMO
Cryptosporidium spp. and Giardia duodenalis are the main non-viral causes of diarrhoea in humans and domestic animals globally. Comparatively, much less information is currently available in free-ranging carnivore species in general and in the endangered Iberian lynx (Lynx pardinus) in particular. Cryptosporidium spp. and G. duodenalis were investigated with molecular (PCR and Sanger sequencing) methods in individual faecal DNA samples of free-ranging and captive Iberian lynxes from the main population nuclei in Spain. Overall, Cryptosporidium spp. and G. duodenalis were detected in 2.4% (6/251) and 27.9% (70/251) of the animals examined, respectively. Positive animals to at least one of them were detected in each of the analysed population nuclei. The analysis of partial ssu rRNA gene sequences revealed the presence of rodent-adapted C. alticolis (n = 1) and C. occultus (n = 1), leporid-adapted C. cuniculus (n = 2), and zoonotic C. parvum (n = 2) within Cryptosporidium, and zoonotic assemblages A (n = 5) and B (n = 3) within G. duodenalis. Subgenotyping analyses allowed for the identification of genotype VaA19 in C. cuniculus (gp60 locus) and sub-assemblages AI and BIII/BIV in G. duodenalis (gdh, bg, and tpi loci). This study represents the first molecular description of Cryptosporidium spp. and G. duodenalis in the Iberian lynx in Spain. The presence of rodent/leporid-adapted Cryptosporidium species in the surveyed animals suggests spurious infections associated to the Iberian lynx's diet. The Iberian lynx seems a suitable host for zoonotic genetic variants of Cryptosporidium (C. parvum) and G. duodenalis (assemblages A and B), although the potential risk of human transmission is regarded as limited due to light parasite burdens and suspected low excretion of infective (oo)cysts to the environment by infected animals. More research should be conducted to ascertain the true impact of these protozoan parasites in the health status of the endangered Iberian lynx.
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Inactivating TP53 mutations leads to a loss of function of p53, but can also often result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53) proteins which promotes tumor development and progression. The GOF activities of TP53 mutations are well documented, but the mechanisms involved remain poorly understood. Here, we study the mutp53 interactome and find that by targeting minichromosome maintenance complex components (MCMs), GOF mutp53 predisposes cells to replication stress and chromosomal instability (CIN), leading to a tumor cell-autonomous and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent cytosolic DNA response that activates downstream non-canonical nuclear factor kappa light chain enhancer of activated B cell (NC-NF-κB) signaling. Consequently, GOF mutp53-MCMs-CIN-cytosolic DNA-cGAS-STING-NC-NF-κB signaling promotes tumor cell metastasis and an immunosuppressive tumor microenvironment through antagonizing interferon signaling and regulating genes associated with pro-tumorigenic inflammation. Our findings have important implications for understanding not only the GOF activities of TP53 mutations but also the genome-guardian role of p53 and its inactivation during tumor development and progression.
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Neoplasias , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Neoplasias/genética , DNA , Instabilidade Cromossômica/genética , Nucleotidiltransferases/metabolismo , Interferons/metabolismo , Microambiente TumoralRESUMO
Objetivo: presentar los avances diagnósticos, moleculares y radiológicos, así como en las estrategias terapéuticas para gliomas difusos en los últimos 5 años (2018-2023) en la Fundación Universitaria de Ciencias de la Salud (FUCS), Bogotá D.C., Colombia. Materiales y métodos: se describen las técnicas diagnósticas y terapéuticas utilizadas para gliomas difusos con casos ilustrativos. Resultados: se muestran los avances de las herramientas diagnósticas y terapéuticas para el manejo de gliomas difusos. Discusión: en los últimos 5 años se ha avanzado en la clasificación, diagnóstico y tratamiento de los gliomas difusos, gracias a los avances tecnológicos como los marcadores moleculares, la tractografía y la fusión de imágenes para la neuronavegación y las técnicas de estimulación cortical. Esto ha permitido que el tratamiento de los pacientes con dichos tumores mejore la tasa de morbilidad, la calidad de vida libre de enfermedad y la supervivencia global. Conclusiones: las técnicas de diagnóstico como la tractografía, la fusión integral de imágenes intraoperatorias y el mapeo cerebral electrofisiológico con estimulación cortical y subcortical han mejorado el diagnóstico y tratamiento de los gliomas difusos.
Objective: to present the diagnostic, molecular, radiological, and therapeutic advances, to address diffuse gliomas, made at Fundación Universitaria de Ciencias de la Salud (FUCS), Bogotá D.C., Colombia, in the last 5 years (2018-2023). Materials and methods: diagnostic and therapeutic techniques to address diffuse gliomas are described through illustrative cases. Results: the advances in diagnostic and therapeutic tools for managing diffuse gliomas, are shown. Discussion: in the last 5 years progress in characterizing, diagnosing, and treating diffuse gliomas, thanks to technological breakthroughs, such as molecular markers, tractography, image fusion for neuronavigation, and cortical stimulation techniques, has been achieved. This has allowed improving morbidity rate, disease-free quality of life and overall survival through the treatment provided to patients afflicted with gliomas. Conclusions: Diagnostic techniques based on tractography, comprehensive intraoperative image fusion, and electrophysiological brain mapping with cortical and subcortical stimulation, have improved the diagnostic and therapeutic approaches for diffuse gliomas.
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HumanosRESUMO
Background & objective: Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in people living with HIV (PLWH) and the expression of some microRNAs could be useful as biomarkers for the diagnosis of NAFLD. The aim of this study was to identify patterns of differential expression of microRNAs in PLWH and assess their diagnostic value for NALFD. Methods: A discovery case-control study with PLWH was carried out. The expression of miRNAs was determined using HTG EdgeSeq technology. Cases were defined as patients with severe NAFLD and controls as patients without NAFLD, characterized using the controlled attenuation parameter (CAP). Cases and controls were matched 1:1 for age, sex, BMI, CD4+ lymphocyte count, active HCV infection, and ART regimen. Results: Serum 2,083 simultaneous microRNA transcripts were analyzed using HTG technology and compared between cases and controls. Forty-five patients, 23 cases, and 22 controls were included in the study. In the analysis of the expression pattern of the 2,083 microRNAs, no differential expression patterns were found between both groups of patients included in the study. Conclusion: Analysis of the microRNA transcriptome profile of nonobese PLWH with severe NAFLD did not appear to differ from that of patients without NAFLD. Thus, microRNA might not serve as a proper biomarker for predicting severe NALFD in this population.
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Infecções por HIV , MicroRNAs , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/diagnóstico , MicroRNAs/genética , HIV , Estudos de Casos e Controles , Infecções por HIV/complicações , Infecções por HIV/genética , BiomarcadoresRESUMO
BACKGROUND AND OBJECTIVE: Patients with chronic kidney disease (CKD) on hemodialysis present high cardiovascular comorbidity. Peripheral arterial disease (PAD) is associated with higher mortality and the interest in its early detection and treatment is increasing. The objective of this study is to determine the frequency and severity of symptomatic PAD, and to establish its relationship with mortality in HD patients that have received treated early and compare them with a cohort of our center already reported. MATERIAL AND METHODS: Retrospective study on a cohort of incident patients since 2014 and followed up until December 2019. Demographic data, cardiovascular risk, the presence of symptomatic PAD at baseline and during follow-up were collected. Trophic lesions were graded using the Rutherford scale. RESULTS: Initially, there were 91 patients and 7 cases that were not included in the study were lost to follow-up. Age 64⯱â¯16 years, men 51.6% (47/91). The percentage of baseline PAD was 10.7% (9/84). During a median follow-up of 35 months (20-57), the diagnosis of PAD increased to 25% (21/84). Half of the patients with PAD 52.38% (11/21) obtained a score greater than 3 in the Rutherford Clinical Classification, which corresponds to severe disease. 13/21 patients required reoperation due to recurrence of symptoms (61.9% of cases with PAD). The development of PAD was significantly associated with: an elevated index of Charlson (3.9±2.1 vs. 7.7⯱â¯3.5; P = 0.001),being male (19 vs. 2; P = 0.001), diabetic (no: 7; yes: 15; P = 0.001) and with a history of chronic ischemic heart disease (no: 13; yes: 8; P = 0.001), 38.1% (8/21) had ischemic heart disease in patients who developed PAD, while in the absence of PAD the presence of ischemic heart disease was 9.5% (6/63). Furthermore, more than half (66.7% [14/21]) of those who developed PAD were diabetic. Univariate analysis showed that age, C reactive protein, albumin, and number of surgical interventions, but not PAD, were associated with mortality. In the multivariate analysis adjusted for other factors, only C reactive protein was related to overall survival Exp ß: 2.17; P = 0.011; CI (1.19-3.97). Regarding cardiovascular mortality, in the multivariate Cox analysis, only PAD was related to mortality of cardiovascular origin Exp ß: 1.73; P = 0.006; CI (1.17-2.56). CONCLUSIONS: A significant number of patients on hemodialysis develop PAD requiring peripheral vascular surgery. PAD was not associated with overall mortality in our cohort, but it did show an association with cardiovascular mortality. Prospective studies with a larger sample size are necessary. New surgical treatments and Follow-up by vascular surgeons could improve the severity of PAD and the long-term prognosis.
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Diabetes Mellitus , Isquemia Miocárdica , Doença Arterial Periférica , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudos Retrospectivos , Estudos Prospectivos , Proteína C-Reativa , Doença Arterial Periférica/epidemiologia , Diálise RenalRESUMO
Background: Diffusion tensor imaging (DTI) tractography facilitates maximal safe resection and optimizes planning to avoid injury during subcortical dissection along descending motor pathways (DMPs). We provide an affordable, safe, and timely algorithm for preoperative DTI motor reconstruction for gliomas adjacent to DMPs. Methods: Preoperative DTI reconstructions were extracted from a prospectively acquired registry of glioma resections adjacent to DMPs. The surgeries were performed over a 7-year period. Demographic, clinical, and radiographic data were extracted from patients' electronic medical records. Results: Nineteen patients (12 male) underwent preoperative tractography between January 1, 2013, and May 31, 2020. The average age was 44.5 years (range, 19-81 years). A complete radiological resection was achieved in nine patients, a subtotal resection in five, a partial resection in three, and a biopsy in two. Histopathological diagnoses included 10 patients with high-grade glioma and nine with low-grade glioma. A total of 16 perirolandic locations (10 frontal and six frontoparietal) were recorded, as well as two in the insula and one in the basal ganglia. In 9 patients (47.3%), the lesion was in the dominant hemisphere. The median preoperative and postoperative Karnofsky Performance Scores were 78 and 80, respectively. Motor function was unchanged or improved over time in 15 cases (78.9%). Conclusion: This protocol of DTI reconstruction for glioma removal near the DMP shows good results in low-term neurological functional outcomes.