RESUMO
The DNA-sensing enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) regulates inflammation and immune defense against pathogens and malignant cells. Although cGAS has been shown to exert antitumor effects in several mouse models harboring transplanted tumor cell lines, its role in tumors arising from endogenous tissues remains unknown. Here, we show that deletion of cGAS in mice exacerbated chemical-induced colitis and colitis-associated colon cancer (CAC). Interestingly, mice lacking cGAS were more susceptible to CAC than those lacking stimulator of interferon genes (STING) or type I interferon receptor under the same conditions. cGAS but not STING is highly expressed in intestinal stem cells. cGAS deficiency led to intestinal stem cell loss and compromised intestinal barrier integrity upon dextran sodium sulfate-induced acute injury. Loss of cGAS exacerbated inflammation, led to activation of STAT3, and accelerated proliferation of intestinal epithelial cells during CAC development. Mice lacking cGAS also accumulated myeloid-derived suppressive cells within the tumor, displayed enhanced Th17 differentiation, but reduced interleukin (IL)-10 production. These results indicate that cGAS plays an important role in controlling CAC development by defending the integrity of the intestinal mucosa.
Assuntos
Neoplasias do Colo/enzimologia , Mucosa Intestinal/enzimologia , Proteínas de Neoplasias/metabolismo , Nucleotidiltransferases/metabolismo , Animais , Neoplasias do Colo/genética , Camundongos , Camundongos Knockout , Células Supressoras Mieloides/enzimologia , Proteínas de Neoplasias/genética , Nucleotidiltransferases/genética , Células-Tronco/enzimologia , Células Th17/enzimologiaRESUMO
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of hepatocellular carcinoma (HCC), but the underlying mechanisms behind the correlation of NAFLD with HCC are unclear. We aimed to uncover the genes and potential mechanisms that drive this progression. This study uncovered the genes and potential mechanisms through a multiple 'omics integration approach. Quantitative proteomics combined with phenotype-association analysis was performed. To investigate the potential mechanisms, a comprehensive transcriptome/lipidome/phenome-wide association analysis was performed in genetic reference panel BXD mice strains. The quantitative proteomics combined with phenotype-association results showed that VDAC1 was significantly increased in tumor tissues and correlated with NAFLD-related traits. Gene co-expression network analysis indicated that VDAC1 is involved in mitochondria dysfunction in the tumorigenic/tumor progression. The association between VDAC1 and mitochondria dysfunction can be explained by the fact that VDAC1 was associated with mitochondria membrane lipids cardiolipin (CL) composition shift. VDAC1 was correlated with the suppression of mature specie CL(LLLL) and elevation level of nascent CL species. Such profiling shift was supported by the significant positive correlation between VDAC1 and PTPMT1, as well as negative correlation with CL remodeling enzyme Tafazzin (TAZ). This study confirmed that the expression of VADC1 was dysregulated in NAFLD-driven HCC and associated with NAFLD progression. The VDAC1-driven mitochondria dysfunction is associated with cardiolipin composition shift, which causes alteration of mitochondria membrane properties.
Assuntos
Carcinoma Hepatocelular/etiologia , Neoplasias Hepáticas/etiologia , Mitocôndrias/genética , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Canais de Ânion Dependentes de Voltagem/genética , Idoso , Animais , Carcinoma Hepatocelular/diagnóstico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Variação Genética , Humanos , Neoplasias Hepáticas/diagnóstico , Masculino , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Proteoma , Proteômica/métodos , Locos de Características Quantitativas , Transdução de Sinais , Canais de Ânion Dependentes de Voltagem/metabolismoRESUMO
The occurrence and development of osteoclasts can directly affect the severity of bone destruction in middle ear cholesteatoma. At the same time, cell communication between keratinocytes and fibroblasts can stimulate osteoclast differentiation. However, the molecular mechanism of osteoclast differentiation in cholesteatoma is still poorly understood. In this study, we try to isolate the exosomes of keratinocytes from patients with middle ear cholesteatoma, and explore the effects of keratinocyte-derived exosomes (Ker-Exo) on osteoclast differentiation by co-culturing Ker-Exo with fibroblasts and osteoclast precursor cells. As a result, we confirmed that Ker-Exo primed fibroblasts can up-regulate the expression of RANKL and promote osteoclast differentiation. We revealed that the effect of Ker-Exo depened on its miRNA-17 conponent. Analysis confirmed that miRNA-17 was down-regulated in Ker-Exo, and they can increase RANKL level in fibroblasts, thus promoting the differentiation of osteoclasts. In conclusions, we provide evidence that exosomes miRNA-17 secreted by keratinocytes in patients with middle ear cholesteatoma can up-regulate the expression of RANKL in fibroblasts and induce osteoclast differentiation.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Colesteatoma da Orelha Média/patologia , Exossomos/patologia , MicroRNAs/metabolismo , Osteoclastos/patologia , Animais , Técnicas de Cocultura , Exossomos/química , Humanos , Queratinócitos/patologia , MicroRNAs/análise , Ligante RANK/metabolismoRESUMO
The preoperative diagnosis of primary ovarian pregnancy (POP) remains elusive and the final diagnosis relies heavily on histologic findings. The diagnostic criteria for POP, established in 1878 by Spiegelberg, are based primarily on the identification of an embryonic sac within the ovary and the localization of conception products therein. However, these diagnostic criteria may be overly strict, which may not only significantly underestimate the prevalence of POP, but also potentially mislead patient management. In this series, we present 7 cases that showed no embryonic sac within the ovary (thus not meeting the Spiegelberg criteria for POP), but were nonetheless classified by the authors as POP based on the unequivocal presence of chorionic villi and implantation sites within the ovary. Immmunohistochemical studies for beta-human chorionic gonadotropin, human placental lactogen, and inhibin highlighted the trophoblastic populations. These findings indicate that POP may occur even if no embryonic sac is pathologically demonstrable. Accordingly, we propose the following modified diagnostic criteria for POP: (1) no pathologic evidence of ipsilateral fallopian tube involvement is present; and (2) evidences of gestation, including presence of chorionic villi and/or implantation site are present within the ovary. If both criteria are met, the diagnosis of POP should be rendered. These proposed diagnostic criteria should lead to more accurate diagnoses of POP, provide more contemporary insights into its true prevalence, heighten clinical awareness of the disease, and ultimately, optimize its clinical management.
Assuntos
Gonadotropina Coriônica Humana Subunidade beta/metabolismo , Inibinas/metabolismo , Lactogênio Placentário/metabolismo , Gravidez Ovariana/diagnóstico por imagem , Adulto , Vilosidades Coriônicas/diagnóstico por imagem , Vilosidades Coriônicas/patologia , Feminino , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Ovário/diagnóstico por imagem , Ovário/patologia , Gravidez , Gravidez Ovariana/patologia , Trofoblastos/patologiaRESUMO
Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice is a widely used transgenic animal model of prostate cancer (PCa). We performed a label-free quantitative proteomics analysis combined with a bioinformatics analysis on the entire prostate protein extraction from TRAMP mice and compared it with WT littermates. From 2379 total identified proteins, we presented a modest mice prostate reference proteome containing 919 proteins. 61 proteins presented a significant expression difference between two groups. The integrative bioinformatics analysis predicted the overexpression of platelet-derived growth factor B (PDGF-B) in tumor tissues and supports the hypothesis of the PDGF-B signaling network as a key upstream regulator in PCa progression. Furthermore, we demonstrated that Crenolanib, a novel PDGF receptor inhibitor, inhibited PCa cell proliferation in a dose-dependent manner. Finally, we revealed the importance of PDGF-B regulatory network in PCa progression, which will assist us in understanding the role and mechanisms of PDGF-B in promoting cancer growth and provide valuable knowledge for future research on anti-PDGF therapy.
Assuntos
Biologia Computacional/métodos , Redes Reguladoras de Genes , Neoplasias da Próstata/química , Proteômica/métodos , Proteínas Proto-Oncogênicas c-sis/genética , Animais , Progressão da Doença , Masculino , Camundongos , Camundongos Transgênicos , Próstata/química , Neoplasias da Próstata/patologia , Proteoma/análiseRESUMO
We previously reported six different p53 isoforms in renal cell carcinoma (RCC). In the present study, influences of p53ß on recurrence-free survival (RFS) and overall survival (OS) were evaluated. Patients diagnosed with RCC in our center were into this study. mRNA expressions of p53 isoforms (p53α, p53ß, p53γ) in tumors were determined by RT-PCR and real-time PCR. Functional yeast-based assay was performed to analyze p53 mutational status. p53ß transfected 786-O and CAKi-1 cells were cultured to examine expressions of B-cell lymphoma 2-associated X protein (bax) and caspase-3, and ratios of apoptosis. After surgeries, all patients were followed up at programmed intervals. 266 patients were analyzed in this study. Median follow-up time was 5.3 years. RT-PCR (r = -0.72, P = 0.016) and real-time PCR (r = -0.65, P = 0.033) both showed only p53ß expressed higher level in lower tumor stage versus higher stage. p53 wild-type and p53 mutation had comparable RFS (P = 0.361) and OS (P = 0.218), respectively. Kaplan-Meier analysis showed high p53ß expression was associated with significantly improved RFS and OS, regardless of p53 mutational status. High p53ß expression indicated better RFS [hazard ratio (HR) 2.599, 95% confidence interval (CI) 1.472-4.551, P = 0.038] and OS (HR 2.604, 95% CI 1.453-4.824, P = 0.031). p53ß transfected 786-O and CAKi-1 cells expressed significantly higher level of bax and caspase-3, and had higher ratios of apoptosis than untransfected cells. Taken together, higher level of p53ß predict better prognosis in patients with RCC through enhancing apoptosis in tumors.
Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Apoptose/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Isoformas de Proteínas/genéticaRESUMO
Epithelial-mesenchymal transition (EMT) plays an important role in the invasiveness and metastasis of gastric cancer. Therefore, identifying key molecules involved in EMT will provide new therapeutic strategy for treating patients with gastric cancer. TIPE1 is a newly identified member of the TIPE (TNFAIP8) family, and its contributions to progression and metastasis have not been evaluated. In this study, we found that the levels of TIPE1 were significantly reduced and inversely correlated with differentiation status and distant metastasis in primary gastric cancer tissues. We further observed overexpression of TIPE1 in aggressive gastric cancer cell lines decreased their metastatic properties both in vitro and in vivo as demonstrated by markedly inhibiting EMT and metastasis of gastric cancer cells in nude mice. Consistently, gene silencing of TIPE1 in well-differentiated gastric cancer cell line (AGS) inhibited these processes. Mechanistically, we found that TIPE1-medicated Wnt/ß-catenin signalling was one of the critical signal transduction pathways that link TIPE1 to EMT inhibition. Importantly, TIPE1 dramatically restrained the expression and activities of MMP2 and MMP9 which are demonstrated to promote tumour progression and are implicated in EMT. Collectively, these findings provide new evidence for a better understanding of the biological activities of TIPE1 in progression and metastasis of gastric cancer and suggest that TIPE1 may be an innovative diagnostic and therapeutic target of gastric cancer.
Assuntos
Movimento Celular , Regulação para Baixo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Via de Sinalização Wnt , Animais , Carcinogênese/genética , Carcinogênese/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Nus , Pessoa de Meia-Idade , Modelos Biológicos , Invasividade Neoplásica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias Gástricas/genéticaRESUMO
In order to better understand the mechanisms underlying the development of papillary thyroid carcinoma (PTC), and to identify new potential biomarkers, high-resolution label-free mass spectrometry was performed on PTC tissues and adjacent normal thyroid tissues from six patients. In this process, 2788 proteins were identified, out of which 49 proteins presented significant differences between PTC tissues and adjacent normal thyroid tissues. Gene ontology revealed that the majority of these proteins are involved in the catalytic activity and binding. We selected three proteins with differential expressions: PDZ and LIM domain 5 (PDLIM5), PDLIM1 and ALDH1A1; Protein expressions were further verified by RT-PCR and western blot. Among these, expression of PDLIM5 and PDLIM1 was up-regulated, while that of ALDH1A1 was down-regulated in PTC tissues. Next, we confirmed their expression through quantitative dot blot (QDB) technique. We found that knockdown of PDLIM5 expression in the B-CPAP cell line could inhibit the migration, invasion and proliferation of PTC cells. In addition, PDLIM5 knockdown reduced Ras and Phospho-ERK1/2 expression. Thus, we suggested that PDLIM5 promotes PTC via activation of the Ras-ERK pathway. Our research provides new molecular insight into the function of PDLIM5, which may assist in studying the mechanism of PTC. In addition, PDLIM5 could be further explored as a potential candidate for PTC treatment.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Papilar/metabolismo , Proteínas com Domínio LIM/metabolismo , Proteômica , Neoplasias da Glândula Tireoide/metabolismo , Western Blotting , Carcinoma Papilar/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Coloração e Rotulagem , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/patologia , Proteínas ras/metabolismoRESUMO
BACKGROUND: Metformin (Met) is a widely available diabetic drug and shows suppressed effects on renal cell carcinoma (RCC) metabolism and proliferation. Laboratory studies in RCC suggested that metformin has remarkable antitumor activities and seems to be a potential antitumor drug. But the facts that metformin may be not effective in reducing the risk of RCC in cancer clinical trials made it difficult to determine the benefits of metformin in RCC prevention and treatment. The mechanisms underlying the different conclusions between laboratory experiments and clinical analysis remains unclear. The goal of the present study was to determine whether long-term metformin use can induce resistance in RCC, whether metformin resistance could be used to explain the disaccord in laboratory and clinical studies, and whether the drug valproic acid (VPA), which inhibits histone deacetylase, exhibits synergistic cytotoxicity with metformin and can counteract the resistance of metformin in RCC. METHODS: We performed CCK8, transwell, wound healing assay, flow cytometry and western blotting to detect the regulations of proliferation, migration, cell cycle and apoptosis in 786-O, ACHN and metformin resistance 786-O (786-M-R) cells treated with VPA, metformin or a combination of two drugs. We used TGF-ß, SC79, LY294002, Rapamycin, protein kinase B (AKT) inhibitor to treat the 786-O or 786-M-R cells and detected the regulations in TGF-ß /pSMAD3 and AMPK/AKT pathways. RESULTS: 786-M-R was refractory to metformin-induced antitumor effects on proliferation, migration, cell cycle and cell apoptosis. AMPK/AKT pathways and TGF-ß/SMAD3 pathways showed low sensibilities in 786-M-R. The histone H3 acetylation diminished in the 786-M-R cells. However, the addition of VPA dramatically upregulated histone H3 acetylation, increased the sensibility of AKT and inhibited pSMAD3/SMAD4, letting the combination of VPA and metformin remarkably reappear the anti-tumour effects of metformin in 786-M-R cells. CONCLUSIONS: VPA not only exhibits synergistic cytotoxicity with metformin but also counteracts resistance to metformin in renal cell carcinoma cell. The re-sensitization to metformin induced by VPA in metformin-resistant cells may help treat renal cell carcinoma patients.
Assuntos
Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Transição Epitelial-Mesenquimal , Histonas/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Metformina/farmacologia , Ácido Valproico/farmacologia , Acetilação , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Resistência a Medicamentos , Humanos , Transdução de Sinais/efeitos dos fármacosRESUMO
As a chronic inflammatory and angiogenic disease with increased morbidity and mortality, rheumatoid arthritis (RA) is characterized by the proliferation of synovial tissue and the accumulation of excessive mononuclear infiltration, which always results in the joint deformity, disability, and eventually the destruction of the bone and cartilage. Traditional Chinese Medicine (TCM), with rich history of proper effectiveness in treating the inflammatory joint disease containing RA, has long combated such illness from, actually, an integrative and holistic point of view. However, its "multi-components" and "multi-targets" features make it very difficult to decipher the molecular mechanisms of RA from a systematic perspective if employing only routine methods. Presently, an innovative systems-pharmacology approach was introduced, which combined the ADME screening model, drug targeting, and network pharmacology, to explore the action mechanisms of botanic herbs for the treatment of RA. As a result, we uncovered 117 active compounds and 85 key molecular targets from seven RA-related herbs, which are mainly implicated in four signaling pathways, that is, vascular endothelial growth factor, PI3K-Akt, Toll-like receptor, and T-cell-receptor pathways. Additionally, the network relationships among the active components, target proteins, and pathways were further built to uncover the pharmacological characters of these herbs. Besides, molecular dynamics (MD) simulations and molecular mechanics-Poisson-Boltzmann surface area calculations were carried out to explore the binding interactions between the compounds and their receptors as well as to investigate the binding affinity of the ligand to their protein targets. In vitro experiments by ligand binding assays validate the reliability of the drug-target interactions as well as the MD results. The high binding affinities and good inhibitions of the active compounds indicate that the potential therapeutic effects of these herbal medicines for treating RA are exerted probably through the modulation of these relevant proteins, which further validates the rationality and reliability of the drug-target interactions as well as our the network-based analytical methods. This work may be of help for not only understanding the action mechanisms of TCM and for discovering new drugs from plants for the treatment of RA, but also providing a novel potential method for modern medicine in treating complex diseases.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Herbária/métodos , Medicina Tradicional Chinesa/métodos , Simulação de Dinâmica Molecular , Paeonia/químicaRESUMO
Osteoblastoma is a rare benign primary bone tumor, which occurs in any part of the skeleton. Extraskeletal osteoblastoma is rather rare. We presented an extremely rare case of extraskeletal osteoblastoma located in the breast. The tumor recurred 7 months later after resection and transformed to aggressive osteoblastoma. The histopathological features, ultrasonic manifestations and ultrasonic differential diagnoses of the primary and recurrent tumors were discussed. The recommended treatment of the tumor is surgical excision. Due to its tendency of recurrence and potential malignant transformation, adequate resection and careful follow up is essential.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Aprendizado de Máquina , Osteoblastoma/diagnóstico por imagem , Ultrassonografia Doppler em Cores/métodos , Mama/diagnóstico por imagem , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Curva de Aprendizado , Redes Neurais de Computação , Osteoblastoma/patologia , Osteoblastoma/cirurgia , Curva ROC , RecidivaRESUMO
BACKGROUND: Papillary thyroid carcinoma (PTC), which accounts for 80% of all thyroid cancers, has an increasing incidence over these years. Single nucleotide polymorphisms (SNPs) of BRAF were considered to be one of well-established risk factors leading to development of PTC. The aim of this study was to investigate whether the common mutations of BRAF could elevate significantly the risk of PTC in a Chinese population. METHODS: Four SNPs (rs11762469, rs17623204, rs1267636 and rs3748093) of BRAF were selected through our filter by Haploview 4.2 software with HapMap databases. We used the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to genotype the four SNPs in blood samples of 618 subjects (206 patients with PTC and 412 healthy controls). The correlation between BRAF polymorphisms and PTC risk was assessed using student t-test and chi-square test. RESULTS: The results showed that mutation in rs3748093 was significantly associated with an increased risk of PTC in allele model (A allele vs. T allele, OR = 1·68, 95% CI = 1·16-2·43, P = 0·006), dominant model (TA + AA vs TT, OR = 1·64, 95% CI = 1·08-2·48, P = 0·019) and homozygote model (AA vs. TT, OR = 2·94, 95% CI = 1·00-8·61, P = 0·040). However, the other three SNPs (rs11762469, rs17623204 and rs1267636) were shown to have no association with the risk of PTC. CONCLUSIONS: Our results indicated that polymorphism of rs3748093*A was significantly correlated with an increased risk of PTC in a Chinese population. Further investigation on the aetiological mechanism of PTC is needed to validate our results.
Assuntos
Carcinoma Papilar/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/genética , Adulto , Povo Asiático/genética , Carcinoma Papilar/etnologia , Carcinoma Papilar/patologia , China , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Fatores de Risco , Neoplasias da Glândula Tireoide/etnologia , Neoplasias da Glândula Tireoide/patologiaRESUMO
BACKGROUND: Sperm-associated antigen 9 (SPAG9), a recently characterized oncogene, may serve as a marker for the early diagnosis of endometrial cancer. However, whether SPAG9 can be a prognostic marker of complex atypical endometrial hyperplasia (CAEH) or grade 1 endometrioid adenocarcinoma (EA) treated with progestin is still unknown. METHODS: Progestin therapy was performed in 27 women diagnosed with CAEH (19/27, CAEH group) or grade 1 EA (8/27, EA group). The expression of SPAG9 was measured in pre and post progestin-treated endometrial specimens by immunohistochemistry. The expression of SPAG9 was also examined by real-time polymerase chain reaction (PCR) and Western blot in Ishikawa cells and ECC-1 cells with or without progestin treatment. RESULTS: (1) CAEH showed a significantly better therapeutic efficacy than EA. (2) The expression of SPAG9 was lower in CAEH than in EA. (3) SPAG9 expression significantly declined in the endometrial tissues of women responding to progestin. (4) Significant downregulations of SPAG9 were validated by reverse transcription PCR (RT-PCR) and Western blot both in Ishikawa cells and ECC-1 cells treated with progestin. CONCLUSION: SPAG9 may be associated with the efficacy of progestin treatment in CAEH and grade 1 EA. It may help to distinguish CAEH from grade 1 EA and serve as a new prognostic marker of CAEH or grade 1 EA treated with progestin.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/análise , Biomarcadores Tumorais/análise , Carcinoma Endometrioide/diagnóstico , Hiperplasia Endometrial/diagnóstico , Neoplasias do Endométrio/diagnóstico , Acetato de Medroxiprogesterona/uso terapêutico , Adulto , Antineoplásicos Hormonais/uso terapêutico , Western Blotting , Carcinoma Endometrioide/tratamento farmacológico , Linhagem Celular Tumoral , Detecção Precoce de Câncer/métodos , Hiperplasia Endometrial/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Humanos , Imuno-Histoquímica , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVES: The aim of this study was to evaluate the differences in sonographic features of medullary thyroid carcinomas according to nodule size and compared with findings for papillary thyroid carcinomas. METHODS: This study included 38 medullary thyroid carcinoma nodules and 91 papillary thyroid carcinoma nodules, which were confirmed by pathologic examination between May 2008 and September 2013. Nodules were divided into those that were greater than 10 mm (large nodules) and 10 mm or less (small nodules). The differences in sonographic features (composition, echogenicity, margin, calcifications, and shape) between groups were analyzed with a χ(2) test. RESULTS: Large medullary thyroid carcinomas more frequently showed an ovoid-to-round shape and a smooth margin; small medullary thyroid carcinomas more frequently showed a taller-than-wide shape and a spiculated margin; the differences were statistically significant between the groups (P < .05). Compared with papillary thyroid carcinomas, large medullary thyroid carcinomas tended to have an ovoid-to-round shape, a smooth margin, and macrocalcifications and were more frequently diagnosed as indeterminate nodules (P < .05); however, there were no significant differences in the internal composition, calcifications, echogenicity, margin, and shape between small medullary thyroid carcinomas and small papillary thyroid carcinomas (P > .05). CONCLUSIONS: Our data indicate that the sonographic features of medullary thyroid carcinomas are associated with tumor size; furthermore, the sonographic features of medullary thyroid carcinomas are similar to those of small papillary thyroid carcinomas but greatly different from those of large papillary thyroid carcinomas. Large medullary thyroid carcinomas are more commonly diagnosed as indeterminate nodules by sonography than large papillary thyroid carcinomas, and fine-needle aspiration biopsy or serum calcitonin measurement may be helpful.
Assuntos
Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma/diagnóstico por imagem , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Adulto , Idoso , Carcinoma/patologia , Carcinoma Neuroendócrino/patologia , Carcinoma Papilar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/patologia , Carga Tumoral , Ultrassonografia , Adulto JovemRESUMO
It is crucial to decipher the modulation of regulatory T cells (Tregs) in tumor microenvironment (TME) induced by chemotherapy, which may contribute to improving the efficacy of neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer (NSCLC). We retrospectively collected specimens from patients with II-III NSCLC, constituting two cohorts: a neoadjuvant chemotherapy (NAC) cohort (N = 141) with biopsy (N = 58) and postoperative specimens (N = 141), and a surgery-only cohort (N = 122) as the control group. Then, the cell density (Dens), infiltration score (InS), and Treg-cell proximity score (TrPS) were conducted using a panel of multiplex fluorescence staining (Foxp3, CD4, CD8, CK, CD31, ÉSMA). Subsequently, the association of Tregs with cancer microvessels (CMVs) and cancer-associated fibroblasts (CAFs) was analyzed. Patients with NAC treatment have a higher density of Tregs in both paired (P < 0.001) and unpaired analysis (P = 0.022). Additionally, patients with NAC treatment showed higher infiltration score (paired, P < 0.001; unpaired, P = 0.014) and more CD8+T cells around Tregs (paired/unpaired, both P < 0.001). Subgroup analysis indicated that tumors with a diameter of ≤ 5 cm exhibited increase in both Dens(Treg) and InS(Treg), and gemcitabine, pemetrexed and taxel enhanced Dens(Treg) and TrPS(CD8) following NAC. Multivariate analysis identified that the Dens(Tregs), InS(Tregs) and TrPS(CD8) were significantly associated with better chemotherapy response [OR = 8.54, 95%CI (1.69, 43.14), P = 0.009; OR = 7.14, 95%CI (1.70, 30.08), P = 0.024; OR = 5.50, 95%CI (1.09, 27.75), P = 0.039, respectively] and positive recurrence-free survival [HR = 3.23, 95%CI (1.47, 7.10), P = 0.004; HR = 2.70; 95%CI (1.27, 5.72); P = 0.010; HR = 2.55, 95%CI (1.21, 5.39), P = 0.014, respectively]. Moreover, TrPS(CD8) and TrPS(CD4) were negatively correlated with the CMVs and CAFs. These discoveries have deepened our comprehension of the immune-modulating impact of chemotherapy and underscored that the modified spatial landscape of Tregs after chemotherapy should be taken into account for personalized immunotherapy, aiming to ultimately improve clinical outcomes in patients with NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Terapia Neoadjuvante , Linfócitos T Reguladores , Microambiente Tumoral , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Terapia Neoadjuvante/métodos , Feminino , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Pessoa de Meia-Idade , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Idoso , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacosRESUMO
Primary diffuse central nervous system large B-cell lymphoma (CNS-pDLBCL) and high-grade glioma (HGG) often present similarly, clinically and on imaging, making differentiation challenging. This similarity can complicate pathologists' diagnostic efforts, yet accurately distinguishing between these conditions is crucial for guiding treatment decisions. This study leverages a deep learning model to classify brain tumor pathology images, addressing the common issue of limited medical imaging data. Instead of training a convolutional neural network (CNN) from scratch, we employ a pre-trained network for extracting deep features, which are then used by a support vector machine (SVM) for classification. Our evaluation shows that the Resnet50 (TL + SVM) model achieves a 97.4% accuracy, based on tenfold cross-validation on the test set. These results highlight the synergy between deep learning and traditional diagnostics, potentially setting a new standard for accuracy and efficiency in the pathological diagnosis of brain tumors.
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BACKGROUND: Neoadjuvant chemotherapy (NAC) combined with immunotherapy is increasingly used in non-small cell lung cancer (NSCLC). Tissue-resident memory T (TRM) cells are the primary subset responding to anti-cancer immunity. However, the immunomodulatory effects of NAC on TRM cells remain unknown. METHODS: We established two NSCLC cohorts including patients undergoing upfront surgery (US) and NAC followed by surgery. Beyond the unpaired comparison between the US cohort (n = 122) and NAC cohort (n = 141) with resection samples, 58 matched pre-NAC biopsy samples were available for paired comparisons. Using multiplex immunofluorescence, we characterized TRM cells (CD103+CD8+) and four heterogeneous TRM subsets, including naive TRM1 (PD-1-Tim-3-), pre-exhausted TRM2 (PD-1+Tim-3-), TRM3 (PD-1-Tim-3+), and terminally exhausted TRM4 (PD-1+Tim-3+). Cell density, cytotoxicity, and two spatial features were defined to evaluate the effect of NAC on TRM subsets. RESULTS: The cell densities, infiltration scores, and cancer-cell proximity scores of TRM cells, especially TRM1&2 subsets, were significantly increased after NAC and associated with better prognosis of patients. In Contrast, no significant change was observed in the TRM4 subset, which was associated with poor prognosis. Besides, the cytotoxicity of TRM subsets was unaltered after NAC. Compared with patients without major pathologic response (MPRs), patients with MPR had higher densities of TRM1&2 subsets and higher cancer-cell proximity scores of TRM2&3 subsets. Furthermore, increased density of CD31 + cancer microvessels was positively associated with both TRM and Tnon-RM cells after NAC. CONCLUSIONS: NAC may remodel the cell density and spatial distribution of TRM subsets, which is associated with favorable therapeutic effect and prognosis in patients with NSCLC.
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This study aimed to investigate impacts of Omicron infection on cancer patients in China. A retrospective study was conducted, including 347 cancer patients undergoing radiotherapy or chemoradiotherapy between July 2022 and March 2023. Three groups involved: 108 patients without SARS-CoV-2 infection (non-COVID-19 group), 102 patients beginning treatment 10 days after first SARS-CoV-2 infection (≥ 10 days COVID-19 group), and 137 patients beginning treatment less than 10 days after first SARS-CoV-2 infection (< 10 days COVID-19 group). SAA, hsCRP, ALT, etc., were used to assess COVID-19 infection. Serum levels of SAA, hsCRP and IL-6 were all raised in two COVID-19-infected groups (SAA < 0.01, hsCRP < 0.01, IL-6 < 0.05), but PCT, ALT, LDH and HBDH levels were only elevated in ≥ 10 days COVID-19 group (PCT = 0.0478, ALT = 0.0022, LDH = 0.0313, HBDH = 0.0077). Moreover, moderate and severe infected cases were higher in ≥ 10 days COVID-19 group than < 10 days COVID-19 group (12/102 vs 5/137, p = 0.0211), but no significance in myelosuppression and completion rates among three groups. Omicron infection led to inflammation, liver and cardiovascular injury on cancer patients, but delay duration of radiotherapy or chemoradiotherapy after infection did not affect the completion rates and myelosuppression of current therapy. Besides, severity of Omicron infection was even worse among cancer patients who received delayed treatment.
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COVID-19 , Quimiorradioterapia , Neoplasias , SARS-CoV-2 , Humanos , COVID-19/terapia , Feminino , Masculino , Pessoa de Meia-Idade , Neoplasias/radioterapia , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Quimiorradioterapia/efeitos adversos , Estudos Retrospectivos , Idoso , SARS-CoV-2/isolamento & purificação , Adulto , China/epidemiologiaRESUMO
The study aimed to determine the specific relative biological effectiveness (RBE) of various cells in the hippocampus following proton irradiation. Sixty Sprague-Dawley rats were randomly allocated to 5 groups receiving 20 or 30 Gy of proton or photon irradiation. Pathomorphological neuronal damage in the hippocampus was assessed using Hematoxylin-eosin (HE) staining. The expression level of NeuN, Nestin, Caspase-3, Olig2, CD68 and CD45 were determined by immunohistochemistry (IHC). The RBE range established by comparing the effects of proton and photon irradiation at equivalent biological outcomes. Proton20Gy induced more severe damage to neurons than photon20Gy, but showed no difference compared to photon30Gy. The RBE of neuron was determined to be 1.65. Similarly, both proton20Gy and proton30Gy resulted in more inhibition of oligodendrocytes and activation of microglia in the hippocampal regions than photon20Gy and photon30Gy. However, the expression of Olig2 was higher and CD68 was lower in the proton20Gy group than in the photon30Gy group. The RBE of oligodendrocyte and microglia was estimated to be between 1.1 to 1.65. For neural stem cells (NSCs) and immune cells, there were no significant difference in the expression of Nestin and CD45 between proton and photon irradiation (both 20 and 30 Gy). Therefore, the RBE for NSCs and immune cell was determined to be 1.1. These findings highlight the varying RBE values of different cells in the hippocampus in vivo. Moreover, the actual RBE of the hippocampus may be higher than 1.1, suggesting that using as RBE value of 1.1 in clinical practice may underestimate the toxicities induced by proton radiation.
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Terapia com Prótons , Prótons , Ratos , Animais , Terapia com Prótons/métodos , Nestina , Eficiência Biológica Relativa , Ratos Sprague-Dawley , HipocampoRESUMO
DNA walkers have been widely explored and applied as biosensor elements to detect disease-related biomarkers. Traditional interface-anchored DNA walkers typically have a fixed swing arm range and an orientation of the preset track, which might complicate the design of a sensor system and limit its application in more scenes. We propose a simple electrochemical aptasensor to accurately detect Alzheimer's disease (AD) based on a nicking enzyme-powered DNA walker. In this method, bifunctional magnetic nanoparticles are used to identify and capture Aß oligomers (AßO) and Tau and release the DNA walker. As the DNA walker moves freely on the surface of the electrode, the nicking enzymes circularly cleave and release the two signal substrate chains, significantly amplifying the signal. It has been demonstrated that the constructed sensor can sensitively detect AßO and Tau, and the combined analysis of dual markers improves the accuracy of AD diagnosis. Furthermore, this method can distinguish normal individuals from AD patients in real cerebrospinal fluid samples. The excellent performance of this biosensor makes it promising for clinical applications in diagnosing AD patients and prognosis assessment.