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1.
Surg Oncol ; 29: 90-96, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31196500

RESUMO

INTRODUCTION: The aim of this study was to analyze the prognosis of gastric cancer patients categorized as pT4aN0M0, pT1N3aM0/pT2N2M0/pT3N1M0 of stage IIB and stage IIIA and to compare the optimistic prognostic stratification between the AJCC 8th edition staging system and the AJCC modified 8th (m8th) edition staging system by incorporating pT4aN0M0 into stage IIIA. MATERIAL AND METHODS: A total of 1770 patients who underwent gastrectomy were enrolled in this study. The homogeneity, the discriminatory ability, the monotonicity of the gradient assessments, and the discriminatory ability of the AJCC 8th and m8th edition staging systems were compared by using the likelihood ratio χ2 test, a linear trend χ2 test, the Akaike information criteria (AIC) and Bayesian information criterion (BIC) calculations, respectively. RESULTS: For patients staged IIB, the 5-year survival rate of the patients categorized as pT4aN0M0 were significantly worse than that of the patients categorized as pT1N3aM0/pT2N2M0/pT3N1M0 (59.9% vs. 72.4%, P = 0.036). By contrast, the prognoses of the patients between the pT4aN0M0 category and those staged IIIA were analogous (59.9% vs. 61.5%, P = 0.693). Compared with the 8th edition system, the modified 8th edition staging system had a better homogeneity (higher likelihood ratio χ [2] score, 441.17 vs. 436.24), discriminatory ability, monotonicity of gradients (higher linear trend χ2 score, 436.78 vs. 416.15) and smaller AIC (10364.98 vs. 10369.91) and BIC values (10447.13 vs. 10452.06). CONCLUSIONS: The prognosis of pT4aN0M0 was poorer than those of pT1N3aM0, pT2N2M0, and pT3N1M0, which were staged IIB. There is a better prognostic stratification for the AJCC 8th edition staging system of gastric cancer by incorporating pT4aN0M0 into stage IIIA.

2.
Dig Liver Dis ; 51(10): 1430-1437, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31054962

RESUMO

BACKGROUND AND AIMS: The liver function reserve in Child-Pugh (C-P) grade A hepatocellular carcinoma (HCC) patients varies widely, and the value of platelet-albumin-bilirubin (PALBI) grade in predicting posthepatectomy liver failure (PHLF) grade B/C and overall survival (OS) remains unknown. METHODS: From Dec 2004 to Dec 2013, 2038 C-P grade A HCC patients after resection were enrolled. Univariate and multivariate analyses were performed to clarify the risk factors for PHLF grade B/C and OS. RESULTS: The PALBI grade had higher area under the curve values than albumin-bilirubin (ALBI) and C-P grade in predicting PHLF grade B/C (0.693, 0.683, 0.529 in the entire cohort; 0.677, 0.646, 0.516 in patients who underwent major resection). PALBI grade differentiated C-P grade A patients into three groups with distinct prognoses (P < 0.001), whereas ALBI grade differentiated C-P grade A patients into two groups (P < 0.001). Furthermore, PALBI grade identified three groups with clearly different prognoses in ALBI grade 1 patients (P = 0.032). Multivariate analyses showed that PALBI grade was one of the independent and significant prognostic factors of PHLF grade B/C and OS. CONCLUSIONS: PALBI grade offers a simple, objective and discriminatory method for risk stratification of PHLF grade B/C and OS in C-P grade A HCC patients following resection.

3.
Cell Death Dis ; 10(5): 369, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068575

RESUMO

In our previous report, we identified miR-34c-3p as an independent factor contributing to the carcinogenesis of hepatocellular carcinoma (HCC) by targeting NCK Associated Protein 1 (NCKAP1). NCKAP1 has been known to promote the malignancy of cancer cells by disrupting the structural stability of WAS protein family member 1 (WASF1) and is correlated with poor prognosis of patients in several cancer types. Our results, however, show that NCKAP1 is correlated with a favorable outcome in HCC patients. The underlying mechanism of this contradictory phenomenon is unknown. The current study was designed to explore the mechanism of NCKAP1 in HCC. As a result, clinicopathological correlations and results from in vivo and in vitro models indicated that NCKAP1 was a tumor suppressor gene. Cell cycle analysis suggested that NCKAP1 inhibit cells from entering G2/M phase. Western blot analysis showed that WASF1 was barely expressed in HCC cell lines compared to that of breast cancer cell lines, which serve as positive controls. Furthermore, Rb1 and p53 expression was upregulated in cell lines overexpressing NCKAP1. Expression of several cell cycle regulating proteins also varied in the HCC cell lines. In conclusion, although previous studies have identified NCKAP1 as a cell invasion promoter by binding to WASF1, we found that NCKAP1 is a tumor suppress gene that modulates the cell cycle of HCC cell lines by targeting Rb1/p53 regulation.

4.
Ann Surg ; 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31058700

RESUMO

OBJECTIVE: This study was intended to identify prognostic biomarkers for lymph node (LN)-positive locoregional esophageal squamous cell carcinoma (ESCC) patients. SUMMARY OF BACKGROUND DATA: Surgery is a major treatment for LN-positive locoregional ESCC patients in China. However, patient outcomes are poor and heterogeneous. METHODS: ESCC-associated miRNAs were identified by microarray and validated by quantitative real-time polymerase chain reaction analyses in ESCC and normal esophageal epithelial samples. A multi-miRNA based classifier was established using a least absolute shrinkage and selection operator model in a training set of 145 LN-positive locoregional ESCCs, and further assessed in internal testing and independent validation sets of 145 and 243 patients, respectively. RESULTS: Twenty ESCC-associated miRNAs were identified and validated. A 4-miRNA based classifier (miR-135b-5p, miR-139-5p, miR-29c-5p, and miR-338-3p) was generated to classify LN-positive locoregional ESCC patients into high and low-risk groups. Patients with high-risk scores in the training set had a lower 5-year overall survival rate [8.7%, 95% confidence interval (CI): 0-20.3] than those with low-risk scores (50.3%, 95% CI: 40.0-60.7; P < 0.0001). The prognostic accuracy of the classifier was validated in the internal testing (P < 0.0001) and independent validation sets (P = 0.00073). Multivariate survival analyses showed that the 4-miRNA based classifier was an independent prognostic factor, and the combination of the 4-miRNA based classifier and clinicopathological prognostic factors significantly improved the prognostic accuracy of clinicopathological prognostic factors alone. CONCLUSION: Our 4-miRNA based classifier is a reliable prognostic prediction tool for overall survival in LN-positive locoregional ESCC patients and might offer a novel probability of ESCC treatment individualization.

5.
J Biol Chem ; 294(25): 9734-9745, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31073033

RESUMO

Early diagnosis of nasopharyngeal carcinoma (NPC) is difficult because of a lack of specific symptoms. Many patients have advanced disease at diagnosis, and these patients respond poorly to treatment. New treatments are therefore needed to improve the outcome of NPC. To better understand the molecular pathogenesis of NPC, here we used an NPC cell line in a genome-wide CRISPR-based knockout screen to identify the cellular factors and pathways essential for NPC (i.e. dependence factors). This screen identified the Moz, Ybf2/Sas3, Sas2, Tip60 histone acetyl transferase complex, NF-κB signaling, purine synthesis, and linear ubiquitination pathways; and MDM2 proto-oncogene as NPC dependence factors/pathways. Using gene knock out, complementary DNA rescue, and inhibitor assays, we found that perturbation of these pathways greatly reduces the growth of NPC cell lines but does not affect growth of SV40-immortalized normal nasopharyngeal epithelial cells. These results suggest that targeting these pathways/proteins may hold promise for achieving better treatment of patients with NPC.

6.
J Zhejiang Univ Sci B ; 20(1): 105-108, 2019 Jan..
Artigo em Inglês | MEDLINE | ID: mdl-30614234

RESUMO

Lynch syndrome (LS), an autosomal dominantly inherited disease previously known as hereditary non-polyposis colorectal cancer (HNPCC), leads to a high risk of colorectal cancer (CRC) as well as malignancy at certain sites including endometrium, ovary, stomach, and small bowel (Hampel et al., 2008; Lynch et al., 2009). Clinically, LS is considered the most common hereditary CRC-predisposing syndrome, accounting for about 3% of all CRC cases (Popat et al., 2005). LS is associated with mutations of DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, PMS2, and EPCAM (Ligtenberg et al., 2009; Lynch et al., 2009), which can trigger a high frequency of replication errors in both microsatellite regions and repetitive sequences in the coding regions of various cancer-related genes. Immunohistochemistry (IHC) tests followed by genetic analysis of these mutations play a significant role in diagnosis, treatment determination, and therapeutic response prediction of LS (Lynch et al., 2009; Alex et al., 2017; Ryan et al., 2017). Here, we report substitution of one base-pair in exon 1 of MLH3 (c.1397C>A) and a frameshift mutation in exon 19 of MLH1 (c.2250_2251ins AA) in a 43-year-old Chinese male with an LS pedigree.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Mutação da Fase de Leitura , Proteína 1 Homóloga a MutL/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , China , Éxons , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Proteínas MutL/genética , Linhagem
7.
Shock ; 52(5): e107-e116, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30562238

RESUMO

Fluid resuscitation is the first-line antishock treatment in severe acute pancreatitis (SAP). Currently, although mentions of complications related to aggressive fluid resuscitation are very frequent, a lack of proper handling of complications remains. One of the most important complications is intestinal barrier injury, including intestinal ischemia-reperfusion injury following aggressive fluid resuscitation. Once injured, the intestinal barrier may serve as the source of additional diseases, including systemic inflammatory response syndrome and multiple organ dysfunction syndrome, which aggravate SAP. This study focused on the underlying mechanisms of gut barrier dysfunction in rats induced by aggressive fluid resuscitation in SAP. This study further indicated the important role of necroptosis in intestinal barrier injury which could be relieved by using necroptosis-specific inhibitor Nec-1 before aggressive fluid resuscitation, thus reducing intestinal barrier damage. We also found pancreas damage after intestinal ischemia/reperfusion challenge and indicated the effects of high mobility group protein B1 in the vicious cycle between SAP and intestinal barrier damage.

8.
Cancer Manag Res ; 10: 5451-5460, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30519093

RESUMO

Background: Histone deacetylase 6 (HDAC6) exerts enzymatic deacetylation activity on histones and on non-histone substrates and plays a key role in microtubule dynamics and chaperone activities. In addition, previous studies have demonstrated its role in cancer progression. However, its clinical significance in esophageal squamous cell cancer (ESCC) has not been elucidated. We investigated the correlation of HDAC6 expression and clinical outcome in a group of T3N1-3M0 surgically resected ESCCs. Methods: Tissue microarrays were conducted on 209 surgically resected T3N1-3M0 ESCC tumors, including 163 pairs of primary tumors (PTs) and their corresponding metastatic lymph nodes (MLNs). Immunohistochemistry was utilized to evaluate HDAC6 protein levels. The relationship between patient outcomes and HDAC6 expression was analyzed statistically. Results: The level of HDAC6 expression in ESCC MLNs was found to be significantly lower than that in PTs (P<0.001). Patients with lower MLN HDAC6 expression demonstrated improved overall survival (P=0.011) and disease-free survival (P=0.012) than those with higher HDAC6 expression. HDAC6 expression levels in PTs revealed no prognostic significance. Multivariate analysis showed that the MLN HDAC6 expression level was an independent prognostic factor for both overall survival (HR 1.456, P=0.029) and disease-free survival (HR 1.432, P=0.033). Conclusion: High expression of HDAC6 in MLNs but not in PTs suggests a poor prognosis for patients with resected T3N1-3M0 ESCC. We should take into account the protein expression of MLNs when assessing prognosis in patients with lymph-node involvement.

9.
Int J Cancer ; 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30521064

RESUMO

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety-three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population. This article is protected by copyright. All rights reserved.

10.
EBioMedicine ; 37: 110-124, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30361064

RESUMO

BACKGROUND: Dysregulation of the cell cycle has been implicated in esophageal squamous cell carcinoma (ESCC) progression. This study aimed to evaluate the role of miR-424 in cell cycle regulation and ESCC proliferation. METHODS: The role of miR-424 in cell proliferation was evaluated in vitro and in vivo. Transcriptional activation of miR-424 was determined using chromatin immunoprecipitation, and binding of miR-424 to targets was verified using miRNA ribonucleoprotein complex immunoprecipitation. FINDINGS: miR-424 was upregulated and correlated with poor survival in ESCC patients. Repression or overexpression of miR-424 respectively decreased or increased ESCC cell proliferation in vitro and in vivo. miR-424 expression is transcriptionally regulated by E2F1 and increased during G1/S transition. Knockdown or overexpression of miR-424 respectively inhibited or promoted both G1/S and G2/M cell cycle transitions in ESCC cells, and these effects were mediated by two newly identified miR-424 targets, PRKCD and WEE1, respectively. Consequently, elevation of PRKCD by miR-424 knockdown led to enhanced stability of the p21Cip1 protein via increased activation of PRKCD and downstream p38 MAPK and JNK signaling to block CDK2 activation and G1/S transition, while elevated WEE1 maintained CDC2 in an inactive state to block G2/M transition. However, circLARP4 could sponge the binding of miR-424 to PRKCD, thus compromising the regulation of G1/S progression by miR-424. INTERPRETATION: miR-424 coordinates a previously unknown, multilayered regulation of ESCC cell cycle progression to promote ESCC proliferation, and may be used as a novel prognostic marker and an effective therapeutic target for ESCCs. FUND: National Natural Science Foundation of China.

11.
Cancer Manag Res ; 10: 4509-4515, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30349383

RESUMO

Introduction: We aimed to evaluate the clinicopathologic characteristics and clinical outcomes of the mixed type versus the pure type of tubular carcinoma (TC) of the breast in a retrospective cohort study. Materials and methods: Patients were categorized into the following three groups: patients with pure TC of the breast (the PTC group), patients with TC and carcinoma in situ of the breast (the TC-CIS group), and patients with TC and other invasive carcinomas of the breast (the TC-IC group). We compared the clinicopathologic characteristics and treatment outcomes of the three groups. The primary end point of this study was breast cancer-specific survival (BCSS). Secondary end points included distant metastasis-free survival (DMFS) and locoregional recurrence (LRR). Results: A total of 68 patients were included in this study, including 31 patients in the PTC group, 12 in the TC-CIS group, and 25 in the TC-IC group. Our data showed that PTC and TC-CIS were more likely to be smaller in size (P=0.014) and had substantially less nodal involvement (P=0.019), compared with TC-IC. The median follow-up time was 64.3 months (range, 3.78-223.2 months) for all patients. No locoregional relapse was observed in any group during the follow-up period. The 10-year BCSS of the PTC, TC-CIS, and TC-IC groups was 100%, 100%, and 95.2%, respectively, and the 10-year DMFS was 92.3%, 100%, and 96.0%, respectively. There was no significant difference in terms of BCSS (P=0.53) or DMFS (P=0.84) between the three groups. Conclusion: This study indicates that both the pure type and mixed type of TC of the breast show very low LRR and distant metastasis rate and have excellent survival. The TC-IC group is likely to show good prognosis similar to the PTC group. Further clinical trials with larger sample sizes as well as molecular and genetic studies are warranted.

12.
Cancer Commun (Lond) ; 38(1): 61, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305149

RESUMO

BACKGROUND: The optimal strategy for adjuvant therapy after curative resection for hepatocellular carcinoma (HCC) patients with solitary tumor and microvascular invasion (MVI) is controversial. This trial evaluated the efficacy and safety of adjuvant transcatheter arterial chemoembolization (TACE) after hepatectomy versus hepatectomy alone in HCC patients with a solitary tumor ≥ 5 cm and MVI. METHODS: In this randomized, open-labeled, phase III trial, HCC patients with a solitary tumor ≥ 5 cm and MVI were randomly assigned (1:1) to receive either 1-2 cycles of adjuvant TACE after hepatectomy (Hepatectomy-TACE) or hepatectomy alone (Hepatectomy Alone). The primary endpoint was disease-free survival (DFS); the secondary endpoints included overall survival (OS) and adverse events. RESULTS: Between June 1, 2009, and December 31, 2012, 250 patients were enrolled and randomly assigned to the Hepatectomy-TACE group (n = 125) or the Hepatectomy Alone group (n = 125). Clinicopathological characteristics were balanced between the two groups. The median follow-up time from randomization was 37.5 months [interquartile range 18.3-48.2 months]. The median DFS was significantly longer in the Hepatectomy-TACE group than in the Hepatectomy Alone group [17.45 months (95% confidence interval [CI] 11.99-29.14) vs. 9.27 months (95% CI 6.05-13.70), hazard ratio [HR] = 0.70 (95% CI 0.52-0.95), P = 0.020], respectively. The median OS was also significantly longer in the Hepatectomy-TACE group than in the Hepatectomy Alone group [44.29 months (95% CI 25.99-62.58) vs. 22.37 months (95% CI 10.84-33.91), HR = 0.68 (95% CI 0.48-0.97), P = 0.029]. Treatment-related adverse events were more frequently observed in the Hepatectomy-TACE group, although these were generally mild and manageable. The most common grade 3 or 4 adverse events in both groups were neutropenia and liver dysfunction. CONCLUSION: Hepatectomy followed by adjuvant TACE is an appropriate option after radical resection in HCC patients with solitary tumor ≥ 5 cm and MVI, with acceptable toxicity.

13.
J Cancer ; 9(14): 2415-2427, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30026838

RESUMO

Introduction: EGF, latrophilin, and seven transmembrane domain containing 1 (ELTD1) constitutes an orphan G-protein-coupled receptor (GPCR) of the adhesion family. High expression of ELTD1 is correlated with favorable prognosis of hepatocellular carcinoma (HCC). After silencing ELTD1 expression, however, tumor invasiveness is drastically reduced. The underlying mechanism of this apparent contradictory phenomenon is unknown. Because adhesion GPCRs couple extracellular adhesion to intracellular signaling, as a member of this family, ELTD1 function may be related to its tumor microenvironment. We therefore investigated the interaction between ELTD1 and the HCC tumor microenvironment. Methods: ELTD1 expression was assessed by immunohistochemical analyses of tissue samples from two independent groups of 333 patients with HCC. Correlations between the ELTD1 expression and the clinicopathological values were examined. We also constructed ELTD1 overexpression and knockdown HCC cell lines and conducted a series of in vivo and in vitro ELTD1 functional assays. We further collected carcinoma associated fibroblast (CAF) culture supernatants to culture HCC cell lines and repeat the respective functional assays in comparison with the control group. Results: Clinicopathologic correlations and in vivo models indicated ELTD1 as a tumor suppressor gene, whereas in vitro experiments suggested that ELTD1 could promote malignancy in HCC cell lines. Immunohistochemical staining of the generated ELTD1 overexpression xenograft tumors demonstrated that the CAF markers vimentin and α-SMA were highly expressed compared to the control group. This suggests that ELTD1 expression is correlated to CAF distribution. In addition, culturing with CAF supernatants inhibited HCC cell proliferation and invasion rates, confirming the correlation between CAF and ELTD1. Conclusion: The results of this study indicated that ELTD1 regulation of HCC progression is CAF-dependent, suggesting that ELTD1 function is regulated by its tumor microenvironment. Further investigation is required to determine the underlying mechanisms.

14.
J Surg Res ; 225: 108-117, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29605020

RESUMO

BACKGROUND: Intestinal dysfunction, especially acute pathologies linked to intestinal ischemia/reperfusion (I/R) injury, is profoundly affected by inflammation and improper execution of cell death. Few studies have examined the efficacy of combined strategies in regulated intestinal epithelial necrosis after intestinal I/R. Here, we evaluated the functional interaction between poly (adenosine diphosphate-ribose) polymerase 1 (PARP-1)-induced parthanatos and receptor-interacting protein 1/3 (RIP1/3) kinase-induced necroptosis in the pathophysiological course of acute ischemic intestinal injury. METHODS: Anesthetized adult male Sprague-Dawley rats were subjected to superior mesenteric artery occlusion consisting of 1.5 h of ischemia and 6 h of reperfusion. The PARP-1-specific inhibitor PJ34 (10 mg/kg) and the RIP1-specific inhibitor Necrostatin-1 (1 mg/kg) were intraperitoneally administered 30 min before the induction of ischemia. RESULTS: Intestinal I/R was found to result in PARP-1 activation and RIP1/3-mediated necrosome formation. PJ34 or Necrostatin-1 treatment significantly improved the mucosal injury, while the combined inhibition of PARP-1 and RIP1/3 conferred optimal protection of the intestine. Meanwhile, results from terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay showed a decrease in intestinal epithelial cell death. Interestingly, we further showed that PARP-1 might act as a downstream signaling molecule of RIP1 in the process of I/R-induced intestinal injury and that the RIP1/PARP-1-dependent cell death signaling pathway functioned independently of caspase 3 inhibition. CONCLUSIONS: The results of our study provide a molecular basis for combination therapy that targets both pathways of regulated necrosis (parthanatos and necroptosis), to treat acute intestinal I/R-induced intestinal epithelial barrier disruption.

15.
EBioMedicine ; 28: 62-69, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29396302

RESUMO

SATB2 (Special AT-rich sequence-binding protein 2) has recently been shown to be a specific biomarker of colorectal cancer (CRC). The aim of this study was to investigate the diagnostic potential of SATB2 as a means of detecting a CRC origin for liver metastases. SATB2 expression was examined in a resection cohort of 101 CRC and 273 non-CRC adenocarcinoma samples using immunohistochemistry (IHC). The diagnostic accuracy of CRC origins of liver metastases based on SATB2 and a three marker panel of SATB2, CK20 and CDX2 was evaluated using an independent cohort of 192 liver biopsies. IHC showed 97 of the 101 (96.0%) primary CRC samples were SATB2 positive, compared to only 6 of the 273 (2.1%) samples of other cancer types. The sensitivity, specificity and AUC values of SATB2 expression in resection samples were 97%, 97.1% and 0.977, respectively. Meanwhile, for the liver biopsy samples, the sensitivity, specificity and AUC values of a CRC liver metastases was 92.2%, 97.8% and 0.948 for SATB2, 95.1%, 91.0% and 0.959 for CK20, and 100%, 85.4% and 0.976 for CDX2, respectively. Further analysis demonstrated that all three-marker positivity was detected in 92/103 (89.3%) CRC and 2/89 (2.2%) non-CRC liver metastases sampled by biopsy. Our findings suggest that SATB2, as measured by IHC, could serve as a promising diagnostic biomarker of CRC metastases. Combining evaluation of SATB2 with CK20 and CDX2 to form a three marker panel further improved the detection of metastatic CRCs in liver biopsy tissues.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha Fina , Feminino , Humanos , Imuno-Histoquímica , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Curva ROC
16.
J Natl Cancer Inst ; 110(9): 975-984, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29471527

RESUMO

Background: Previous studies demonstrated that prognosis of germline deficiency in mismatch repair protein (dMMR) was different from that of sporadic dMMR. The underlying mechanism has not been studied. Methods: From a prospectively maintained database, we collected dMMR colorectal cancer (CRC) patients identified by postoperative immunohistochemistry screening. According to genetic test, patients were grouped as Lynch-associated or sporadic dMMR. We compared the clinical-pathological features, prognosis, and immunoreactive differences between the two groups. By whole-exome sequencing and neoantigen detection pipeline, mutational frequencies and neoantigen burdens were also compared. All statistical tests were two-sided. Results: Sixty-seven sporadic dMMR and 85 Lynch-associated CRC patients were included in the study. Sporadic dMMR patients were older (P < .001) and their tumors were poorly differentiated (P = .03). The survival was better in the Lynch-associated group (P = .001). After adjustment, the difference still remained statistically significant (hazard ratio = 0.29, 95% confidence interval = 0.09 to 0.95, P = .04). The scores of Crohn's-like reaction (CRO; P < .001), immunoreactions in the invasive margin (IM; P = .01), tumor stroma (TS; P = .009), and cancer nest (CN; P = .02) of the Lynch-associated group were statistically significantly higher. The numbers of CD3+, CD8+, Foxp3+ tumor-infiltrating lymphocytes (TILs) in IM; CD3+, CD4+ TILs in TS; and CD3+, CD4+, CD8+ TILs in CN were statistically significantly higher in Lynch-associated dMMR patients. Based on the 16 patients who under went whole-exome sequencing, there were also more somatic mutations and neoantigen burdens in the Lynch-associated group compared with the sporadic dMMR group (439/pt vs 68/pt, P = .006; 628/pt vs 97/pt, P = .009). Conclusions: There are heterogeneities in dMMR CRCs. Lynch-associated dMMR patients present with more somatic mutations and neoantigens compared with sporadic dMMR, which probably results in stronger immunoreactions and survival improvement.

17.
Cell Death Dis ; 8(9): e3043, 2017 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-28880268

RESUMO

We have previously reported that Cezanne could be a prognostic biomarker for survival in hepatocellular carcinoma (HCC) patients. However, the role of Cezanne genes in HCC cells and its response to postoperative adjuvant transcatheter arterial chemoembolization (TACE) in HCC patients remains unknown. In this study, Cezanne expression was detected in human HCC using real-time PCR, western blot and immunohistochemistry. The function of Cezanne in HCC cells was determined by Transwell invasion assays and nude mice metastasis assay. The response of Cezanne in patients who received adjuvant TACE after hepatectomy was evaluated. Functional study demonstrated that interference of Cezanne expression promoted the migration and invasion of HCC cells in vitro and boosted metastasized HCC formation in mice. Upregulation of Cezanne diminished the adhesion and migration of hepatoma cells. Further study indicated that Cezanne might inhibit invasion of HCC cells by inducing epithelial-mesenchymal transition (EMT). In addition, patients with low Cezanne expression had significant improvement in prognosis after receiving adjuvant TACE. In contrast, patients with high Cezanne expression had a poorer response to adjuvant TACE. Moreover, Cezanne status was associated with response to adjuvant TACE in patients subgroup stratified by vascular invasion, tumor size and tumor number. In conclusion, Cezanne may be a novel antioncogene that has a pivotal role in the invasion of HCC and contribute to the selection of patients who may benefit from adjuvant TACE to prevent recurrence.


Assuntos
Carcinoma Hepatocelular/genética , Quimioembolização Terapêutica , Endopeptidases/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Neoplasias Pulmonares/genética , Recidiva Local de Neoplasia/genética , Idoso , Animais , Antígenos CD , Caderinas/genética , Caderinas/metabolismo , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/secundário , Carcinoma Hepatocelular/cirurgia , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Endopeptidases/metabolismo , Transição Epitelial-Mesenquimal , Feminino , Hepatectomia/métodos , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Recidiva Local de Neoplasia/cirurgia , Transplante de Neoplasias , Prognóstico , Transdução de Sinais , Carga Tumoral , Vimentina/genética , Vimentina/metabolismo
18.
Proc Natl Acad Sci U S A ; 114(36): 9683-9688, 2017 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-28831010

RESUMO

Nasopharyngeal carcinoma (NPC) most frequently occurs in southern China and southeast Asia. Epidemiology studies link NPC to genetic predisposition, Epstein-Barr virus (EBV) infection, and environmental factors. Genetic studies indicate that mutations in chromatin-modifying enzymes are the most frequent genetic alterations in NPC. Here, we used H3K27ac chromatin immune precipitation followed by deep sequencing (ChIP-seq) to define the NPC epigenome in primary NPC biopsies, NPC xenografts, and an NPC cell line, and compared them to immortalized normal nasopharyngeal or oral epithelial cells. We identified NPC-specific enhancers and found these enhancers were enriched with nuclear factor κB (NF-κB), IFN-responsive factor 1 (IRF1) and IRF2, and ETS family members ETS1 motifs. Normal cell-specific enhancers were enriched with basic leucine zipper family members and TP53 motifs. NPC super-enhancers with extraordinarily broad and high H3K27ac signals were also identified, and they were linked to genes important for oncogenesis including ETV6. ETV6 was also highly expressed in NPC biopsies by immunohistochemistry. High ETV6 expression correlated with a poor prognosis. Furthermore, we defined the EBV episome epigenetic landscapes in primary NPC tissue.


Assuntos
Carcinoma/genética , Elementos Facilitadores Genéticos , Neoplasias Nasofaríngeas/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Adolescente , Adulto , Idoso , Animais , Azepinas/farmacologia , Carcinoma/etiologia , Carcinoma/metabolismo , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos/efeitos dos fármacos , Epigênese Genética , Infecções por Vírus Epstein-Barr/complicações , Feminino , Genoma Viral , Xenoenxertos , Sequenciamento de Nucleotídeos em Larga Escala , Código das Histonas/genética , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/etiologia , Neoplasias Nasofaríngeas/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Prognóstico , Proteínas Proto-Oncogênicas c-ets/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Triazóis/farmacologia , Adulto Jovem
19.
J Renin Angiotensin Aldosterone Syst ; 18(3): 1470320317717831, 2017 Jul-Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28685619

RESUMO

AIM: The purpose of this study was to explore whether mTOR/p70S6K1 signaling is activated in renal fibrosis of immunoglobulin A nephropathy. METHODS: Seventy-two children with immunoglobulin A nephropathy were divided into three groups according to their clinical features and pathological grades. Six normal renal specimens were included in the control group. The expression levels of angiotensin II, mTOR, p70S6K1, E-cadherin, and α-smooth muscle actin in renal tissues were determined by immunohistochemistry method, the potential correlations of these indexes and relationship between these indexes and the clinicopathological indexes were analyzed. RESULTS: Compared to the control group, the expression levels of angiotensin II, mTOR, p70S6K1, and α-smooth muscle actin were significantly higher and the expression levels of E-cadherin were lower both in glomeruli and tubulointerstitium of immunoglobulin A nephropathy children. And the most significant differences were found in the nephrotic syndrome group and pathological grade IV group. In immunoglobulin A nephropathy renal tissues, the expression levels of angiotensin II in glomeruli and tubulointerstitium were both positively correlated with the expression levels of mTOR and α- smooth muscle actin, and negatively correlated with the expression levels of E-cadherin. CONCLUSION: The mTOR/p70S6K1 signaling was activated in renal tissues of children with immunoglobulin A nephropathy, and future studies will need to address the mechanism of mTOR/p70S6K1 signaling in the progress of renal fibrosis in immunoglobulin A nephropathy.


Assuntos
Glomerulonefrite por IGA/metabolismo , Rim/metabolismo , Rim/patologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Actinas/metabolismo , Adolescente , Angiotensina II/metabolismo , Antígenos CD , Caderinas/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Fibrose , Glomerulonefrite por IGA/patologia , Humanos , Masculino , Proteínas Quinases S6 Ribossômicas 70-kDa/genética
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