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Epithelioid glioblastoma (eGBM) is a rare subtype of GBM. Given the update of the definition of GBM, the understanding of the molecular characteristics and prognosis of "true" adult eGBM remains limited. Herein, we retrospectively analyzed the clinicopathological data of 39 adult eGBM cases. Adult eGBM primarily affected females, with a male-to-female ratio of 1:2.3. The average age of diagnosis was 53 years, and the tumor affected the temporal lobe in 41% of cases (16/39, 41%). Microscopically, the tumors consisted mainly or entirely of epithelioid cells. Perivascular infiltration (10/39, 25.6%) and leptomeningeal dissemination (7/39, 17.9%) were not uncommon. BRAF V600E mutation was detected in 40.9% of cases (n = 9/22). Next-generation sequencing revealed that CDKN2A/B homogeneous deletion was the most frequently mutated gene (8/10, 80%), followed by TERT promoter mutation (7/10, 70%), Cyclin-dependent kinases 4 or 6 (CDK4/6) amplification (5/10, 50%) and BRAF V600E mutation (50%, 5/10). Notably, the incidence of ARID1B mutation in eGBM was 50% (5/10), representing the first report of such a mutation in this subtype of GBM. ARID1B was known to be a subunit of the SWI/SNF chromatin remodeler. Chromosome analysis showed a 7+/10- signature in 90% (9/10) cases. Adult eGBM carried a dismal prognosis compared to GBM with IDH and H3 wild-type (typical GBM) (OS: 13.89 vs 24.30 months; P = .003) and even typical GBM without MGMT promoter methylation (OS: 13.89 vs 22.08 months; P = .036). Based on these findings, it can be concluded that adult eGBM harbors a high frequency of the 7+/10- signature and alterations in the MAPK pathway, SWI/SNF complex and cyclin-related genes and portends an extremely poor prognosis.
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Neoplasias Encefálicas , Metilases de Modificação do DNA , Glioblastoma , Mutação , Proteínas Proto-Oncogênicas B-raf , Fatores de Transcrição , Proteínas Supressoras de Tumor , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/mortalidade , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Prognóstico , Adulto , Idoso , Fatores de Transcrição/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/mortalidade , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Cromossômicas não Histona/genética , Telomerase/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/genética , Regiões Promotoras Genéticas/genética , Enzimas Reparadoras do DNA/genéticaRESUMO
BACKGROUND: Metastatic breast carcinoma is commonly considered during differential diagnosis when metastatic disease is detected in females. In addition to the tumor morphology and documented clinical history, sensitive and specific immunohistochemical (IHC) markers such as GCDFP-15, mammaglobin, and GATA3 are helpful for determining breast origin. However, these markers are reported to show lower sensitivity in certain subtypes, such as triple-negative breast cancer (TNBC). MATERIALS AND METHODS: Using bioinformatics analyses, we identified a potential diagnostic panel to determine breast origin: matrix Gla protein (MGP), transcriptional repressor GATA binding 1 (TRPS1), and GATA-binding protein 3 (GATA3). We compared MGP, TRPS1, and GATA3 expression in different subtypes of breast carcinoma of (n = 1201) using IHC. As a newly identified marker, MGP expression was also evaluated in solid tumors (n = 2384) and normal tissues (n = 1351) from different organs. RESULTS: MGP and TRPS1 had comparable positive expression in HER2-positive (91.2% vs. 92.0%, p = 0.79) and TNBC subtypes (87.3% vs. 91.2%, p = 0.18). GATA3 expression was lower than MGP (p < 0.001) or TRPS1 (p < 0.001), especially in HER2-positive (77.0%, p < 0.001) and TNBC (43.3%, p < 0.001) subtypes. TRPS1 had the highest positivity rate (97.9%) in metaplastic TNBCs, followed by MGP (88.6%), while only 47.1% of metaplastic TNBCs were positive for GATA3. When using MGP, GATA3, and TRPS1 as a novel IHC panel, 93.0% of breast carcinomas were positive for at least two markers, and only 9 cases were negative for all three markers. MGP was detected in 36 cases (3.0%) that were negative for both GATA3 and TRPS1. MGP showed mild-to-moderate positive expression in normal hepatocytes, renal tubules, as well as 31.1% (99/318) of hepatocellular carcinomas. Rare cases (0.6-5%) had focal MGP expression in renal, ovarian, lung, urothelial, and cholangiocarcinomas. CONCLUSIONS: Our findings suggest that MGP is a newly identified sensitive IHC marker to support breast origin. MGP, TRPS1, and GATA3 could be applied as a reliable diagnostic panel to determine breast origin in clinical practice.
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Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Biomarcadores Tumorais/metabolismo , Fator de Transcrição GATA3/genética , Mamoglobina A/análise , Mamoglobina A/metabolismo , Proteínas de Ligação ao Cálcio , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteína de Matriz GlaRESUMO
Drug-induced liver injury (DILI) has become a significant health care problem worldwide. Centella asiatica (L.) urban was traditionally used to prevent or treat various diseases, yet whether it works on hepatic injury remains unclear. In this study, multiple experimental models with different damage degrees and types of liver injury have been established to evaluate the hepatoprotective effects of an n-butanol extract of Centella asiatica (CA-BU). Our results revealed that CA-BU improved hepatocyte L02 cells survival from H2 O2 -induced oxidative damage in a concentration-dependent manner. We further verified the hepatoprotective effects of CA-BU in mice models of acetaminophen-induced acute liver injury (one of the most common DILIs clinically) and CCl4 -induced acute chemical liver injury, and a rat model of chronic alcoholic steatohepatitis. Furthermore, network pharmacology approaches were performed to explore the underlying mechanisms, and we predicted AKT1, EGFR, VEGFA, and STAT3 as the potential therapeutic targets. In follow-up studies, we will focus on targets verification and provide a deeper insight into the mechanisms of CA-BU against liver damage. Finally, we hope that these findings will provide new ideas and insights for the treatment of acute or chronic liver injury in the clinic.
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BACKGROUND: Differences between the features of primary cancer and matched metastatic cancer have recently drawn attention in research. This study investigated the concordance in microsatellite instability (MSI) and mismatch repair (MMR) status between primary and corresponding metastatic colorectal cancer (CRC). METHODS: Consecutive patients with metastatic CRC who had both primary and metastatic tumors diagnosed at our institution in January 2008 through December 2016 were identified. Immunohistochemistry was used to test the MMR status of both primary and matched metastatic tumors, and PCR analysis was performed to test MSI in patients with deficient MMR (dMMR) status. RESULTS: A total of 369 patients were included. Of the 46 patients with MSI-high primary tumors, 37 (80.4%) also had MSI-high metastatic tumors, whereas 9 (19.6%) had microsatellite stable (MSS) metastatic tumors. A high concordance was found in patients with liver, lung, or distant lymph node metastases. Interestingly, the discrepancy was more likely to be limited to peritoneal (5/20) or ovarian (4/4) metastasis (chi-square test, P<.001). These organ-specific features were also found in the pooled analysis. Along with the change of MSI-high in primary cancer to MSS in metastatic cancer, lymphocyte infiltration decreased significantly (P=.008). However, the change did not influence survival; the median overall survival of MSI-high and MSS metastatic tumors was 21.3 and 21.6 months, respectively (P=.774). The discrepancy rate was 1.6% for patients with proficient MMR primary tumors. CONCLUSIONS: For patients with dMMR primary tumors, the concordance of MSI and MMR status in primary CRC and corresponding metastatic cancer is potentially organ-specific. High concordance is found in liver, lung, and distant lymph node metastases, whereas discrepancy is more likely to occur in peritoneal or ovarian metastasis. Rebiopsy to evaluate MSI-high/dMMR status might be needed during the course of anti-PD-1 therapy in cases of peritoneal or ovarian metastasis.
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Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA/genética , Adulto , Idoso , Neoplasias Colorretais/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Metástase NeoplásicaRESUMO
BACKGROUND: Topoisomerase II alpha (TOP2A) protein has been shown to be a proliferation marker associated with tumor grade and Ki67 index. The prognostic effect of TOP2A seems different among different subtypes of breast cancer. The current study evaluated the prognostic impact of TOP2A protein on luminal breast cancer. METHOD: Altogether 434 stage I-II luminal breast cancer patients who underwent curative surgery in Sun Yat-Sen University Cancer Center between 2007 and 2009 were enrolled. TOP2A protein expression was assessed by immunohistochemistry. Clinical and pathological data were retrospectively collected. RESULT: With a cut-off value of 30%, 127 (29.3%) patients were classified as TOP2A overexpression. TOP2A overexpression was associated with a higher tumor grade and Ki67 index. Patients with TOP2A high expression showed a significantly higher rate of distant metastasis and shorter distant metastasis free survival (DMFS) compared with patients with low TOP2A expression. The prognostic influence of TOP2A expression was more significant in years 5-8 after diagnosis, and more pronounced in stage II patients, luminal B disease, and patients treated with adjuvant endocrine therapy alone. Multivariate survival analysis revealed TOP2A overexpression was an independent fact for worse DMFS. CONCLUSION: TOP2A protein showed a time dependent influence on prognosis in stage I-II luminal breast cancer, suggesting it might be a potential predictor of late recurrence for this group of patients.
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Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , DNA Topoisomerases Tipo II/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , DNA Topoisomerases Tipo II/genética , Feminino , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Prognóstico , RecidivaRESUMO
PURPOSE: To explore the role of CD15 expression in the prognosis of clear cell renal cell carcinoma (ccRCC) in Chinese patients. METHODS: The study included 301 patients who had undergone surgery for localized ccRCC. All paraffin-embedded tumor sections were collected to make a set of tissue microarrays. CD15 expression was assessed by immunohistochemistry. The relationship between CD15 expression and survival parameters, clinicopathology features was assessed. Kaplan-Meier and Cox proportional hazards model were utilized to determine the correlation between CD15 expression and overall survival (OS). RESULTS: The median follow-up time was 54.6 months (range, 3-121 months). The positive rate of CD15 expression was 81.7% (246/301). The cut-off value of CD15 expression was defined as the maximum for Youden index by plotting the receiver operating characteristic curve for survival status. As the threshold was 0.5, all cases were divided into two groups: positive expression group and negative expression group. In correlation analysis, loss of CD15 expression was correlated with female gender, higher Fuhrman nuclear grade, with sarcomatoid differentiation, with necrosis, and with vascular invasion. Kaplan-Meier analysis indicated that the OS time of patients with loss of CD15 expression was shorter than that of patients with positive CD15 expression (P = 0.013). CONCLUSION: CD15 is a significant prognostic factor in clear cell renal cell carcinoma.
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Povo Asiático , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Antígenos CD15/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Criança , Pré-Escolar , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Adulto JovemRESUMO
BACKGROUND: Lauren-classification and human epidermal growth factor receptor 2 (HER2) status are two important pathological features of gastric cancer patients. The prognostic value of HER2 in gastric cancer remains controversial. Intestinal type gastric cancer has better prognosis and higher HER2 positive proportion. What is the interaction between these two factors? We hypothesized that a combination of Lauren-classification and human epidermal growth factor receptor 2 (HER2) status (L-H status) might be more meaningful than either factor alone. METHODS: We collected 838 gastric cancer patients at all stages who had received treatment in our cancer center. This study was registered in the website of ClinicalTrials.Gov, with the number NCT01927146. We divided the patients into six groups according to their L-H status: Group A, HER2 negative and intestinal type; Group B, HER2 positive and intestinal type; Group C, HER2 negative and diffuse type; Group D, HER2 positive and diffuse type; Group E, HER2 negative and mixed type; and Group F, HER2 positive and mixed type. RESULTS: Diffuse type and intestinal type accounted for 51.0% and 33.9%, respectively. The proportion of HER2 positive patients was 11.2%, 25.4%, 2.1% and 10.2% in the whole patient group, intestinal, diffuse and mixed type, respectively. Median overall survival was 34.0 months, 25.3 months, 27.6 months, 19.2 months, 25.9 months and 26.4 months in the six groups patients, P = 0.053. There was a significant difference in survival among the first four groups (P < 0.001). HER2 was an independent prognostic factor in the intestinal type and in stage I + II patients, but not in the diffuse type or stage III + IV patients. L-H status was an independent prognostic factor in patients at all stages. For the diffuse and intestinal types, the multivariate analysis showed that HER2 was not an independent prognostic factor, while Lauren classification and L-H status were. Moreover, L-H status was a better prognostic factor than the Lauren classification. CONCLUSIONS: L-H status is a prognostic factor in diffuse and intestinal type patients, but not in the mixed type. Patients with HER2 negative and intestinal type had the best survival, while patients with HER2 positive status and diffuse type had the worst survival.
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Adenocarcinoma/química , Adenocarcinoma/classificação , Receptor ErbB-2/análise , Neoplasias Gástricas/química , Neoplasias Gástricas/classificação , Adenocarcinoma/secundário , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Feminino , Gastrectomia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Adulto JovemRESUMO
Clear cell renal cell carcinoma (ccRCC) is a malignancy with a dismal prognosis, caused by the buildup of fat and glycogen. Sirtuin 1 (Sirt1) is a deacetylase that regulates lipid metabolism. In this study, we collected tumor and paracancer tissues from 386 ccRCC patients and followed their prognosis over an extended time period. The expression of Sirt1 in these tissues was assessed using immunohistochemistry, and LinkedOmics database analysis identified differentially expressed genes associated with Sirt1. The survival curve was generated using the Kaplan-Meier method, and immune infiltration was analyzed using the Tumor Immune Estimation Resource (TIMER) web tool. Our findings revealed that Sirt1 was expressed in tumor tissues, but not in normal tissues, and its high expression was associated with a worse prognosis. Furthermore, we observed a positive correlation between high Sirt1 expression and perirenal fat invasion and necrosis, leading to poorer survival outcomes. We established a nomogram to predict prognosis, and a correlation was observed with immune infiltration. In conclusion, our results suggest that high Sirt1 expression is associated with lipid metabolism disorder and immune infiltration, ultimately contributing to a dismal prognosis in ccRCC.
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Biomarcadores Tumorais , Carcinoma de Células Renais , Neoplasias Renais , Metabolismo dos Lipídeos , Sirtuína 1 , Humanos , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Metabolismo dos Lipídeos/genética , Neoplasias Renais/imunologia , Neoplasias Renais/mortalidade , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Renais/metabolismo , Masculino , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Feminino , Prognóstico , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão Gênica , Idoso , Estimativa de Kaplan-MeierRESUMO
To evaluate the protective effect of LIPUS at the early stage of brain trauma in rats, 45 rats were randomly divided into 3 groups: sham (n = 15), TBI (n = 15) and LIPUS treatment groups (n = 15). Ipsilateral and contralateral cortical and thalamic parameters obtained by diffusion tensor imaging (DTI) and fast low-angle shot magnetic resonance imaging (FLASH-MRI) were measured at different times after trauma. For fractional anisotropy (FA) and T2* values, two-way repeated measures ANOVA with Tukey's post hoc was used for intergroup comparisons. With observation time prolonged, the FA values of the ipsilateral cortex in the TBI group gradually increased and were significantly higher than those in the LIPUS treatment group on Day 7 (adjusted P = 0.0067). FA values in the contralateral cortex decreased at this time and were significantly lower than those in the LIPUS treatment group (adjusted P = 0.0192). Meanwhile, compared with LIPUS group, FA values were significantly higher in the injured thalamus (adjusted P = 0.0025). Combined with correlation analysis, FA values were positively correlated with neuronal damage (P = 0.0148, r2 = 0.895). At 7 days after trauma, T2* values in the ipsilateral cortex of the TBI group were significantly lower. After analysis of ferritin content and correlation, we found that T2* values were negatively correlated with ferritin (P = 0.0259, r2 = -0.849). By measuring post-traumatic changes in FA and T2* values, it is possible to demonstrate a neuronal protective effect of LIPUS in the early phase of TBI rats and promote brain rehabilitation.
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Lesões Encefálicas Traumáticas , Imagem de Tensor de Difusão , Animais , Lesões Encefálicas Traumáticas/terapia , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Ratos , Masculino , Ratos Sprague-Dawley , Anisotropia , Tálamo/diagnóstico por imagem , Tálamo/metabolismo , Tálamo/patologia , Imageamento por Ressonância Magnética , Modelos Animais de DoençasRESUMO
OBJECTIVE: The current study aimed to investigate the dynamic changes in brain glymphatic function during chemotherapy in breast cancer patients (BCP) and their correlation with cognitive function. MATERIALS AND METHODS: A total of 40 healthy female participants (control group) and 80 female BCP were included. Various cognitive assessment tools were used to evaluate cognitive function. Diffusion tensor imaging along the perivascular space was employed to measure brain glymphatic function. RESULTS: Following chemotherapy, BCP exhibited a significant decline in various cognitive scores. After chemotherapy, the along the perivascular space index, a parameter indicating brain glymphatic function, was slightly higher than that at baseline and the control group levels and was correlated with cognitive scores. CONCLUSION: This study unveiled a close relationship between the dynamic changes in brain glymphatic function after chemotherapy and cognitive function in BCP. Our findings contribute to a deeper understanding of the brain mechanisms underlying chemotherapy-related cognitive impairment and provide a theoretical basis for future interventions and treatments. In addition, they offer a new perspective for exploring the relationship between brain function and cognitive states.
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Encéfalo , Neoplasias da Mama , Imagem de Tensor de Difusão , Sistema Glinfático , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Neoplasias da Mama/patologia , Pessoa de Meia-Idade , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Estudos de Casos e Controles , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Comprometimento Cognitivo Relacionado à Quimioterapia , Cuidados Pré-Operatórios/métodosRESUMO
Autophagy is an evolutionarily conserved process that involves lysosomal degradations of cellular organelles. Microtubule-associated protein 1 light chain 3A (LC3A), an autophagic gene, is differentially expressed in human cancers. However, the relationship between LC3A expression and hepatocellular carcinoma (HCC) has not been investigated. Tissue microarray-based immunohistochemistry was used to examine the expression patterns of LC3A in HCC. The resulting data were analyzed using receiver operating characteristic curves, Spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression modeling. Two distinct patterns of LC3A expression were observed in HCC: "stone-like" structuring and diffuse cytoplasmic expression. High levels of LC3A expression were more frequently observed in HCC tissues compared to the adjacent non-tumorous tissue. Correlation analyses indicated that high expression of the "stone-like" LC3A was correlated with greater levels of serum AFP, poorer tumor differentiation and the presence of vascular invasion. Kaplan-Meier survival analysis showed a significant association between high expression of the "stone-like" LC3A and unfavorable prognosis (P<0.001). Importantly, multivariate analysis (P<0.05) identified the "stone-like" expression of LC3A in HCC as an independent prognostic factor. Collectively, our data provide compelling evidence that "stone-like" expression of LC3A plays an important role in HCC progression and may act as a biomarker of prognosis for patients with HCC.
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Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Proteínas Associadas aos Microtúbulos/metabolismo , Adulto , Carcinoma Hepatocelular/metabolismo , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise Serial de TecidosRESUMO
iASPP (inhibitory member of the ASPP family), the conserved key inhibitor of p53, is overexpressed and plays an important oncogenetic role in many human cancers. However, its function in cervical cancer remains unknown. The objective of this study was to investigate the expression and clinical relevance of iASPP in cervical cancer. The mRNA and protein expression levels of iASPP were determined by real-time quantitative reverse transcription with the polymerase chain reaction and Western blot. Paraffin sections of 149 patients with FIGO Ib1-IIa squamous cell cervical cancer were stained by using immunohistochemistry for iASPP, and its relationship with clinicopathologic parameters and prognosis of cervical cancer patients was analyzed. The mRNA and protein expression levels of iASPP were significantly elevated in cervical cancer tissues. The increased nuclear iASPP expression was correlated strongly with higher FIGO staging, deep cervical stromal invasion, pelvic lymph node metastasis, and poor overall and disease-free survival of patients with cervical cancer (all P<0.05). Multivariate Cox analysis showed that high nuclear iASPP expression was an independent prognostic factor for overall survival. Furthermore, patients with high nuclear iASPP expression were much more resistant to radiation or chemotherapy, resulting in poor overall and disease-free survival than those with low expression after receiving radiation or chemotherapy (all P<0.05) and indicating correlations with chemoresistance and radioresistance. This study thus demonstrates that iASPP is highly elevated in human cervical cancer, and that overexpression of nuclear iASPP is correlated with poor prognosis and chemoresistance/radioresistance, suggesting that iASPP might serve as a novel potential prognostic marker and therapeutic target for cervical cancer.
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Biomarcadores Tumorais/biossíntese , Carcinoma de Células Escamosas/genética , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Proteínas Repressoras/biossíntese , Neoplasias do Colo do Útero/genética , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Neoplasias do Colo do Útero/patologiaRESUMO
Interleukin (IL)-17 is the signature cytokine of T helper 17 cells. The role of IL-17 in the tumor microenvironment is still controversial. Few studies describing IL-17 expression in ovarian cancer have been reported. We have therefore analyzed the in situ tumor expression of IL-17 in advanced ovarian cancer and the possible correlation of IL-17 expression with tumor-associated macrophages (TAMs) and with survival in advanced ovarian cancer. Clinical data of 104 patients with stage III-IV epithelial ovarian cancer at the Sun Yat-sen University Cancer Center between 2000 and 2008 were retrospectively reviewed. Immunohistochemical staining of IL-17 and CD163 (marker for TAMs) was performed. Our data showed that levels of IL-17 were significantly increased in ovarian cancer compared with normal ovarian tissues (P<0.001). The high IL-17 expression group included more patients with grade 1 tumors than the low IL-17 expression group (P=0.042). High IL-17 expression correlated with improved progression-free survival (PFS) in advanced ovarian cancer (P<0.001). However, no significant difference was observed in overall survival between the high and low IL-17 expression groups. Multivariate analysis revealed that the density of IL-17-producing cells was a positive prognostic factor for PFS (P=0.001). Moreover, a positive correlation between the density of IL-17-producing cells and TAMs was identified (r=0.354, P<0.001). Our results indicate that the infiltration of IL-17-producing cells might contribute to improved PFS in advanced ovarian cancer. Our findings provide a new insight into the complex role of IL-17 in the tumor microenvironment of ovarian cancer.
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Interleucina-17/biossíntese , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Feminino , Humanos , Interleucina-17/metabolismo , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Prognóstico , Estudos Retrospectivos , Microambiente TumoralRESUMO
BACKGROUND: Bone is one of the most frequent sites for breast cancer metastasis. Breast cancer bone metastasis (BCBM) leads to skeletal morbidities including pain, fractures, and spinal compression, all of which severely impact quality of life. Immunotherapy is a promising therapy for patients with advanced cancer, but whether it may provide benefit to metastatic bone cancer is currently unknown. Thus, a better understanding of the immune landscape of bone-disseminated breast cancers may reveal new therapeutic strategies. In this study, we use histopathological analysis to investigate changes within the immune microenvironment of primary breast cancer and paired BCBM. METHODS: Sixty-three patients with BCBM, including 31 with paired primary and bone metastatic lesions, were included in our study. The percentage of stroma and stromal tumor-infiltrating lymphocytes (TILs) was evaluated by histopathological analysis. The quantification of stromal TILs (CD4 + and CD8 +), macrophages (CD68 + and HLA-DR +), programmed cell death protein 1 (PD-1), and programmed cell death protein ligand 1 (PD-L1) was evaluated through immunohistochemical (IHC) staining. Statistical analysis was performed with paired t test, Wilcoxon test, spearman correlation test, and univariate and multivariate cox regression. RESULTS: Median survival after BCBM pathological diagnosis was 20.5 months (range: 3-95 months). Of the immune parameters measured, none correlated with survival after bone metastasis was diagnosed. Compared to the primary site, bone metastases exhibited more tumor stroma (mean: 58.5% vs 28.87%, p < 0.001) and less TILs (mean: 8.45% vs 14.03%, p = 0.042), as determined by H&E analysis. The quantification of primary vs metastatic tissue area with CD4 + (23.95/mm2 vs 51.69/mm2, p = 0.027 and with CD8 + (18.15/mm2 vs 58.95/mm2, p = 0.004) TILs similarly followed this trend and was reduced in number for bone metastases. The number of CD68 + and HLA-DR + macrophages showed no significant difference between primary sites and bone metastases. PD-1 expression was present in 68.25% of the bone metastasis, while PD-L1 expression was only present in 7.94% of the bone metastasis. CONCLUSIONS: Our findings suggest that compared to the primary breast cancer site, bone metastases harbor a less active immune microenvironment. Despite this relatively dampened immune landscape, expression of PD-1 and PD-L1 in the bone metastasis indicates a potential benefit from immune checkpoint inhibitors for some BCBM cases.
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Neoplasias Ósseas , Neoplasias da Mama , Microambiente Tumoral , Feminino , Humanos , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Qualidade de Vida , Microambiente Tumoral/imunologia , Neoplasias Ósseas/secundárioRESUMO
Purpose: In order to evaluate the neuroprotective effect of low-intensity pulsed ultrasound (LIPUS) for acute traumatic brain injury (TBI), we studied the potential of apparent diffusion coefficient (ADC) values and ADC-derived first-order features regarding this problem. Methods: Forty-five male Sprague Dawley rats (sham group: 15, TBI group: 15, LIPUS treated: 15) were enrolled and underwent magnetic resonance imaging. Scanning layers were acquired using a multi-shot readout segmentation of long variable echo trains (RESOLVE) to decrease distortion. The ultrasound transducer was applied to the designated region in the injured cortical areas using a conical collimator and was filled with an ultrasound coupling gel. Regions of interest were manually delineated in the center of the damaged cortex on the diffusion weighted images (b = 800 s/mm2) layer by layer for the TBI and LIPUS treated groups using the open-source software ITK-SNAP. Before analysis and modeling, the features were normalized using a z-score method, and a logistic regression model with a backward filtering method was employed to perform the modeling. The entire process was completed using the R language. Results: During the observation time, the ADC values ipsilateral to the trauma in the TBI and LIPUS groups increased rapidly up to 24 h. After statistical analysis, the 10th percentile, 90th percentile, mean, skewness, and uniformity demonstrated a significant difference among three groups. The receiver operating characteristic curve (ROC) analysis shows that the combined LR model exhibited the highest area under the curve value (AUC: 0.96). Conclusion: The combined LR model of first-order features based on the ADC map can acquire a higher diagnostic performance than each feature only in evaluating the neuroprotective effect of LIPUS for TBI. Models based on first-order features may have potential value in predicting the therapeutic effect of LIPUS in clinical practice in the future.
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Metastasis is the leading cause of death of patients with esophageal squamous cell carcinoma (ESCC). Although an increasing number of studies have demonstrated the involvement of G3BP2 in several human cancers, how G3BP2 interacts with long noncoding RNAs and regulates mRNA transcripts in mediating ESCC metastasis remains unclear. In this study, we uncovered that G3BP2 was upregulated in ESCC. Further analysis revealed that upregulation of G3BP2 was significantly correlated with lymph node metastasis, depth of tumor invasion and unfavorable outcomes in ESCC patients. Both in vitro and in vivo functional assays demonstrated that G3BP2 dramatically enhanced ESCC cell migration and invasion. Mechanistically, LINC01554 maintained the high G3BP2 expression in ESCC by protecting G3BP2 from degradation through ubiquitination and the interaction domains within LINC01554 and G3BP2 were identified. In addition, RNA-seq revealed that HDGF was regulated by G3BP2. G3BP2 bound to HDGF mRNA transcript to stabilize its expression. Ectopic expression of HDGF effectively abolished the G3BP2 depletion-mediated inhibitory effect on tumor cell migration. Intriguingly, introduction of compound C108 which can inhibit G3BP2 remarkedly suppressed ESCC cell metastasis in vitro and in vivo. Collectively, this study describes a newly discovered regulatory axis, LINC01554/G3BP2/HDGF, that facilitates ESCC metastasis and will provide novel therapeutic strategies for ESCC.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma de Células Escamosas do Esôfago/genética , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Humanos , Camundongos , Camundongos Nus , Transfecção , Regulação para CimaRESUMO
The smooth transportation of substances through the brain extracellular space (ECS) is crucial to maintaining brain function; however, the way this occurs under simulated microgravity remains unclear. In this study, tracer-based magnetic resonance imaging (MRI) and DECS-mapping techniques were used to image the drainage of brain interstitial fluid (ISF) from the ECS of the hippocampus in a tail-suspended hindlimb-unloading rat model at day 3 (HU-3) and 7 (HU-7). The results indicated that drainage of the ISF was accelerated in the HU-3 group but slowed markedly in the HU-7 group. The tortuosity of the ECS decreased in the HU-3 group but increased in the HU-7 group, while the volume fraction of the ECS increased in both groups. The diffusion rate within the ECS increased in the HU-3 group and decreased in the HU-7 group. The alterations to ISF drainage and diffusion in the ECS were recoverable in the HU-3 group, but neither parameter was restored in the HU-7 group. Our findings suggest that early changes to the hippocampal ECS and ISF drainage under simulated microgravity can be detected by tracer-based MRI, providing a new perspective for studying microgravity-induced nano-scale structure abnormities and developing neuroprotective approaches involving the brain ECS.
Assuntos
Espaço Extracelular/diagnóstico por imagem , Hipocampo/patologia , Imageamento por Ressonância Magnética/métodos , Simulação de Ausência de Peso , Animais , Líquido Extracelular , Hipocampo/diagnóstico por imagem , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: It has been suggested that p300 participates in the regulation of a wide range of cell biological processes and mutation of p300 has been identified in certain types of human cancers. However, the expression dynamics of p300 in hepatocellular carcinoma (HCC) and its clinical/prognostic significance are unclear. METHODS: In this study, the methods of reverse transcription-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry (IHC) were utilized to investigate protein/mRNA expression of p300 in HCCs. Receiver operating characteristic (ROC) curve analysis, spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. RESULTS: Up-regulated expression of p300 mRNA and protein was observed in the majority of HCCs by RT-PCR and Western blotting, when compared with their adjacent non-malignant liver tissues. According to the ROC curves, the cutoff score for p300 high expression was defined when more than 60% of the tumor cells were positively stained. High expression of p300 was examined in 60/123 (48.8%) of HCCs and in 8/123 (6.5%) of adjacent non-malignant liver tissues. High expression of p300 was correlated with higher AFP level, larger tumor size, multiplicity, poorer differentiation and later stage (P < 0.05). In univariate survival analysis, a significant association between overexpression of p300 and shortened patients' survival was found (P = 0.001). In different subsets of HCC patients, p300 expression was also a prognostic indicator in patients with stage II (P = 0.007) and stage III (P = 0.011). Importantly, p300 expression was evaluated as an independent prognostic factor in multivariate analysis (P = 0.021). Consequently, a new clinicopathologic prognostic model with three poor prognostic factors (p300 expression, AFP level and vascular invasion) was constructed. The model could significantly stratify risk (low, intermediate and high) for overall survival (P < 0.0001). CONCLUSIONS: Our findings provide a basis for the concept that high expression of p300 in HCC may be important in the acquisition of an aggressive phenotype, suggesting that p300 overexpression, as examined by IHC, is an independent biomarker for poor prognosis of patients with HCC. The combined clinicopathologic prognostic model may become a useful tool for identifying HCC patients with different clinical outcomes.
Assuntos
Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Proteína p300 Associada a E1A/genética , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Transativadores/genética , Regulação para Cima/genéticaRESUMO
Chemoresistance is one of the leading causes for the failure of tumor treatment. Hence, it is necessary to study further and understand the potential mechanisms of tumor resistance to design and develop novel anti-tumor drugs. Post-translational modifications are critical for proteins' function under physiological and pathological conditions, among which ubiquitination is the most common one. The protein degradation process mediated by the ubiquitin-proteasome system is the most well-known function of ubiquitination modification. However, ubiquitination also participates in the regulation of many other biological processes, such as protein trafficking and protein-protein interaction. A group of proteins named deubiquitinases can hydrolyze the isopeptide bond and disassemble the ubiquitin-protein conjugates, thus preventing substrate proteins form degradation or other outcomes. Ubiquitin-specific protease 7 (USP7) is one of the most extensively studied deubiquitinases. USP7 exhibits a high expression signature in various malignant tumors, and increased USP7 expression often indicates the poor tumor prognosis, suggesting that USP7 is a marker of tumor prognosis and a potential drug target for anti-tumor therapy. In this review, we first discussed the structure and function of USP7. Further, we summarized the underlying mechanisms by which tumor cells develop resistance to anti-tumor therapies, provided theoretical support for targeting USP7 to overcome drug resistance, and some inspiration for the design and development of USP7 inhibitors.
RESUMO
Lapping is one of the standard essential methods to realise the global planarization of SiC and other semiconductor substrates. It is necessary to deeply study the mechanism to obtain SiC lapping process parameters with a strong comprehensive lapping performance (i.e., high material removal rate (MRRm), small surface roughness (Ra), and low total thickness variation (TTV)). The effects of the lapping process parameters and their interactions on lapping performance for SiC were investigated using orthogonal experiments; the effects on the MRRm, Ra, TTV, and optimal parameters under the conditions of a single evaluation index were investigated using intuitive analysis (range analysis, variance analysis, and effect curve analysis). The entropy value method and grey relational analysis were used to transform the multi-evaluation-index optimisation into a single-index optimisation about the grey relational grade (GRG) and to comprehensively evaluate the lapping performance of each process parameter. The results showed that the lapping plate types, abrasive size, and their interaction effect had the most significant effects on MRRm and Ra, with a contribution of over 85%. The interaction between the lapping plate types and abrasive size was also found to have the most significant effect on TTV, with a contribution of up to 51.07%. As the lapping plate's hardness and abrasive size increased, the MRRm and Ra also gradually increased. As the lapping normal-pressure increased, MRRm increased, Ra gradually decreased, and TTV first decreased and then increased. MRRm, Ra, and TTV first increased and then decreased with increasing abrasive concentration. Compared to the optimisation results obtained by intuitive analysis, the process parameter optimised by the grey relational analysis resulted in a smooth surface with an MRRm of 90.2 µm/h, an Ra of 0.769 nm, and a TTV of 3 µm, with a significant improvement in the comprehensive lapping performance. This study reveals that a combination of orthogonal experiments and grey relational analysis can provide new ideas for optimising the process parameters of SiC.