Development and validation of a nomogram to predict which patients with colorectal cancer liver metastases would benefit from primary tumor resection.

PURPOSE: The use of primary tumor resection (PTR) in the treatment of colorectal cancer liver metastases (CRLM) patients has become increasingly controversial. Our goal is to establish a nomogram to screen for the candidates that would benefit from PTR in CRLM patients. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was searched for 8366 patients with colorectal liver cancer metastases (CRLM) from 2010 to 2015. Overall survival (OS) rates were calculated using the Kaplan-Meier curve. After propensity score matching (PSM), predictors were analyzed by logistic regression analysis, and a nomogram was created to predict for survival benefit of PTR using R software. RESULTS: After PSM, there were 814 patients in both PTR group and non-PTR group, respectively. The median OS time in the PTR group was 26 months (95%CI = 23.33 ~ 28.67) and the median OS time in the non-PTR group was 15 months (95%CI = 13.36 ~ 16.64). The Cox regression analysis found that PTR was an independent predictive factor (HR = 0.46, 0.41 ~ 0.52) for OS. Additionally, logistic regression was used to study the factors impacting PTR benefit, and the results showed that CEA (P = 0.016), chemotherapy (P < 0.001), N stage (P < 0.001), histological grade (P < 0.001), and lung metastasis (P = 0.001) are independent predictive factors affecting the therapeutic outcome of PTR in patients with CRLM. The developed nomogram displayed good discriminative ability in predicting the beneficial probability of PTR surgery, with the area under the curve (AUC) values of 0.801 in training set and 0.739 in validation set respectively. CONCLUSION: We developed a nomogram that predicts the survival benefits of PTR in CRLM patients with relatively high accuracy, and quantifies the predictive factors for PTR-related benefits.

Development and validation of a nomogram to predict overall survival in young non-metastatic rectal cancer patients after curative resection: a population-based analysis.

PURPOSE: This study aimed to establish and validate a nomogram for predicting overall survival (OS) in young non-metastatic rectal cancer (RC) patients after curative resection. METHODS: Young RC patients (under 50 years of age) from 2010 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Those patients randomly assigned to a training cohort and a validation cohort at a ratio of 7:3. The independent prognostic factors for OS were identified by univariate and multivariate Cox regression analysis. A nomogram model was built based on the independent prognostic variables and was evaluated by concordance index (C-index), receiver operating characteristics (ROC) curves, calibration plot, and decision curve analysis (DCA). RESULTS: A total number of 3026 young RC patients were extracted from SEER database. OS nomogram was constructed based on race, histological type, tumor grade, T stage, N stage, carcinoembryonic antigen (CEA) level, and number of lymph nodes (LN) examined. C-index, ROC curves, calibration plot, and DCA curves presented satisfactory performance of the above nomogram in predicting the prognosis of young non-metastatic RC patients after curative resection. The nomogram can identify three subgroups of patients at different risks, which showed different prognostic outcomes both in the training cohort and validation cohort. CONCLUSION: We successfully established a reliable and insightful nomogram to predict OS for young non-metastatic RC patients after curative resection. The nomogram may provide accurate prognosis prediction to guide individualized follow-up and treatment plans.

Long non-coding RNA BX357664 inhibits gastric cancer progression by sponging miR-183a-3p to regulate the PTEN expression and PI3K/AKT pathway.

Lately, long non-coding RNA (lncRNA) is recognized as a key regulator of gastric cancer (GC) which has aroused great interest in the fields of medicine, toxicology, and functional food. Studies related to LncRNA expression microarray data indicate that BX357664 is down-regulated in GC specimens. However, the expression pattern and molecular mechanism of BX357664 in GC have not been studied so far. The purpose of this study was to investigate the expression of lncRNA BX357664 in GC and its function in GC cell lines. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the level of BX357664 in 50 pairs of cancer tissues and adjacent non-cancer tissues collected from GC patients. It was found that BX357664 level was lowered in cancer specimens than adjacent non-cancer tissues and correlated with tumor size and TNM stage. Also, we used cell counting kit 8 (CCK8), cell clone formation assay and transwell assay, which affirmed that up-regulation of BX357664 inhibited the proliferation, migration, and invasion of GC cells, but promoted apoptosis. In the dual-luciferase report analysis, BX357664 acted as a miR-183-3p ceRNA to target and regulate the expression of PTEN and affect the PI3K/AKT pathway. These results indicate that BX357664 can inhibit the proliferation and metastasis of GC through the miR-183-3p/PTEN/PI3K/AKT pathway, which may serve as potential targets for the treatment of GC in the future.

NDRG3 facilitates colorectal cancer metastasis through activating Src phosphorylation.

BACKGROUND: NDRG3 is an N-myc downregulated gene (NDRG). The aim of this article was to identify the role of NDRG3 in colorectal cancer (CRC) and to determine the mechanism underlying its function. METHODS: Using immunohistochemical staining, expression and clinicopathological variables of NDRG3 were analyzed in 170 CRC samples. Overexpression of NDRG3 was employed in SW1116 cells, downregulation of NDRG3 was achieved in RKO cells, then migration and invasion assays were performed in vitro, and a mouse model was constructed in vivo. RESULTS: Increased expression of NDRG3 was observed in primary CRC tissues, and this expression was correlated with distant metastasis. Consistently, ectopic expression of NDRG3 in SW1116 cells enhanced cell migration and invasion, while knockdown of NDRG3 in RKO cells significantly suppressed CRC cell metastasis. The portal vein injection models suggested that NDRG3 overexpression facilitates liver metastasis. These events were associated with the phosphorylation of Src (c-Src) at Tyr 419 site. CONCLUSION: Our results showed that NDRG3 facilitates CRC migration and invasion by activating Src phosphorylation, suggesting the role of NDRG3 as a candidate oncogene.

LIFR promotes tumor angiogenesis by up-regulating IL-8 levels in colorectal cancer.

Leukemia inhibitory factor receptor (LIFR) has been documented as a cancer promoter and to be present at high levels in various types of tumor tissues. In our search for molecules prognostic of colorectal cancer (CRC), we found high levels of LIFR in CRC tissue samples. Further analyses revealed that LIFR was indeed prognostic of CRC patient survival, and was associated with tumor size, lymphatic metastasis and stages. LIFR was found to promote tumor growth, metastasis and angiogenesis both in vitro and in vivo. High levels of LIFR in CRC facilitated proliferation and migration of endothelial cells, resulting in an increase in angiogenic activity. Moreover, interleukin 8 (IL-8) was found to play a role in the LIFR induced angiogenesis. IL-8 levels were correlated with LIFR levels in CRC tissues, whereas depletion of IL-8 led to a reduced angiogenic activity of LIFR in CRC cells. In addition, LIFR increased phosphorylation level of Erk, which regulates il-8 transcription. We conclude that LIFR is possibly a valuable prognostic marker for CRC. Our results also implicate a mechanism by which LIFR regulates tumor angiogenesis through Erk/IL-8 pathway, and that LIFR could be a potential therapeutic target for CRC.

MicroRNA-585 suppresses tumor proliferation and migration in gastric cancer by directly targeting MAPK1.

Increasing evidence reveals that microRNA contributes to the development and progression of gastric cancer (GC), but the roles of miR-585 in GC remain unclear. In this study, we confirmed that miR-585 was down-regulated in GC tissues and cell lines and that miR-585 expression was related to extent of invasion, TNM stage, lymph node invasion and poor prognosis. Our results showed that miR-585 inhibits the proliferation and migration of GC, and MAPK1 is a direct and functional target of miR-585. Our study sheds light on the role of miR-585 as a suppressor for tumor growth and metastasis and raises the intriguing possibility that miR-585 may serve as a new potential marker for monitoring and treating GC.

G9A promotes gastric cancer metastasis by upregulating ITGB3 in a SET domain-independent manner.

Tumor metastasis is the leading cause of death in patients with advanced gastric cancer (GC). Limited therapeutic regimens are available for this condition, which is associated with a poor prognosis, and the mechanisms underlying tumor metastasis remain unclear. In the present study, increased histone methyltransferase G9A expression in GC tissues correlated with advanced stage and shorter overall survival, and in vitro and in vivo experiments revealed that G9A promoted tumor invasion and metastasis. Moreover, we observed that Reg IV induced G9A via the p-ERK/p-SP1 pathway. SP1 directly binds the G9A promoter and enhances G9A expression, and upregulated G9A then forms a transcriptional activator complex with P300 and GR, thereby promoting ITGB3 expression induced by dexamethasone (DEX) and contributing to GC metastasis. However, the G9A-mediated increase in ITGB3 expression was not dependent on the SET domain and methyltransferase activity of G9A. This study demonstrates that G9A is an independent prognostic marker and promotes metastasis in GC, thus suggesting that it may be a tumor biomarker and potential therapeutic target in GC.

Up-regulation of chemokine receptor CCR4 is associated with Human Hepatocellular Carcinoma malignant behavior.

Studies indicate that the chemokine receptor is responsible for poor prognosis of hepatocellular carcinoma (HCC) patients. In this study, we initially demonstrated that CCR4 is overexpressed in HCC specimens, and its elevation in HCC tissues positively correlates with tumor capsule breakthrough and vascular invasion. Although overexpression of CCR4 failed to influent proliferation of HCC cells in vitro apparently, the prominent acceleration on HCC tumor growth in vivo was remarkable. The underlying mechanism may be involved in neovascularization. Interestingly, different from effect on proliferation, CCR4 overexpression could trigger HCC metastasis both in vitro and in vivo also induced HCC cell epithelial-mesenchymal transition (EMT) as well. Then we identified matrix metalloproteinase 2 (MMP2) as a direct target of CCR4 which plays an important role in CCR4-mediated HCC cell invasion, which was up-regulated by ERK/AKT signaling. Positive correlation between CCR4 and MMP2 expression was also observed in HCC tissues. In conclusion, our study suggested that chemokine receptor CCR4 promotes HCC malignancy and facilitated HCC cell metastases via ERK/AKT/MMP2 pathway. These findings suggest that CCR4 may be a potential new diagnostic and prognostic marker in HCC, and targeting CCR4 may be a potential therapeutic option for blocking HCC metastasis.

Glucose-derived AGEs promote migration and invasion of colorectal cancer by up-regulating Sp1 expression.

It is well established that the risk of colorectal cancer (CRC) is significantly increased in diabetic patients. As one of main forms of the advanced glycation end products (AGEs) that accumulate in vivo, glucose-derived AGEs play an important role in the pathogenesis of diabetic complications and may contribute to CRC progression. However, to date, both the contribution of glucose-derived AGEs to the course of CRC and the underlying mechanism are unclear. In the present study, the concentration of glucose-derived AGEs in the serum and tumor tissue of patients with CRC increased. A clinical data analysis demonstrated that the expression of the receptor for AGEs (RAGE), Specificity Protein 1 (Sp1), and matrix metallopeptidase -2 (MMP2) was significantly higher in cancerous tissues compared with non-tumor tissue in Chinese Han patients with CRC and that RAGE expression was closely associated with lymph node metastasis and TNM stage. Furthermore, in vivo and in vitro experiments showed that AGEs promoted invasion and migration of colorectal cancer, and the AGEs treatment increased the expression of RAGE, Sp1, and MMP2 in a dose-dependent manner. A RAGE blocking antibody and an Sp1-specific siRNA attenuated the AGE-induced effects. Moreover, the AGEs treatment increased the phosphorylation of ERK, and reducing the phosphorylation level of ERK by MEK1/2 inhibitor decreased the expression of Sp1. In conclusion, glucose-derived AGEs promote the invasion and metastasis of CRC partially through the RAGE/ERK/SP1/MMP2 cascade. These findings may provide an explanation for the poor prognoses of colorectal cancer in diabetic patients.

Sonographic Features and Diagnosis of Peripheral Schwannomas.

BACKGROUND: To determine the sonographic features of peripheral schwannomas. METHODS: This retrospective study included 54 cases of schwannoma in 51 patients. Ultrasonography (US) and MRI were performed in all patients. The US features of each tumor were analyzed and compared with pathologic findings. The US target sign was compared with the MRI findings. RESULTS: On US, 53 of the 54 schwannomas had a regular shape and clear margins, and one had an irregular shape. Thirty-seven of the 54 schwannomas were categorized as solid, 16 as cystic and solid, and one as entirely cystic; distal sound enhancement was associated with 47 schwannomas. The target sign was seen in 24, the rat tail sign in 28, the vessel accompanying sign in 22, and the split fat sign in 5. The entering and exiting nerves were situated centrally in 9 and eccentrically in 19 schwannomas. Vascularity on color Doppler imaging using a 0 to III scale was graded 0 in 4 schwannomas, I in 10, II in 26, and III in 14. Twenty-four target signs were detected in 54 schwannomas by US, and 28 were detected by MRI. There was good agreement between the target signs noted on US and those seen on MRI (κ = 0.631, p < 0.001). CONCLUSIONS: The sonographic diagnosis of peripheral schwannomas is feasible and reliable. The target sign is a prominent US feature in peripheral schwannomas, comparable to that observed with MRI. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:127-133, 2017.

Cortactin contributes to the tumorigenicity of colorectal cancer by promoting cell proliferation.

Cortactin is a scaffolding protein that regulates Arp2/3-mediated actin polymerization. We showed in a previous study that cortactin was highly expressed in human stage II-III colorectal cancer (CRC) tissues. In the present study, using colony formation and CCK-8 assays, we showed that overexpression of cortactin accelerated the proliferation of CRC cells. Flow cytometric assays revealed that cortactin promoted G1/S phase cell cycle transition. Later, we constructed the phosphorylation mutation of cortactin at the Tyr421 residue. Colony formation and CCK-8 assays showed that cortactin/Tyr421A lost its ability to promote cell proliferation. Western blot analysis indicated that cortactin activated cyclin D1, but not cortactin/Tyr421A. Further study in nude mice revealed that there was a greater decrease in both tumor volume and tumor weight in animals injected with SW480/cortactin/Tyr421A cells than in those injected with SW480/cortactin/WT cells. Thus, the present study demonstrates that the cortactin Tyr421 residue is required to promote cell proliferation both in vitro and in vivo.

Asporin enhances colorectal cancer metastasis through activating the EGFR/src/cortactin signaling pathway.

Asporin has been implicated as an oncogene in various types of human cancers; however, the roles of asporin in the development and progression of colorectal cancer (CRC) have not yet been determined. With clinical samples, we found that asporin was highly expressed in CRC tissues compared to adjacent normal tissues and the asporin expression levels were significantly associated with lymph node metastasis status and TNM stage of the patients. Through knockdown of asporin in CRC cell lines RKO and SW620 or overexpression of asporin in cell lines HT-29 and LoVo, we found that asporin could enhance wound healing, migration and invasion abilities of the CRC cells. Further more, with the human umbilical vein endothelial cells (HUVECs) tube formation assays and the xenograft model, we found that asporin promoted the tumor growth through stimulating the VEGF signaling pathway. The portal vein injection models suggested that asporin overexpression stimulated the liver metastasis of HT29 cell line, while asporin knockdown inhibited the liver metastasis of RKO cell line. In addition, asporin was found to augment the phosphorylation of EGFR/src/cortactin signaling pathway, which might be contributed to the biological functions of asporin in CRC metastasis. These results suggested that asporin promoted the tumor growth and metastasis of CRC, and it could be a potential therapeutic target for CRC patients in future.

Complications in operative fixation of calcaneal fractures.

OBJECTIVE: The purpose of this study focused on a number of factors that have been implicated in calcaneal complications and find the incidence of wound complications. METHODS: This was a retrospective study. A total of 162 patients (176 feet) who underwent calcaneal fractures between 2007 and 2012 were included. The patient's personal details, age, time from injury to surgery, cause of injury, type of fracture, operative details, operating and tourniquet times were collected from hospital computers and paper records. Evidence of complications including wound infection, wound necrosis, pain, malunion, nonunion, impingement, loss of fixation, ect were studied. RESULTS: Forty-seven of one hundred and seventy-six fractures (26.704%) had complications, wound infection was noted in seven fractures (3.977%), twelve fractures developed necrosis (6.818%), 14 fractures (7.955%) developed pain. Malunion was found in five fractures (2.841%), nonunion in two fractures (1.136%) and loss of fixation in four fractures (2.272%). Three neurologic injury was also seen in our study (1.705%). Operating time, time from injury to surgery and type of fracture had some association with complications in operative fixation of calcaneal fractures, which showed a statistically significant improvement (P=0.000, 0.031, 0.020, respectively), but there were no evidence that age and tourniquet time affect the incidence of complication after calcaneal fracture surgery (P=0.119, 0.682, respectively). CONCLUSIONS: Despite developments in the surgical treatment of calcaneal fracture, wound complications still remain inevitable. Advanced imaging techniques, less invasive surgical procedures, wealth of anatomical knowledge, surgical experience and better postoperative care should be ensured.

Cortactin promotes cell migration and invasion through upregulation of the dedicator of cytokinesis 1 expression in human colorectal cancer.

Cortactin (CTTN), a major substrate of the Src tyrosine kinase, has been implicated in cell proliferation, motility and invasion in various types of cancer. However, the molecular mechanisms of CTTN-driven malignant behavior remain unclear. In the current study, we determined the expression of CTTN in colorectal cancer and investigated its underlying mechanism in the metastasis of colorectal cancer. We confirmed increased CTTN expression in lymph node-positive CRC specimens and highly invasive CRC cell lines. Further study has shown that overexpression of CTTN promoted CRC cell migration and invasion, whereas CTTN silencing inhibited CRC cell migratory and invasive capacities in vitro. Mechanistically, CTTN increases expression of dedicator of cytokinesis 1 (DOCK1) and gene silencing of DOCK1 partially abolishes the migration and invasion capacity by CTTN. Our findings indicate that CTTN promotes metastasis of CRC cells by increasing DOCK1 expression and this could offer a promising therapeutic target for colorectal cancer treatment.