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PURPOSE: Hobnail features may enhance the clinical aggressiveness of papillary thyroid carcinoma (PTC). However, whether a low proportion (<30%) of these features contributes to increased PTC aggressiveness remains unclear. This study investigated whether PTC cases with a low proportion hobnail features (<30%) exhibit clinical invasiveness and pathological features of aggressiveness. METHODS: Pathological specimens from patients with postoperatively diagnosed PTC were retrospectively analyzed. Among them, 29 PTC cases with a low proportion of hobnail features (<30%) were compared with 173 consecutive classical PTC (cPTC) cases. Data regarding age at presentation, sex, tumor size, number of tumors, and histological characteristics were obtained by reviewing electronic medical records. Postoperative information was obtained during follow-up visits and telephone interviews. RESULTS: Twenty-nine patients with PTC with a low proportion of hobnail features (<30%) were identified, exhibiting a median age of 34 years. At a median follow-up of 31 (IQR, 23-37) months, two patients had recurrent disease in the PTC with a low proportion of hobnail features (<30%) group, whereas there was no recurrence in the cPTC group. No distant metastasis and postoperative mortality were observed in either group. Compared with the cPTC group, patients with PTC and a low proportion of hobnail features exhibited larger tumor volumes and higher susceptibility to capsular invasion and lymph node metastasis. Tumor size and hobnail features emerged as independent risk factors for lymph node metastasis. CONCLUSION: PTC with a low proportion hobnail features (<30%) and larger tumor volumes are associated with the occurrence of lymph node metastasis. A low proportion of hobnail features (<30%) in PTC may heighten invasiveness, elevating the risk of recurrence.
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With the remarkable success of digital histopathology and the deep learning technology, many whole-slide pathological images (WSIs) based deep learning models are designed to help pathologists diagnose human cancers. Recently, rather than predicting categorical variables as in cancer diagnosis, several deep learning studies are also proposed to estimate the continuous variables such as the patients' survival or their transcriptional profile. However, most of the existing studies focus on conducting these predicting tasks separately, which overlooks the useful intrinsic correlation among them that can boost the prediction performance of each individual task. In addition, it is sill challenge to design the WSI-based deep learning models, since a WSI is with huge size but annotated with coarse label. In this study, we propose a general multi-instance multi-task learning framework (HistMIMT) for multi-purpose prediction from WSIs. Specifically, we firstly propose a novel multi-instance learning module (TMICS) considering both common and specific task information across different tasks to generate bag representation for each individual task. Then, a soft-mask based fusion module with channel attention (SFCA) is developed to leverage useful information from the related tasks to help improve the prediction performance on target task. We evaluate our method on three cancer cohorts derived from the Cancer Genome Atlas (TCGA). For each cohort, our multi-purpose prediction tasks range from cancer diagnosis, survival prediction and estimating the transcriptional profile of gene TP53. The experimental results demonstrated that HistMIMT can yield better outcome on all clinical prediction tasks than its competitors.
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Aprendizado Profundo , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Feminino , Algoritmos , Neoplasias da Mama/genética , Neoplasias da Mama/diagnóstico por imagem , Neoplasias/genética , Neoplasias/diagnóstico por imagem , Genômica/métodosRESUMO
Gastric cancer is a kind of malignant tumor that seriously endangers human life and health. Its incidence rate and mortality rate are among the highest in the global malignant tumors. Therefore, this study explored the role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in the progression of gastric cancer and its underlying mechanism. Patients with gastric cancer were collected, and human GC cell lines (stomach gastric carcinoma 7901, stomach gastric carcinoma 823 , human gastric carcinoma cell line 803 and adenocarcinoma gastric stomach) were used in this study. We utilized glucose consumption, cell migration, and ELISA assay kits to investigate the function of GC. To understand its mechanism, we employed quantitative PCR (qPCR), western blot, and m6A methylated RNA immunoprecipitation assay. FKFB3 protein expression levels in patients with gastric cancer were increased. The induction of PFKFB3 mRNA expression levels in patients with gastric cancer or gastric cancer cell lines. Gastric cancer patients with high PFKFB3 expression had a lower survival rate. PFKFB3 high expression possessed the probability of pathological stage, lymph node metastasis or distant metastasis in patients with gastric cancer. PFKFB3 upregulation promoted cancer progression and Warburg effect progression of gastric cancer. PFKFB3 upregulation reduced pyroptosis and suppressed nucleotidebinding domain, leucinerich repeat containing protein 3-induced pyroptosis of gastric cancer. M6A-forming enzyme methyltransferase-like 3 increased PFKFB3 stability. Taken together, the M6A-forming enzyme methyltransferase-like 3 increased PFKFB3 stability and reduced pyroptosis in the model of gastric cancer through the Warburg effect. The PFKFB3 gene represents a potential therapeutic strategy for the treatment of gastric cancer.
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Adenina , Adenocarcinoma , Neoplasias Gástricas , Humanos , Adenina/análogos & derivados , Proliferação de Células , Metilação , Metiltransferases/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Neoplasias Gástricas/patologiaRESUMO
Core-needle biopsy (CNB) plays a vital role in the initial diagnosis of breast cancer. However, the complex tissue processing and global shortage of pathologists have hindered traditional histopathology from timely diagnosis on fresh biopsies. In this work, we developed a full digital platform by integrating label-free stimulated Raman scattering (SRS) microscopy with weakly-supervised learning for rapid and automated cancer diagnosis on un-labelled breast CNB. Methods: We first compared the results of SRS imaging with standard hematoxylin and eosin (H&E) staining on adjacent frozen tissue sections. Then fresh unprocessed biopsy tissues were imaged by SRS to reveal diagnostic histoarchitectures. Next, weakly-supervised learning, i.e., the multi-instance learning (MIL) model was conducted to evaluate the ability to differentiate between benign and malignant cases, and compared with the performance of supervised learning model. Finally, gradient-weighted class activation mapping (Grad-CAM) and semantic segmentation were performed to spatially resolve benign/malignant areas with high efficiency. Results: We verified the ability of SRS in revealing essential histological hallmarks of breast cancer in both thin frozen sections and fresh unprocessed biopsy, generating histoarchitectures well correlated with H&E staining. Moreover, we demonstrated that weakly-supervised MIL model could achieve superior classification performance to supervised learnings, reaching diagnostic accuracy of 95% on 61 biopsy specimens. Furthermore, Grad-CAM allowed the trained MIL model to visualize the histological heterogeneity within the CNB. Conclusion: Our results indicate that MIL-assisted SRS microscopy provides rapid and accurate diagnosis on histologically heterogeneous breast CNB, and could potentially help the subsequent management of patients.
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Neoplasias da Mama , Mama , Humanos , Feminino , Mama/diagnóstico por imagem , Mama/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Biópsia/métodos , Amarelo de Eosina-(YS) , Microscopia Óptica não Linear , Biópsia por AgulhaRESUMO
Aspergillus endocarditis (AE) is a highly fatal infection that can occur in heart valve replacement, pacemaker implantation and other heart surgeries, and early recognition and sufficient diagnosis are challenging. Here, we report the case of a 68-year-old male with a history of dilated cardiomyopathy and pacemaker implantation who had a repeated fever with failed antibacterial treatment and sterile blood culture. He developed endocarditis, and the culture and biopsy of vegetation tissue showed the abundant presence of septate hyphae, which was subsequently identified as Aspergillus fumigatus by internal transcribed spacer (ITS) sequencing. Although the patient had serious side effects from voriconazole, he had a good prognosis following surgery and prolonged caspofungin antifungal therapy of 42 consecutive days. We discuss the diagnosis and treatment strategy of AE, and recommend galactomannan assays and next-generation sequencing for a timely diagnosis. Early surgical intervention combined with prompt antifungal therapy appears significant for survival.
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Background: Due to the limited diagnostic ability, the low detection rate of early gastric cancer (EGC) is a serious health threat. The establishment of the mapping between endoscopic images and pathological images can rapidly improve the diagnostic ability to detect EGC. To expedite the learning process of EGC diagnosis, a mucosal recovery map for the mapping between ESD mucosa specimen and pathological images should be performed in collaboration with endoscopists and pathologists, which is a time-consuming and laborious work. Methods: 20 patients at the Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College from March 2020 to July 2020 were enrolled in this study. We proposed the improved U-Net to obtain WSI-level segmentation results, and the WSI-level results can be mapped to the macroscopic image of the specimen. For the convenient use, a software pipeline named as "Pathology Helper" for integration the workflow of the construction of mucosal recovery maps was developed. Results: The MIoU and Dice of our model can achieve 0.955 ± 0.0936 and 0.961 ± 0.0874 for WSI-level segmentation, respectively. With the help of "Pathology Helper", we can construct the high-quality mucosal recovery maps to reduce the workload of endoscopists and pathologists. Conclusion: "Pathology Helper" will accelerate the learning of endoscopists and pathologists, and rapidly improve their abilities to detect EGC. Our work can also improve the detection rate of early gastric cancer, so that more patients with gastric cancer will be treated in a timely manner.
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Determination of malignancy in thyroid nodules remains a major diagnostic challenge. Here we report the feasibility and clinical utility of developing an AI-defined protein-based biomarker panel for diagnostic classification of thyroid nodules: based initially on formalin-fixed paraffin-embedded (FFPE), and further refined for fine-needle aspiration (FNA) tissue specimens of minute amounts which pose technical challenges for other methods. We first developed a neural network model of 19 protein biomarkers based on the proteomes of 1724 FFPE thyroid tissue samples from a retrospective cohort. This classifier achieved over 91% accuracy in the discovery set for classifying malignant thyroid nodules. The classifier was externally validated by blinded analyses in a retrospective cohort of 288 nodules (89% accuracy; FFPE) and a prospective cohort of 294 FNA biopsies (85% accuracy) from twelve independent clinical centers. This study shows that integrating high-throughput proteomics and AI technology in multi-center retrospective and prospective clinical cohorts facilitates precise disease diagnosis which is otherwise difficult to achieve by other methods.
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BACKGROUND: Colorectal juvenile polyps are rare and generally considered benign in adults. Carcinogenesis or neoplastic changes are rarely mentioned in the literature. We systematically evaluated the characteristics and potential malignancy of colorectal juvenile polyps in adults. METHODS: We retrospectively reviewed the medical records of 103 adults diagnosed with colorectal juvenile polyps from September 2007 to May 2020 at our hospital. The characteristics, endoscopic findings, occurrence of intraepithelial neoplasia, carcinogenesis and diagnostic value of chicken skin mucosa (CSM) were analyzed. RESULTS: The average age of patients with juvenile polyps was 43.2 years (range, 19 to 78 years). A total of 101 patients (101/103, 98.1%) had a single juvenile polyp, and two patients had multiple polyps (107 polyps in total). Polyp sizes ranged from 0.5 to 5 cm. One (1/107, 0.9%) juvenile polyp was cancerous, and 7 (7/107, 6.5%) developed low-grade intraepithelial neoplasia. Neoplasia and cancerization did not appear in the two patients with multiple polyps. A 27-year-old female had a 2-cm polyp with well-differentiated adenocarcinoma in the mucosa in the sigmoid colon with erosion on the surface. CSM was observed adjacent to 17 polyps, which were all located in the rectum and sigmoid colon, and one polyp showed low-grade intraepithelial neoplasia. CONCLUSIONS: Colorectal juvenile polyps occur in a wide range of locations and in variable sizes and numbers. These polyps are solitary in most patients and have neoplastic potential. CSM is not a tumorigenic marker in colorectal juvenile polyps and usually occurs in the distant colorectum. Colorectal juvenile polyps in adults may progress from low-grade intraepithelial neoplasia to high-grade intraepithelial neoplasia and then to carcinoma and should be treated when discovered and regularly followed as colorectal adenomas.
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Adenoma , Pólipos do Colo , Neoplasias Colorretais , Adenoma/diagnóstico , Adulto , Idoso , Pólipos do Colo/patologia , Colonoscopia , Neoplasias Colorretais/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Colorectal cancer (CRC) is presently the second most prevalent global mortality-inducing cancer. CRC carcinogenesis is a multifactorial process involving internal genetic mutations and the external environment. In addition, non-neoplastic cell activities within tumor microenvironments for CRC development have been established. However, interleukin (IL)-33, secreted by such cell types, plays a pivotal role in cancer progression due to interaction with cellular constituents within the tumor-inflammation microenvironment. IL-33 belongs to the IL-1 cytokine family and acts as binding attachments for the suppressor of tumorigenicity (ST)2 receptor. Therefore, how to coordinate tumor microenvironment, design and optimize treatment strategies suitable for CRC, based on IL-33/ST2 signal is a challenge. Even though it has established influences upon immunity-linked conditions, IL-33 effects on CRC progression and prevention and related mechanisms are still controversial. Our review depicts controversial activities for IL-33/ST2 within carcinogenesis and cancer prevention. Moreover, IL-33/ST2 signaling is a potential therapeutic target for CRC.
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BACKGROUND: Evidence-based decision-making is critical to optimize the benefits and mitigate futility associated with surgery for patients with malignancies. Untreated hepatocellular carcinoma (HCC) has a median survival of only 6 months. The objective was to develop and validate an individualized patient-specific tool to predict preoperatively the benefit of surgery to provide a survival benefit of at least 6 months following resection. METHODS: Using an international multicenter database, patients who underwent curative-intent liver resection for HCC from 2008 to 2017 were identified. Using random assignment, two-thirds of patients were assigned to a training cohort with the remaining one-third assigned to the validation cohort. Independent predictors of postoperative death within 6 months after surgery for HCC were identified and used to construct a nomogram model with a corresponding online calculator. The predictive accuracy of the calculator was assessed using C-index and calibration curves. RESULTS: Independent factors associated with death within 6 months of surgery included age, Child-Pugh grading, portal hypertension, alpha-fetoprotein level, tumor rupture, tumor size, tumor number and gross vascular invasion. A nomogram that incorporated these factors demonstrated excellent calibration and good performance in both the training and validation cohorts (C-indexes: 0.802 and 0.798). The nomogram also performed better than four other commonly-used HCC staging systems (C-indexes: 0.800 vs. 0.542-0.748). CONCLUSIONS: An easy-to-use online prediction calculator was able to identify patients at highest risk of death within 6 months of surgery for HCC. The proposed online calculator may help guide surgical decision-making to avoid futile surgery for patients with HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/cirurgia , Hepatectomia , Humanos , Neoplasias Hepáticas/cirurgia , Nomogramas , Estudos RetrospectivosRESUMO
BACKGROUND: Epithelioid angiosarcoma is a vascular neoplasm that is among the most aggressive subtypes of sarcomas. Its involvement in the gastrointestinal tract is rare. We here report a case of multifocal gastrointestinal epithelioid angiosarcomas presenting with gastrointestinal bleeding. CASE SUMMARY: A 77-year-old woman was admitted because of melena and dizziness for three months. Gastroscopy and colonoscopy were performed, revealing a centrally ulcerated hemorrhagic polypoid lesion in the gastric body and multiple polypoid lesions with blood clots and hemorrhagic tendency in the colon. Histopathological examination of routine endoscopic biopsy samples showed inflammation in the gastric mucosa and tubular adenomas in the colon. The polypoid lesions were removed by endoscopic mucosal resection. Immunohistochemistry suggested a final diagnosis of epithelioid angiosarcomas. The patient refused chemotherapy and died after three months. CONCLUSION: Epithelioid angiosarcomas are characterized by highly vascular nature and tendency to cause gastrointestinal bleeding. Efforts to obtain histological findings using endoscopic mucosal resection are of great importance.
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Ressecção Endoscópica de Mucosa , Hemangioendotelioma Epitelioide , Hemangiossarcoma , Idoso , Feminino , Hemangiossarcoma/cirurgia , Humanos , MelenaRESUMO
Liver cancer is the fourth leading cause of cancer-associated mortality worldwide. Statistics indicate that the incidence of liver cancer has been increasing and that its prognosis remains poor. Fat mass and obesity-associated protein (FTO) is a demethylase that is involved in N6-methyladenosine (m6a) RNA modification; however, to the best of our knowledge, its role in tumorigenesis and development of liver cancer remains unknown. In the present study, cell proliferation, colony formation, apoptosis, Transwell and wound healing assays of small interfering (si)RNA-FTO HepG2 cells were performed, and the levels of m6A RNA methylation were assessed. Additionally, the prognostic value of FTO in liver cancer was analyzed using immunohistochemistry analysis. The results from the EpiQuik m6A RNA methylation quantitative assay revealed that knockdown of FTO increased the total m6A methylation level. Notably, FTO promoted the proliferation and migration of liver cancer cells. Additionally, FTO expression was upregulated in patients with liver cancer and was associated with a high Edmondson Grade, which served as an independent prognostic factor for liver cancer. Results from the Kaplan-Meier survival analysis revealed that low expression levels of FTO predicted a good prognosis. The 5-year overall survival of the low FTO expression group was 68% compared with 48% in the high FTO expression group (P=0.077). In conclusion, the present study suggested that FTO regulates the tumorigenesis and development of liver cancer.
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Bronchogenic cysts are primitive, foregut-derived developmental anomalies with bronchial-type, pseudostratified cylindrical epithelium. They are usually discovered in the thorax. The occurrence of such cysts in the retroperitoneum is extremely rare. Imaging techniques are generally effective in the detection of retroperitoneal bronchogenic cyst. Here, we report two cases (a 27-year-old man and a 33-year-old man) who had no clinical symptoms and were found by chance to have masses in the adrenal gland area during routine physical examination. We found that they had some similar computed tomography imaging features, including complete adrenal structure, cystic fusiform mass in adrenal region, and inclusion of calcifications in the lesions. However, accurate preoperative diagnosis remains difficult and only histology can provide a definitive diagnosis. Surgery remains the treatment of choice.
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Cisto Broncogênico/diagnóstico , Calcinose/diagnóstico , Coristoma/diagnóstico , Espaço Retroperitoneal/anormalidades , Neoplasias das Glândulas Suprarrenais/diagnóstico , Glândulas Suprarrenais/diagnóstico por imagem , Adulto , Doenças Assintomáticas , Cisto Broncogênico/patologia , Cisto Broncogênico/cirurgia , Calcinose/patologia , Calcinose/cirurgia , Coristoma/patologia , Coristoma/cirurgia , Diagnóstico Diferencial , Humanos , Achados Incidentais , Masculino , Espaço Retroperitoneal/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Juvenile polyps are the most common type of polyps in children but are rare in adults. Inflammatory bowel disease (IBD) patients have a similar spectrum of symptoms as patients with juvenile polyps. Both patients with juvenile polyps and those with active IBD have high fecal calprotectin levels. Four cases of children with ulcerative colitis (UC) with solitary juvenile polyps and one case of an adult with UC with juvenile polyposis syndrome have been reported upon diagnosis of UC, while there have been no cases of adults with UC with solitary juvenile polyp reported in the literature. CASE SUMMARY: A 37-year-old man with a 12-year history of UC was admitted to our clinic because of increased stool frequency. UC was diagnosed at the age of 25. As the lesion was confined to the rectum, sulfasalazine suppositories or mesalazine suppositories were used. The patient was followed in an outpatient clinic, and colonoscopy was performed every one or two years. The latest examination was undertaken three years prior in the presence of proctitis. Recently, the patient complained of three to five bowel movements a day. There was mucus in the stool but no visible blood. Colonoscopy revealed a solitary polyp, about 1.5 cm in diameter, with a short and broad peduncle in the transverse colon surrounded by congestive and edematous mucosa. The patient had no family history of colorectal polyps or cancer. The polyp was successfully removed by endoscopic mucosal resection. Histopathological examination revealed that the polyp was a juvenile polyp without any malignant signs. Immunohistochemical staining for p53 showed wild-type expression and p53 overexpression was not detected. Ki-67 labeling index was 3%. CONCLUSION: This is the first case of an adult UC patient with a solitary juvenile polyp at the 12-year follow-up. The correlation between juvenile polyps and the activity of IBD needs further study.
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Colite Ulcerativa/complicações , Pólipos do Colo/diagnóstico , Colonoscopia , Polipose Intestinal/congênito , Síndromes Neoplásicas Hereditárias/diagnóstico , Adulto , Assistência ao Convalescente , Pólipos do Colo/complicações , Gerenciamento Clínico , Humanos , Polipose Intestinal/complicações , Polipose Intestinal/diagnóstico , Masculino , Síndromes Neoplásicas Hereditárias/complicaçõesRESUMO
Long noncoding RNAs (lncRNAs) play important roles in regulating the development and progression of many cancers. However, the clinical significance of specific lncRNAs in the context of nasopharyngeal carcinoma (NPC) and the molecular mechanisms by which they regulate this form of cancer remain largely unclear. In this study we found that the lncRNA PVT1 was upregulated in NPC, and that in patients this upregulation was associated with reduced survival. RNA sequencing revealed that PVT1 was responsible for regulating NPC cell proliferation and for controlling a hypoxia-related phenotype in these cells. PVT1 knockdown reduced NPC cell proliferation, colony formation, and tumorigenesis in a subcutaneous mouse xenograft model systems. We further found that PVT1 serves as a scaffold for the chromatin modification factor KAT2A, which mediates histone 3 lysine 9 acetylation (H3K9), recruiting the nuclear receptor binding protein TIF1ß to activate NF90 transcription, thereby increasing HIF-1α stability and promoting a malignant phenotype in NPC cells. Overexpression of NF90 or HIF-1α restored the proliferation in cells that had ceased proliferating due to PVT1 or KAT2A depletion. Conversely, overexpression of active KAT2A or TIF1ß, but not of KAT2A acetyltransferase activity-deficient mutants or TIF1ß isoforms lacking H3K9ac binding sites, promoted a PVT1-mediated increase in NF90 transcription, as well as increased HIF-1α stability and cell proliferation. PVT1 knockdown enhanced the radiosensitization effect in NPC cells via inhibiting binding between H3K9ac and TIF1ß in a manner. Taken together, our results demonstrate that PVT1 serves an oncogenic role and plays an important role in radiosensitivity in malignant NPC via activating the KAT2A acetyltransferase and stabilizing HIF-1α.
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Histona Acetiltransferases/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , RNA Longo não Codificante/metabolismo , Proliferação de Células , Histona Acetiltransferases/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/isolamento & purificação , Transdução de Sinais/genética , Células Tumorais CultivadasRESUMO
mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG), which is located on chromosome 11q24.1, is a polycistronic microRNA host gene. MIR100HG overexpression in colorectal cancer (CRC) has been demonstrated to be associated with cetuximab resistance; however, the role of MIR100HG in CRC metastasis remains unclear. The present study aimed to investigate the impact of aberrant MIR100HG expression on metastasis and prognosis in patients with CRC. The results from reverse transcription-quantitative PCR demonstrated that MIR100HG expression was higher in CRC tissues compared with in corresponding normal mucosa tissues. In particular, MIR100HG expression was higher in advanced CRC compared with in early stage CRC. Furthermore, the results from Kaplan-Meier analysis followed by a log-rank test revealed that patients with CRC and high MIR100HG expression exhibited poorer disease-free survival and overall survival compared with patients with CRC and lower MIR100HG expression. Furthermore, results from in vitro Transwell assays and in vivo animal assays demonstrated that upregulated MIR100HG expression promoted CRC cell migration and invasion and the formation of liver metastatic colonies in mice. In conclusion, the present study demonstrated that MIR100HG overexpression may contribute to the progression of CRC and may predict a poorer prognosis in patients with CRC. MIR100HG may therefore be considered as a novel therapeutic target and a prognostic biomarker in patients with CRC.
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BACKGROUND: Angiogenic factor with G-patch and FHA domains 1 (AGGF1) can promote angiogenesis and increasing evidence has highlighted the important roles of AGGF1 in tumorigenesis. However, the differential expression as well as the biological functions of AGGF1 in colorectal cancer (CRC) remain to be established. The purpose of the present study is therefore to identify the effect of AGGF1 on prognosis and metastasis in CRC patients. METHODS: The expression level of AGGF1 in CRC was examined by qPCR, western blot and immunohistochemistry in a tissue microarray containing 236 CRC specimens and paired normal mucosae. And the effect of AGGF1 on CRC cell malignance was investigated in our established stable AGGF1 upregulated and knockdown CRC cell lines. RESULTS: The expression level of AGGF1 in CRC tissue was not significantly different to that in adjacent normal mucosa at the mRNA level. However, at the protein level, AGGF1 expression in CRC tissues was significantly higher than in paired normal mucosa, which showed a clear association with TNM stage, AJCC stage, vascular invasion, and differentiation. Further, we revealed an apparent correlation between AGGF1 expression and poorer disease-free survival and overall survival of CRC patients. In addition, we discovered that AGGF1 significantly promoted CRC cell wound healing, migration, and invasion in vitro and distant metastasis in vivo. CONCLUSIONS: Our study demonstrates the aberrant overexpression of AGGF1 in CRC and provides a basis on which to explore the application of AGGF1 as a potential therapeutic target for CRC patients, especially for CRC patients with distant metastasis.
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Proteínas Angiogênicas/genética , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , PrognósticoRESUMO
Bevacizumab (BEV) is widely used for the treatment of patients with recurrent glioblastoma (GBM), but recent evidence demonstrated that BEV induced cytoprotective autophagy, which allows tumor cells to survive. Hydroxychloroquine (HCQ) inhibits lysosomal acidification and blocks autophagy via influencing autophagosome fusion and degradation. HCQ is often used to enhance the efficacy of chemoradiotherapy. However, whether HCQ sensitizes GBM cells to BEV and the molecular mechanism of this effect are not clear. We showed that high concentrations of BEV increased the LC3-II/LC3-I ratio and caused the degradation of Beclin1 in the LN18 and LN229 cell lines, indicating that high concentrations of BEV induced the autophagy of the LN18 and LN229 cells. However, BEV (100⯵g/ml) did not influence the autophagy of the LN18 and LN229 cells, and HCQ at less than 5⯵g/ml significantly accumulated LC3B-II and p62 proteins and blocked the autophagy process. Importantly, we found that HCQ (5⯵g/ml) potentiated the anti-cancer effect of BEV (100⯵g/ml). Therefore, HCQ is a novel strategy that may augment the efficacy of BEV for GBM via the inhibition of autophagy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Autofagia , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/ultraestrutura , Linhagem Celular Tumoral , Sinergismo Farmacológico , Glioblastoma/patologia , Glioblastoma/ultraestrutura , Humanos , Hidroxicloroquina/farmacologia , Proteínas de Neoplasias/metabolismoRESUMO
The combination of gene therapy and radiation is a promising new treatment for cancer. This study aimed to clarify the synergistic effect of targeted oncolytic adenovirus (radiotherapy-tumor necrosis factor-related apoptosis-inducing ligand) and radiotherapy on colorectal cancer cells and elucidate the mechanisms of the underlying antitumor activity. Viability, cell cycle status, and apoptosis of treated colorectal cancer cells were determined via MTT and flow cytometric assays. The molecular mechanism underlying apoptotic pathway activation was elucidated through Western blot analysis of caspase-8, caspase-3, and PARP proteins. Combination treatment with radiotherapy-tumor necrosis factor-related apoptosis-inducing ligand and radiotherapy displayed significantly greater antitumor activity than either of the monotherapies. The primary mechanism behind the antitumor activity in the SW480 and Lovo colorectal cancer cell lines was apoptosis induction through the caspase pathway and G1 phase arrest. In an SW480 xenograft model of colorectal cancer, the combination therapy achieved a significantly greater reduction in tumor volume than the monotherapies. Overall, in this study, we demonstrate that the oncolytic radiotherapy-tumor necrosis factor-related apoptosis-inducing ligand construct can sensitize human colorectal cancer cells to radiation-induced apoptosis both in vitro and in vivo. Therefore, our findings point toward a novel synergistic approach to colorectal cancer treatment.