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BACKGROUND: An urgent need exists for innovative surgical video recording techniques in head and neck reconstructive surgeries, particularly in low- and middle-income countries where a surge in surgical procedures necessitates more skilled surgeons. This demand, significantly intensified by the COVID-19 pandemic, highlights the critical role of surgical videos in medical education. We aimed to identify a straightforward, high-quality approach to recording surgical videos at a low economic cost in the operating room, thereby contributing to enhanced patient care. METHODS: The recording was comprised of six head and neck flap harvesting surgeries using GoPro or two types of digital cameras. Data were extracted from the recorded videos and their subsequent editing process. Some of the participants were subsequently interviewed. RESULTS: Both cameras, set at 4 K resolution and 30 frames per second (fps), produced satisfactory results. The GoPro, worn on the surgeon's head, moves in sync with the surgeon, offering a unique first-person perspective of the operation without needing an additional assistant. Though cost-effective and efficient, it lacks a zoom feature essential for close-up views. In contrast, while requiring occasional repositioning, the digital camera captures finer anatomical details due to its superior image quality and zoom capabilities. CONCLUSION: Merging these two systems could significantly advance the field of surgical video recording. This innovation holds promise for enhancing technical communication and bolstering video-based medical education, potentially addressing the global shortage of specialized surgeons.
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COVID-19 , Gravação em Vídeo , Humanos , COVID-19/epidemiologia , Procedimentos de Cirurgia Plástica/educação , Retalhos Cirúrgicos , SARS-CoV-2 , Cabeça/cirurgia , Pescoço/cirurgiaRESUMO
Autophagy degrades and is thought to recycle proteins, other macromolecules, and organelles. In genetically engineered mouse models (GEMMs) for Kras-driven lung cancer, autophagy prevents the accumulation of defective mitochondria and promotes malignancy. Autophagy-deficient tumor-derived cell lines are respiration-impaired and starvation-sensitive. However, to what extent their sensitivity to starvation arises from defective mitochondria or an impaired supply of metabolic substrates remains unclear. Here, we sequenced the mitochondrial genomes of wild-type or autophagy-deficient (Atg7(-/-)) Kras-driven lung tumors. Although Atg7 deletion resulted in increased mitochondrial mutations, there were too few nonsynonymous mutations to cause generalized mitochondrial dysfunction. In contrast, pulse-chase studies with isotope-labeled nutrients revealed impaired mitochondrial substrate supply during starvation of the autophagy-deficient cells. This was associated with increased reactive oxygen species (ROS), lower energy charge, and a dramatic drop in total nucleotide pools. While starvation survival of the autophagy-deficient cells was not rescued by the general antioxidant N-acetyl-cysteine, it was fully rescued by glutamine or glutamate (both amino acids that feed the TCA cycle and nucleotide synthesis) or nucleosides. Thus, maintenance of nucleotide pools is a critical challenge for starving Kras-driven tumor cells. By providing bioenergetic and biosynthetic substrates, autophagy supports nucleotide pools and thereby starvation survival.
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Autofagia , Neoplasias Pulmonares/metabolismo , Nucleotídeos/metabolismo , Proteínas ras/metabolismo , Animais , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Linhagem Celular Tumoral , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Deleção de Genes , Variação Genética , Genoma Mitocondrial/genética , Glutamina/farmacologia , Neoplasias Pulmonares/fisiopatologia , Camundongos , Mitocôndrias/metabolismo , Nucleosídeos/farmacologia , OxirreduçãoRESUMO
OBJECTIVES: Preoperative diagnosis of oral ameloblastoma (AME) and odontogenic keratocyst (OKC) has been a challenge in dentistry. This study uses radiomics approaches and machine learning (ML) algorithms to characterize cone-beam CT (CBCT) image features for the preoperative differential diagnosis of AME and OKC and compares ML algorithms to expert radiologists to validate performance. METHODS: We retrospectively collected the data of 326 patients with AME and OKC, where all diagnoses were confirmed by histopathologic tests. A total of 348 features were selected to train six ML models for differential diagnosis by a 5-fold cross-validation. We then compared the performance of ML-based diagnoses to those of radiologists. RESULTS: Among the six ML models, XGBoost was effective in distinguishing AME and OKC in CBCT images, with its classification performance outperforming the other models. The mean precision, recall, accuracy, F1-score, and area under the curve (AUC) were 0.900, 0.807, 0.843, 0.841, and 0.872, respectively. Compared to the diagnostics by radiologists, ML-based radiomic diagnostics performed better. CONCLUSIONS: Radiomic-based ML algorithms allow CBCT images of AME and OKC to be distinguished accurately, facilitating the preoperative differential diagnosis of AME and OKC. ADVANCES IN KNOWLEDGE: ML and radiomic approaches with high-resolution CBCT images provide new insights into the differential diagnosis of AME and OKC.
Assuntos
Ameloblastoma , Tomografia Computadorizada de Feixe Cônico , Aprendizado de Máquina , Cistos Odontogênicos , Humanos , Tomografia Computadorizada de Feixe Cônico/métodos , Ameloblastoma/diagnóstico por imagem , Ameloblastoma/cirurgia , Ameloblastoma/patologia , Cistos Odontogênicos/diagnóstico por imagem , Cistos Odontogênicos/cirurgia , Estudos Retrospectivos , Feminino , Masculino , Diagnóstico Diferencial , Adulto , Pessoa de Meia-Idade , Algoritmos , Adolescente , Idoso , Neoplasias Maxilomandibulares/diagnóstico por imagem , Neoplasias Maxilomandibulares/cirurgia , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , RadiômicaRESUMO
BACKGROUND: In recent years, the utilization of autogenous vascularized iliac crest flap for repairing jaw defects has seen a significant rise. However, the visual monitoring of iliac bone flaps present challenges, frequently leading to delayed detection of flap loss. Consequently, there's a urgent need to develop effective indicators for monitoring postoperative complications in iliac crest flaps. METHODS: A retrospective analysis was conducted on 160 patients who underwent vascularized iliac crest flap transplantation for jawbone reconstruction from January 2020 to December 2022. We investigated the changes in D-dimer levels among patients with or without postoperative complications. Additionally, multivariable logistic regression analysis was performed to explore potential individual risk factors, including surgical duration, age, pathology type, absolute and relative D-dimer levels, and gender, culminating in the development of a nomogram. RESULTS: On the first day following surgery, patients who experienced thrombosis exhibited a substantial increase in plasma D-dimer levels, reaching 3.75 mg/L, 13.84 times higher than the baseline. This difference was statistically significant (P < 0.05) compared to patients without postoperative complications. Furthermore, the nomogram we have developed and validated effectively predicts venous thrombosis, assigning individual risk scores to patients. This predictive tool was assessed in both training and validation cohorts, achieving areas under the curve (AUC) of 0.630 and 0.600, with the 95% confidence intervals of 0.452-0.807 and 0.243-0.957, respectively. CONCLUSIONS: Our study illustrates that postoperative plasma D-dimer levels can serve as a sensitive biomarker for monitoring thrombosis-induced flap loss. Moreover, we have developed a novel prediction model that integrates multiple factors, thereby enhancing the accuracy of early identification of patients at risk of thrombosis-associated flap loss. This advancement contributes to improving the overall management and outcomes of such procedures.
Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio , Ílio , Nomogramas , Complicações Pós-Operatórias , Retalhos Cirúrgicos , Humanos , Masculino , Feminino , Estudos Retrospectivos , Ílio/transplante , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Pessoa de Meia-Idade , Adulto , Fatores de Risco , IdosoRESUMO
OBJECTIVE: This study aims to discuss the characteristics and treatment methods of malignant tumors in the parotid region, as well as the therapeutic effects of immediate free flap reconstruction of soft tissue for postoperative defects. MATERIALS AND METHODS: A retrospective review was conducted on 11 cases of soft tissue flap reconstruction for postoperative defects following the resection of malignant tumors in the parotid region. Statistical analysis was performed based on clinical data. RESULTS: Among the 11 cases of malignant tumors in the parotid region, there were 2 cases of secretory carcinoma (SC) of the salivary gland, 2 cases of squamous cell carcinoma (SCC), 2 cases of carcinosarcoma, 1 case of mucoepidermoid carcinoma (MEC), 1 case of epithelial-myoepithelial carcinoma (EMC), 1 case of salivary duct carcinoma (SDC), 1 case of basal cell carcinoma (BCC), and 1 case of osteosarcoma. Among these cases, 4 were initial diagnoses and 7 were recurrent tumors. The defect repairs involved: 8 cases with anterolateral thigh free flap (ALTF), 2 cases with pectoralis major muscle flaps, and 1 case with forearm flap. The size of the flaps ranged from approximately 1 cm × 3 cm to 7 cm × 15 cm. The recipient vessels included: 4 cases with the facial artery, 4 cases with the superior thyroid artery, and 1 case with the external carotid artery. The ratio of recipient vein anastomosis was: 57% for branches of the internal jugular vein, 29% for the facial vein, and 14% for the external jugular vein. Among the 8 cases that underwent neck lymph node dissection, one case showed lymph node metastasis on pathological examination. In the initial diagnosis cases, 2 cases received postoperative radiotherapy, and 1 case received 125I seed implantation therapeutic treatment after experiencing two recurrences. Postoperative follow-up revealed that 2 cases underwent reoperation due to local tumor recurrence, and there were 2 cases lost to follow-up. The survival outcomes after treatment included: one case of distant metastasis and one case of death from non-cancerous diseases. CONCLUSION: Immediate soft tissue flap reconstruction is an important and valuable option to address postoperative defects in patients afflicted with malignant tumors in the parotid region.
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Carcinoma de Células Escamosas , Transplante de Pele , Humanos , Região Parotídea/patologia , Região Parotídea/cirurgia , Recidiva Local de Neoplasia/cirurgia , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/patologia , AlgoritmosRESUMO
The Membrane Attack Complex and Perforin (MACPF) proteins play a crucial role in plant development and adaptation to environmental stresses. Heretofore, few MACPF genes have been functionally identified, leaving gaps in our understanding of MACPF genes in other plants, particularly in the Solanaceae family, which includes economically and culturally significant species, such as tomato, potato, and pepper. In this study, we have identified 26 MACPF genes in three Solanaceae species and in the water lily, which serves as the base group for angiosperms. Phylogenetic analysis indicates that angiosperm MACPF genes could be categorized into three distinct groups, with another moss and spikemoss lineage-specific group, which is further supported by the examination of gene structures and domain or motif organizations. Through inter-genome collinearity analysis, it is determined that there are 12 orthologous SolMACPF gene pairs. The expansion of SolMACPF genes is primarily attributed to dispersed duplications, with purifying selection identified as the principal driving force in their evolutionary process, as indicated by the ω values. Furthermore, the analysis of expression patterns revealed that Solanaceae genes are preferentially expressed in reproductive tissues and regulated by various environmental stimuli, particularly induced by submergence. Taken together, these findings offer valuable insights into and a fresh perspective on the evolution and function of SolMACPF genes, thereby establishing a foundation for further investigations into their phenotypic and functional characteristics.
Assuntos
Magnoliopsida , Solanum tuberosum , Perforina/genética , Complexo de Ataque à Membrana do Sistema Complemento , Filogenia , VerdurasRESUMO
Meprin and TRAF homology (MATH)-domain-containing proteins are pivotal in modulating plant development and environmental stress responses. To date, members of the MATH gene family have been identified only in a few plant species, including Arabidopsis thaliana, Brassica rapa, maize, and rice, and the functions of this gene family in other economically important crops, especially the Solanaceae family, remain unclear. The present study identified and analyzed 58 MATH genes from three Solanaceae species, including tomato (Solanum lycopersicum), potato (Solanum tuberosum), and pepper (Capsicum annuum). Phylogenetic analysis and domain organization classified these MATH genes into four groups, consistent with those based on motif organization and gene structure. Synteny analysis found that segmental and tandem duplication might have contributed to MATH gene expansion in the tomato and the potato, respectively. Collinearity analysis revealed high conservation among Solanaceae MATH genes. Further cis-regulatory element prediction and gene expression analysis showed that Solanaceae MATH genes play essential roles during development and stress response. These findings provide a theoretical basis for other functional studies on Solanaceae MATH genes.
Assuntos
Capsicum , Solanaceae , Solanum lycopersicum , Solanum tuberosum , Solanaceae/genética , Solanaceae/metabolismo , Tiopronina/metabolismo , Filogenia , Solanum lycopersicum/genética , Capsicum/genética , Solanum tuberosum/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regulação da Expressão Gênica de PlantasRESUMO
Microplastics (MPs) interact frequently with dissolved organic matter (DOM) commonly found in the environment, but information on the aging behavior of MPs under the participation of DOM is still lacking. Thus, the polystyrene microplastic (PSMP) aging process with DOM participation was systematically studied by electron paramagnetic resonance spectroscopy, high-performance liquid chromatography, Fourier transform infrared (FTIR) spectroscopy, and two-dimensional correlation spectroscopy analyses under dark and ultraviolet (UV) light conditions. DOM was found to promote electron transfer to generate reactive oxygen species (ROS) under dark conditions and the aging of PSMPs, while the process of DOM generating ROS under UV light was more susceptible to photoelectrons and accelerated the aging process of PSMPs. However, among the four DOM types, fulvic acid (FA) has a more significant promoting effect on the aging process of PSMPs than humic acid, which can be attributed to the stronger conversion ability of FA to semiquinone radicals. Density functional theory calculations are used to describe the difference in the aging process of different structures of plastics with the participation of DOM. This study provides a necessary theoretical basis for the study of the migration of MPs in groundwater and deep surface water.
Assuntos
Microplásticos , Plásticos , Matéria Orgânica Dissolvida , Substâncias Húmicas/análise , Poliestirenos , Espécies Reativas de Oxigênio , Raios UltravioletaRESUMO
BACKGROUND: Esophageal cancer and gastric cancer are two important causes of upper GI malignancies. Literature has shown that minimally invasive esophagectomies (MIE) and gastrectomies (MIG), have shorter length of stay and fewer complications. However, limited literature exists about the association between race and access to MIE and MIG. This study aims to identify the racial disparities in the different approaches to esophagectomy and gastrectomy. We further evaluate the relationship between the race and postoperative complications. METHODS: This IRB-approved retrospective study utilized data from the American College of Surgeons National Quality Improvement Program. All recorded cases of MIE, MIG, open gastrectomy, and esophagectomy between 2012 and 2019 were isolated. Propensity score matching and univariate analysis was performed to assess the independent effect of black self-identified race on access and outcomes. p < 0.05 was required to achieve statistical significance. RESULTS: 7891 cases of esophagectomy and 5,132 cases of gastrectomy cases were identified. Using Propensity and logistic regression, we identified that black self-reported race is an independent predictor of open approach to gastrectomy (OR 1.6871943, 95% CI 1.431464-1.989829, p < 0.001). Black self-reported race was not predictive of operative approach among esophagectomy patients (OR 0.7942576, 95% CI 0.5698645-1.124228, p = 0.183). In contrast, black self-reported is an independent predictor of postoperative complications among esophagectomy patients only. Esophagectomy patients of black self-reported race were more likely to experience any complication (OR 1.4373437, 95% CI 1.1129239-1.8557096, p = 0.00537), severe complications (OR 1.3818966, 95% CI 1.0653087-1.7888454, p = 0.0144), and death (OR 2.00779762, 95% CI 1.08034921-3.56117535, p = 0.0211) within 30 days of their surgeries. CONCLUSION: Our analysis revealed a significant racial disparity in access to MIG and a higher incidence of post-operative complications amongst esophagectomy patients. Minimally invasive techniques are underutilized in racial minorities. The findings herein warrant further investigation to eliminate barriers and disparities.
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Neoplasias Esofágicas , Esofagectomia , Humanos , Esofagectomia/efeitos adversos , Esofagectomia/métodos , Estudos Retrospectivos , Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Neoplasias Esofágicas/cirurgia , Gastrectomia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Resultado do TratamentoRESUMO
Hypertension is a common type of cardiovascular disease that remains a major cause of death in the world. Vascular remodelling is an important complication of hypertension, and vascular smooth muscle cells (VSMCs) play a major role in vascular remodelling. Sauchinone is one of the active lignins which has been found to possess vascular protective effects. However, the functional role of sauchinone in hypertension has not been investigated. The aim of this study was to evaluate the role of sauchinone in the angiotensin II (Ang II)-induced vascular remodelling model in VSMCs. The results showed that treatment of sauchinone inhibited Ang II-induced VSMCs proliferation and migration in VSMCs. Sauchinone treatment suppressed the reactive oxygen species (ROS) production and NADPH oxidase (NOX) activity in Ang II-induced VSMCs. The inhibitory effects of Ang II on expressions of VSMCs phenotype markers including α-smooth muscle actin (α-SMA), calponin, osteopontin were mitigated by sauchinone treatment. Furthermore, sauchinone inhibited Ang II-induced over-activation of TGF-ß1/Smad3 signalling pathway in VSMCs. Taken together, this study identified sauchinone as a potential agent for preventing vascular remodelling in hypertension.
Assuntos
Angiotensina II/farmacologia , Benzopiranos/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dioxóis/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/fisiologiaRESUMO
Membrane Attack Complex and Perforin (MACPF) proteins play crucial roles in plant development and plant responses to environmental stresses. To date, only four MACPF genes have been identified in Arabidopsis thaliana, and the functions of the MACPF gene family members in other plants, especially in important crop plants, such as the Poaceae family, remain largely unknown. In this study, we identified and analyzed 42 MACPF genes from six completely sequenced and well annotated species representing the major Poaceae clades. A phylogenetic analysis of MACPF genes resolved four groups, characterized by shared motif organizations and gene structures within each group. MACPF genes were unevenly distributed along the Poaceae chromosomes. Moreover, segmental duplications and dispersed duplication events may have played significant roles during MACPF gene family expansion and functional diversification in the Poaceae. In addition, phylogenomic synteny analysis revealed a high degree of conservation among the Poaceae MACPF genes. In particular, Group I, II, and III MACPF genes were exposed to strong purifying selection with different evolutionary rates. Temporal and spatial expression analyses suggested that Group III MACPF genes were highly expressed relative to the other groups. In addition, most MACPF genes were highly expressed in vegetative tissues and up-regulated by several biotic and abiotic stresses. Taken together, these findings provide valuable information for further functional characterization and phenotypic validation of the Poaceae MACPF gene family.
Assuntos
Complexo de Ataque à Membrana do Sistema Complemento/genética , Evolução Molecular , Expressão Gênica , Genes de Plantas , Perforina/genética , Proteínas de Plantas/genética , Poaceae/genética , Arabidopsis/genética , Cromossomos de Plantas/genética , Produtos Agrícolas/genética , Duplicação Gênica , Regulação da Expressão Gênica de Plantas , Filogenia , Desenvolvimento Vegetal/genética , Duplicações Segmentares Genômicas , Estresse Fisiológico/genética , Sintenia/genéticaRESUMO
PURPOSE: To describe clinical outcomes in patients with isolated pelvic failures after definitive radiation treatment for cervical cancer. METHODS AND MATERIALS: Cervical cancer patients with isolated pelvic failure after definitive radiation with brachytherapy boost were identified in a tertiary academic center database from 1997 to 2016. All patients received an FDG-PET scan prior to their initial treatment and at the time of their first recurrence. Isolated failures in the cervix or pelvic nodes were biopsy-proven. Distant failure and overall survival (OS) were censored outcomes. RESULTS: Isolated pelvic failure was detected in 67(11%) out of 607 consecutive patients treated with external beam pelvic radiation and brachytherapy boost. The median time to isolated pelvic recurrence was 9â¯months (range 3-198). Median follow-up time for patients alive after isolated pelvic recurrence was 40â¯months (range 0.6-183). Of these 67 patients, 28(42%) received salvage surgery, 17(25%) received chemotherapy alone, and 22(33%) received neither surgery nor chemotherapy. The median time to distant failure after isolated pelvic failure was 20â¯months (95% CI 3-37), with no significant difference between patients treated surgically vs. non-surgically. FDG-avid pelvic and para-aortic nodes at initial presentation were associated with worse distant control after isolated pelvic failure (HRâ¯=â¯3.4, 95% CI 1.0-12). Median OS for patients treated with surgery, chemotherapy alone, and neither surgery nor chemotherapy was 29â¯months (95% CI 16-41), 12â¯months (95% CI 3-21), and 3â¯months (95% CI 1-5), respectively. CONCLUSIONS: Patients who have pelvic and para-aortic nodal disease at initial presentation are at higher risk of failing distantly after isolated pelvic failure, which should be considered when counseling patients on aggressive surgical salvage. Surgical salvage was associated with prolonged survival after isolated pelvic failure.
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Neoplasias Ósseas/secundário , Neoplasias Pulmonares/secundário , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/cirurgia , Neoplasias Peritoneais/secundário , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aorta , Braquiterapia , Feminino , Fluordesoxiglucose F18 , Humanos , Histerectomia , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Exenteração Pélvica , Pelve , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Terapia de Salvação , Taxa de Sobrevida , Neoplasias do Colo do Útero/patologiaRESUMO
PURPOSE: Corticosteroids are commonly used to alleviate symptoms from cerebral vasogenic edema in glioblastoma (GBM) patients. This study evaluated the impact of overall corticosteroid exposure during chemoradiotherapy (CRT) on acute severe lymphopenia (ASL) and survival outcomes of GBM patients. METHODS: GBM patients treated with CRT from 2007 to 2016 were retrospectively analyzed. Overall corticosteroid exposure was estimated as the average daily dexamethasone dose during 6 weeks of CRT. ASL was defined as grade 3 or higher lymphopenia within 3 months of starting CRT. ASL rates, overall survival (OS), and progression-free survival (PFS) were analyzed using Kaplan-Meier method. Multivariable analysis (MVA) was performed using logistic and Cox regression to identify independent predictors of ASL and survival outcomes, respectively. RESULTS: Of the 319 eligible patients, the median daily dexamethasone use was 2 mg/day. The high-dose dexamethasone cohort (> 2 mg/day) had significantly higher ASL and worse OS than the low-dose dexamethasone cohort: 3-month ASL of 43.7% versus 19.8% (p < 0.003) and median OS of 12.6 months versus 17.9 months (p < 0.001), respectively. On MVA, higher dexamethasone use was independently associated with higher ASL and worse OS, but not worse PFS. A subset analysis of patients with gross-total resection found that higher dexamethasone use was significantly associated with ASL, but not OS. CONCLUSION: Increased corticosteroid use among GBM patients during CRT appears to be an independent risk factor for developing subsequent ASL. Its apparent association with worse OS may be influenced by other confounding factors and would need to be validated through prospective investigations.
Assuntos
Corticosteroides/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Glioblastoma/terapia , Linfopenia/epidemiologia , Corticosteroides/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Glioblastoma/mortalidade , Humanos , Linfopenia/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: The detection of distant metastatic disease in cervical cancer patients at diagnosis is critical in accurate prognostication and directing treatment strategies. This study describes the frequency and sites of distant metastatic disease at diagnosis in patients with cervical cancer as detected by positron emission tomography with 18F-fluorodeoxyglucose (FDG-PET). METHODS: Patients with newly diagnosed cervical cancer underwent pre-treatment whole-body FDG-PET starting in 1997 at an academic institution. Patients with evidence of distant FDG-avid disease, defined as disease outside of typical sites of lymphatic spread, were included for analyses. Patients were not surgically staged, but biopsy to confirm metastatic disease was attempted at the discretion of the treating physicians. Overall survival was calculated using Kaplan-Meier analysis. RESULTS: From 1997 to 2017, 72 (6.2%) of 1158 consecutively evaluated cervical cancer patients exhibited FDG-avid distant disease at diagnosis; 27 (38%) of these had biopsy confirmation of distant disease. Only 35 (49%) of FDG-detected metastases were clinically apparent. The sites of distant disease were lung (35%), multiple sites (25%), omentum (16.5%), bone (16.5%), and liver (7%). There were 12 (17%) patients with distant disease who did not display FDG-avid lymph nodes. Median overall survival among patients with distant FDG-avid disease was 7.0 months (95% CI 4.3 to 9.7). Patients with multiple sites of distant disease demonstrated the worst overall survival. CONCLUSIONS: Distant metastatic disease detected by FDG-PET is found in 6.2% of patients with cervical cancer at the time of initial diagnosis and the most common site of disease is the lung. Further prospective investigation is warranted to delineate best treatment practices for cervical cancer patients presenting with distant metastases.
Assuntos
Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Neoplasias do Colo do Útero/diagnóstico por imagem , Feminino , Humanos , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Metástase Linfática , Imageamento por Ressonância Magnética/métodos , Metástase Neoplásica , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/radioterapia , Imagem Corporal Total/métodosRESUMO
The adenosine-induced immunosuppression hampers the immune response toward tumor cells and facilitates the tumor cells to evade immunosurveillance. CD73, an ecto-5-nucleotidase, is the ectoenzyme dephosphorylating extracellular AMP to adenosine. Here, using immunocompetent transgenic head and neck squamous cell carcinoma (HNSCC) mouse model, immune profiling showed high expression of CD73 on CD4+ and CD8+ T cells was associated with an "exhausted" phenotype. Further, treatment with anti-CD73 monoclonal antibody (mAb) significantly blunted the tumor growth in the mouse model, and the blockade of CD73 reversed the "exhausted" phenotype of CD4+ and CD8+ T cells through downregulation of total expression of PD-1 and CTLA-4 on T cells. Whereas the population of CD4+ CD73hi /CD8+ CD73hi T cells expressed higher CTLA-4 and PD-1 as compared to untreated controls. In addition, the human tissue microarrays showed the expression of CD73 is upregulated on tumor infiltrating immune cells in patients with primary HNSCC. Moreover, CD73 expression is an independent prognostic factor for poor outcome in our cohort of HNSCC patients. Altogether, these findings highlight the immunoregulatory role of CD73 in the development of HNSCC and we propose that CD73 may prove to be a promising immunotherapeutic target for the treatment of HNSCC.
Assuntos
5'-Nucleotidase/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Tolerância Imunológica/imunologia , Linfócitos do Interstício Tumoral/imunologia , 5'-Nucleotidase/antagonistas & inibidores , 5'-Nucleotidase/genética , Animais , Anticorpos Monoclonais/farmacologia , Apoptose , Biomarcadores Tumorais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Antígeno CTLA-4/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Seguimentos , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , PTEN Fosfo-Hidrolase/fisiologia , Fenótipo , Prognóstico , Receptor do Fator de Crescimento Transformador beta Tipo I/fisiologia , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
MicroRNA-98-5p (miR-98-5p) is a stress-related microRNA (miRNA) that plays an important role in regulating cell survival, apoptosis, and oxidative stress in multiple cell types and diseases. However, little is known about the role of miR-98-5p in cerebral ischemia/reperfusion injury. In this study, we investigated the role and mechanism of miR-98-5p in regulating neuronal injury induced by oxygen-glucose deprivation/reoxygenation (OGD/R), an in vitro model of cerebral ischemia/reperfusion injury. We found that miR-98 expression was significantly altered in neurons in response to OGD/R treatment. Functional experiments showed that overexpression of miR-98-5p inhibited OGD/R-induced apoptosis and reactive oxygen species (ROS) production in neurons, whereas inhibition of miR-98-5p showed the opposite effect. Interestingly, bioinformatics analysis predicted that BTB and CNC homology 1 (Bach1) was a potential target gene of miR-98-5p, that was verified by dual-luciferase reporter assay. Moreover, overexpression of miR-98-5p inhibited Bach1 expression while suppression of miR-98-5p promoted Bach1 expression in neurons. Notably, miR-98-5p was shown to regulate the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the activity of the antioxidant response element (ARE). However, overexpression of Bach1 or silencing of Nrf2 significantly abolished the miR-98-5p-mediated neuroprotective effect. Overall, these results demonstrate that miR-98-5p ameliorates OGD/R-induced neuronal injury in vitro through targeting to promote activation of Nrf2/ARE signaling. Our study suggests that miR-98-5p may play a potential role in cerebral ischemia/reperfusion injury and represents a potential therapeutic target for neuroprotection.
Assuntos
Elementos de Resposta Antioxidante/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Glucose/deficiência , MicroRNAs/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Oxigênio/efeitos adversos , Animais , Linhagem Celular , Regulação da Expressão Gênica , Inativação Gênica , Camundongos , MicroRNAs/genética , Modelos Biológicos , Neuroproteção , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisRESUMO
Angiogenesis is an essential event in tumor growth and metastasis, and immune system also contributes to the tumor evasion. Emerging evidences have suggested the bidirectional link between angiogenesis and immunosuppression. Myeloid-derived suppressor cell (MDSC) is a kind of immunosuppressive cells and plays an important role in this process. However, the actual regulatory mechanisms of angiogenesis and MDSCs in head and neck squamous cell carcinoma (HNSCC) were unclear. In this study, through analyzing the immunohistochemistry staining of human HNSCC tissue microarray, we found that the microvascular density (MVD) was significantly increased in HNSCC patients. We also characterized angiogenic factors p-STAT3, VEGFA, CK2, and MDSCs marker CD11b in HNSCC tissue array, and found the close expression correlation among these markers. To determine the role of JAK2/STAT3 pathway in tumor microenvironment of HNSCC, we utilized AG490 (an inhibitor of JAK2/STAT3) for further research. Results showed that inhibition of JAK2/STAT3 suppressed angiogenesis by decreasing VEGFA and HIF1-α both in vitro and vivo. Moreover, in HNSCC transgenic mouse model, inhibiting JAK2/STAT3 not only suppressed angiogenesis but also reduced MDSCs in the tumor microenvironment through suppressing VEGFA and CK2. Our findings demonstrated the close relationship between angiogenesis and MDSCs in HNSCC, and inhibition of JAK2/STAT3 could reduce tumor-induced angiogenesis and decrease MDSCs.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Janus Quinase 2/antagonistas & inibidores , Células Supressoras Mieloides/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Fator de Transcrição STAT3/antagonistas & inibidores , Tirfostinas/uso terapêutico , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Neoplasias de Cabeça e Pescoço/irrigação sanguínea , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Janus Quinase 2/metabolismo , Camundongos Transgênicos , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Tirfostinas/farmacologiaRESUMO
Immature myeloid cells including myeloid-derived suppressor cells (MDSCs) and tumour-associated macrophages (TAMs) promote tumour growth and metastasis by facilitating tumour transformation and angiogenesis, as well as by suppressing antitumour effector immune responses. Therefore, strategies designed to reduce MDSCs and TAMs accumulation and their activities are potentially valuable therapeutic goals. In this study, we show that negative immune checkpoint molecule B7-H3 is significantly overexpressed in human head and neck squamous cell carcinoma (HNSCC) specimen as compared with normal oral mucosa. Using immunocompetent transgenic HNSCC models, we observed that targeting inhibition of B7-H3 reduced tumour size. Flow cytometry analysis revealed that targeting inhibition of B7-H3 increases antitumour immune response by decreasing immunosuppressive cells and promoting cytotoxic T cell activation in both tumour microenvironment and macroenvironment. Our study provides direct in vivo evidence for a rationale for B7-H3 blockade as a future therapeutic strategy to treat patients with HNSCC.
Assuntos
Antígenos B7/antagonistas & inibidores , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Células Mieloides/patologia , Animais , Antígenos B7/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Modelos Animais de Doenças , Humanos , Macrófagos/patologia , Camundongos Knockout , Células Mieloides/metabolismo , Células Supressoras Mieloides/patologia , Prognóstico , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismoRESUMO
BACKGROUND: Cancer immunotherapy offers a promising approach in cancer treatment. The adenosine A2A receptor (A2AR) could protect cancerous tissues from immune clearance via inhibiting T cells response. To date, the role of A2AR in head and neck squamous cell carcinoma (HNSCC) has not been investigated. Here, we sought to explore the expression and immunotherapeutic value of A2AR blockade in HNSCC. METHODS: The expression of A2AR was evaluated by immunostaining in 43 normal mucosae, 48 dysplasia and 165 primary HNSCC tissues. The immunotherapeutic value of A2AR blockade was assessed in vivo in genetically defined immunocompetent HNSCC mouse model. RESULTS: Immunostaining of HNSCC tissue samples revealed that increased expression of A2AR on tumor infiltrating immune cells correlated with advanced pathological grade, larger tumor size and positive lymph node status. Elevated A2AR expression was also detected in recurrent HNSCC and HNSCC tissues with induction chemotherapy. The expression of A2AR was found to be significantly correlated with HIF-1α, CD73, CD8 and Foxp3. Furthermore, the increased population of CD4+Foxp3+ regulatory T cells (Tregs), which partially expressed A2AR, was observed in an immunocompetent mouse model that spontaneously develops HNSCC. Pharmacological blockade of A2AR by SCH58261 delayed the tumor growth in the HNSCC mouse model. Meanwhile, A2AR blockade significantly reduced the population of CD4+ Foxp3+ Tregs and enhanced the anti-tumor response of CD8+ T cells. CONCLUSIONS: These results offer a preclinical proof for the administration of A2AR inhibitor on prophylactic experimental therapy of HNSCC and suggest that A2AR blockade can be a potential novel strategy for HNSCC immunotherapy.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/metabolismo , Imunomodulação , Receptor A2A de Adenosina/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , 5'-Nucleotidase/metabolismo , Antagonistas do Receptor A2 de Adenosina/farmacologia , Adulto , Idoso , Animais , Biomarcadores , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imuno-Histoquímica , Quimioterapia de Indução , Contagem de Linfócitos , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , PTEN Fosfo-Hidrolase/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptor A2A de Adenosina/genética , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Recidiva , Carcinoma de Células Escamosas de Cabeça e Pescoço , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
SRC family kinases (SFKs), a group of nonreceptor tyrosine kinases, modulate multiple cellular functions, such as cell proliferation, differentiation and metabolism. SFKs display aberrant activity in progressive stages of human cancers. However, the precise role of SFKs in the head and neck squamous cell carcinoma (HNSCC) signaling network is far from clear. In this study, we found that the inhibition of SFKs activity by dasatinib effectively reduced the tumor size and population of MDSCs in the HNSCC mouse model. Molecular analysis indicates that phosphorylation of LYN, rather than SRC, was inhibited by dasatinib treatment. Next, we analyzed LYN expression by immunostaining and found that it was overexpressed in the human HNSCC specimens. Moreover, LYN expression in stromal cells positively correlated with myeloid-derived suppressor cells (MDSCs) makers CD11b and CD33 in human HNSCC. The dual positive expression of LYN in epithelial and stromal cells (EPI+ SRT+ ) was associated with unfavorable overall survival of HNSCC patients. These findings indicate that SFKs may be a potential target for an effective immunotherapy of HNSCC by decreasing MDSCs and moreover, LYN will have an impact on such therapeutic strategy.