Macrophage-derived SHP-2 inhibits the metastasis of colorectal cancer via Tie2-PI3K signals.

This research aimed to explore the influence of Src homology-2 containing protein tyrosine phosphatase (SHP-2) on the functions of tyrosine kinase receptors with immunoglobulin and EGF homology domains 2 (Tie2)-expressing monocyte/macrophages (TEMs) and the influence of the angiopoietin(Ang)/Tie2-phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) (Ang/Tie2-PI3K/Akt/mTOR) signaling pathway on the tumor microvascular remodeling in an immunosuppressive microenvironment. In vivo, SHP-2-deficient mice were used to construct colorectal cancer (CRC) liver metastasis models. SHP-2-deficient mice had significantly more metastatic cancer and inhibited nodules on the liver surface than wild-type mice, and the high-level expression of p-Tie2 was found in the liver tissue of the macrophages' specific SHP-2-deficient mice (SHP-2MAC-KO) + planted tumor mice. Compared with the SHP-2 wild type mice (SHP-2WT) + planted tumor group, the SHP-2MAC-KO + planted tumor group experienced increased expression of p-Tie2, p-PI3K, p-Akt, p-mTOR, vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), matrix metalloproteinase 2 (MMP2), and MMP9 in the liver tissue. TEMs selected by in vitro experiments were co-cultured with remodeling endothelial cells and tumor cells as carriers. It was found that when Angpt1/2 was used for stimulation, the SHP-2MAC-KO + Angpt1/2 group displayed evident increases in the expression of the Ang/Tie2-PI3K/Akt/mTOR pathway. The number of cells passing through the lower chamber and the basement membrane and the number of blood vessels formed by cells compared with the SHP-2WT + Angpt1/2 group, while these indexes were subjected to no changes under the simultaneous stimulation of Angpt1/2 + Neamine. To sum up, the conditional knockout of SHP-2 can activate the Ang/Tie2-PI3K/Akt/mTOR pathway in TEMs, thereby strengthening tumor micro angiogenesis in the microenvironment and facilitating CRC liver metastasis.

Metastatic SMARCB1 Deficient Skin Carcinoma With Neuroendocrine Differentiation in the Parotid Glands Clinically Mimicking Primary Salivary Gland Malignancy: Unusual Case With Diagnostic Pitfalls.

BACKGROUND/AIM: SMARCB1(INI1)-deficient cutaneous carcinomas are an emerging subset of rare tumors, with only a few cases reported, making its diagnosis challenging. CASE REPORT: A 84-year-old male with a history of prostate adenocarcinoma and skin squamous cell cancer presented with a rapidly growing upper neck mass. Computed tomography (CT) and positron emission tomography (PET)/CT scans were suspicious of a salivary gland neoplasm of the parotid glands. Needle core biopsy of the right parotid gland mass showed poorly differentiated carcinoma. The patient underwent bilateral superficial parotidectomies and neck lymph nodes dissection. Histologically, the tumor showed rhabdoid and plasmacytoid morphology with diffuse loss of SMARCB1, positive deltaNp63 (p40), focally positive synaptophysin, and 80% of Ki67 index. Retrospectively, SMARCB1 deficiency carcinoma with squamous and neuroendocrine differentiation was confirmed in the prior skin lesion of the right frontal scalp. The patient had a poor prognosis even though post-surgical radiation therapy was given. CONCLUSION: We present a unique case of metastatic SMARCB1-deficient cutaneous carcinoma in the parotid glands with both squamous and neuroendocrine differentiation. This entity should be considered in any difficult-to-classify skin carcinoma, as timely definitive diagnosis will be mandatory for optimizing therapy.

Preclinical pharmacodynamic evaluation of antibiotic nitroxoline for anticancer drug repurposing.

The established urinary antibiotic nitroxoline has recently regained considerable attention, due to its potent activities in inhibiting angiogenesis, inducing apoptosis and blocking cancer cell invasion. These features make nitroxoline an excellent candidate for anticancer drug repurposing. To rapidly advance nitroxoline repurposing into clinical trials, the present study performed systemic preclinical pharmacodynamic evaluation of its anticancer activity, including a methyl thiazolyl tetrazolium assay in vitro and an orthotopic urological tumor assay in vivo. The current study determined that nitroxoline exhibits dose-dependent anti-cancer activity in vitro and in urological tumor orthotopic mouse models. In addition, it was demonstrated that the routine nitroxoline administration regimen used for urinary tract infections was effective and sufficient for urological cancer treatment, and 2 to 4-fold higher doses resulted in obvious enhancement of anticancer efficacy without corresponding increases in toxicity. Furthermore, nitroxoline sulfate, one of the most common metabolites of nitroxoline in the urine, effectively inhibited cancer cell proliferation. This finding increases the feasibility of nitroxoline repurposing for urological cancer treatment. Due to the excellent anticancer activity demonstrated in the present study, and its well-known safety profile and pharmacokinetic properties, nitroxoline has been approved to enter into a phase II clinical trial in China for non-muscle invasive bladder cancer treatment (registration no. CTR20131716).

Coexisting and possible primary extra-gastrointestinal stromal tumors of the pancreas and liver: A single case report.

Gastrointestinal stromal tumors (GIST) are mesenchymal neoplasms of the gastrointestinal tract (GI) that are defined, in part, by the expression of CD117, a c-Kit proto-oncogene protein. GISTs emerge outside of the GI at a very low frequency, typically in a single organ or location. GISTs that occasionally emerge outside of the GI are classified as extra-gastrointestinal stromal tumors (EGIST). The present study reports an extremely rare case of EGIST detected in the pancreas and the liver. The pancreatic and liver tumors were 4.5×2.5 cm and 2.0×1.5 cm in size, respectively. Both tumors consisted of CD117-positive spindle cells with a similar mitotic rate of 1-2 per 50 high power fields. The pancreatic and the hepatic EGISTs were at a low risk of malignancy, and both tumors were proposed to be primary stromal tumors. To the best of our knowledge, this is the first report of likely primary EGIST identified in the pancreas and liver of the same patient.

AGR2 is associated with gastric cancer progression and poor survival.

Anterior gradient protein 2 (AGR2) has been reported as a novel biomarker with a potential oncogenic role. However, its association with the prognosis and survival rate of gastric cancer (GC) has not yet been determined. Therefore, the present study aimed to examine the expression and prognostic significance of AGR2 in patients with GC. Immunohistochemistry was used to analyze AGR2 and cathepsin D (CTSD) protein expression in 436 clinicopathologically characterized GC cases and 92 noncancerous tissue samples. AGR2 and CTSD expression were both elevated in GC lesions compared with noncancerous tissues. In 204/436 (46.8%) GC patients, high expression of AGR2 was positively correlated with the expression of CTSD (r=0.577, P<0.01). Furthermore, several clinicopathological parameters were significantly associated with AGR2 expression level, including tumor size, depth of invasion and TNM stage (P<0.05). Using Kaplan-Meier survival analysis, it was determined that the mean survival time of patients with low levels of AGR2 expression was significantly longer than those with high ARG2 expression (in stages I, II and III; P<0.05). For stage IV disease, no significant difference in survival time was identified. Multivariate survival analysis demonstrated that AGR2 was an independent prognostic factor and was associated in the progression of GC. The findings of the present study indicate that AGR2 expression is significantly associated with location and size of GC, depth of invasion, TNM stage, lymphatic metastasis, vessel invasion, distant metastasis, Lauren's classification, high CTSD expression and poor prognosis. Thus, AGR2 may be a novel GC marker and may present a potential therapeutic target for GC.

Meta-Analysis of Efficacy and Safety of Apixaban in Patients Undergoing Catheter Ablation for Atrial Fibrillation.

BACKGROUND: The efficacy and safety of apixaban in patients undergoing catheter ablation (CA) for atrial fibrillation (AF) are little investigated. METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE were searched up to September 2015. Four literatures comparing apixaban with vitamin K antagonists (VKAs) were included. Data were pooled in Review Manager Software, using Mantel-Haenszel methods with a fixed-effects model. The funnel plots and Egger's test were used to examine publication bias. Heterogeneity was assessed using the I(2) test. Risk ratios (RR) and 95% confidence intervals (CI) of each study were calculated and pooled. RESULTS: No significant differences were observed in rates of total bleeding (RR = 0.91, 95% CI [0.57, 1.46], I(2) = 0.0%), thromboembolic complications (RR = 0.75, 95% CI [0.03, 18.22], I(2) = 0.0%), or total events (RR = 0.90, 95% CI [0.56, 1.44], I(2) = 0.0%) between apixaban and VKAs group. The frequency of major bleeding was similar between apixaban and VKAs group (RR = 1.34, 95% CI [0.34, 5.30], I(2) = 0.0%). CONCLUSION: Apixaban was as effective and safe as VKAs in the periprocedural period of CA.

Clinical features and risk factors for blood stream infections of Candida in neonates.

Candida species are the leading cause of invasive fungal infections in children admitted to hospital. However, few data exist with regard to the clinical features, risk factors and prognosis for candidemia in neonates. The present retrospective study included 40 neonates from the Affiliated Children's Hospital of the Capital Institute of Pediatrics (Beijing, China) in the time period between January 1, 2006 and December 31, 2010 (candidemia group, n=19; non-candidemia group, n=21). The clinical characteristics, prognosis and previously identified risk factors for the two groups were recorded. According to the forward stepwise multivariate logistic regression analysis, administration of antibiotics >2 weeks prior, the use of glycopeptide antibiotics, maternal candidal vaginitis and secondary gastrointestinal surgery were identified as predictors of candidiasis. When compared with the non-gastrointestinal dysfunction group, the proportion of neonates that had been subjected to parenteral nutrition, central venous catheters, gastrointestinal surgery, secondary gastrointestinal surgery, repeated tracheal intubation and glycopeptide antibiotic administration was significantly higher in the gastrointestinal dysfunction group (P<0.05). Long-term application of antibiotics, use of glycopeptide antibiotics, maternal candidal vaginitis and secondary gastrointestinal surgery appeared to be the risk factors of candidemia in neonates. The neonates co-existed with gastrointestinal dysfunction suffering from candidemia were likely to experience growth retardation at 6 months after hospital discharge. Candidemia is potentially life-threatening situation for neonates, and if patients do not succumb it may affect their early development.

Low local blood perfusion, high white blood cell and high platelet count are associated with primary tumor growth and lung metastasis in a 4T1 mouse breast cancer metastasis model.

It was originally thought that no single routine blood test result would be able to indicate whether or not a patient had cancer; however, several novel studies have indicated that the median survival and prognosis of cancer patients were markedly associated with the systemic circulation features of cancer patients. In addition, certain parameters, such as white blood cell (WBC) count, were largely altered in malignant tumors. In the present study, routine blood tests were performed in order to observe the change of blood cells in tumor-bearing mice following the implantation of 4T1 breast cancer cells into the mammary fat pad; in addition, blood flow in breast tumor sites was measured indirectly using laser Doppler perfusion imaging (LDPI), in an attempt to explain the relevance between the blood circulation features and the growth or metastasis of breast cancer in mice model. The LDPI and blood test results indicated that the implantation of 4T1 breast cancer cells into BALB/c mice led to thrombosis as well as high WBC count, high platelet count, high plateletcrit and low blood perfusion. Following implantation of the 4T1 cells for four weeks, the lung metastatic number was determined and the Pearson correlation coefficient revealed that the number of visceral lung metastatic sites had a marked negative association with the ratio of basophils (BASO%; r=-0.512; P<0.01) and the mean corpuscular hemoglobin was significantly correlated with primary tumor weight (r=0.425; P<0.05). In conclusion, the results of the present study demonstrated that tumor growth led to thrombosis and acute anemia in mice; in addition, when blood BASO% was low, an increased number of lung metastases were observed in tumor-bearing mice.

Effect of different time phases of radionuclide hepatobiliary scintigraphy on the differential diagnosis of congenital biliary atresia.

To investigate the value and essentiality of 6- and 24-h delay hepatobiliary scintigraphy in the differential diagnosis of biliary atresia (BA), we retrospectively analyzed 197 infants (121 boys/76 girls; age range, 3-205 days; average age, 63.9 days) admitted to Jiangxi Children's Hospital for persistent jaundice (> 2 weeks), hepatosplenomegaly, and abnormal liver function. After receiving anti-inflammatory treatment and cholagogic pre-treatment for 7-10 days without a clear diagnosis, the children underwent 99mTc-labeled diethylacetanilide-iminodiacetic acid hepatobiliary scintigraphy. BA and infant hepatitis syndrome were diagnosed in 107 and 90 infants, respectively after laparoscopic cholangiography, surgical pathology, or 6-month clinical follow-up. The diagnostic efficiencies of hepatobiliary scintigraphy for BA were evaluated within 50 min and at 6 and 24 h. The areas under the receiver operating characteristic curves within 50 min, at 6 and 24 h were 0.696, 0.829 , and 0.779 , suggesting poor diagnostic value within 50 min, but improvement at 6 and 24 h. The compliance rate of 6- and 24-h imaging for BA diagnosis was 89.34% (176/197; paired chi-square test Kappa value, 0.77; P > 0.05), signifying high consistency. The diagnostic efficiency values of 6-/24-h imaging for BA diagnosis were sensitivity (90.65/89.72%), specificity (74.44/78.89%), accuracy (83.25/84.77%), positive and negative predictive values (80.83/83.48% and 87.01/86.59%), with no significant difference (P > 0.05). To provide optimal treatment in early BA, the- 6-h hepatobiliary scintigraphy had practical value, especially when combined with tomographic or dynamic imaging; 24-h delay imaging was deemed unnecessary because it was not significantly superior.

MicroRNA-34a-5p enhances sensitivity to chemotherapy by targeting AXL in hepatocellular carcinoma MHCC-97L cells.

Mature microRNA (miRNA) 34a-5p, which is a well-known tumor suppressor in hepatitis virus-associated hepatocellular carcinoma (HCC), plays an important role in cell processes, such as cell proliferation and apoptosis, and is therefore an optimal biomarker for future clinical use. However, the role of miRNA-34a-5p in chemoresistance has yet to be identified. In the present study, the expression of miRNA-34a-5p was assessed by an in situ hybridization assay in HCC tissues and was found to be significantly decreased compared with the pericarcinomatous areas of the tissue specimens, which consisted of samples obtained from 114 patients with HCC. High expression of miRNA-34a-5p was found to be associated with a favorable overall survival time in HCC patients. Functional tests performed by transfecting miRNA-34a-5p mimics or inhibitors into MHCC-97L cells illustrated that miRNA-34a-5p inhibited proliferation, elevated apoptosis and decreased chemoresistance to cisplatin in HCC cells. AXL is the direct target of miRNA-34a-5p, as confirmed by sequence analysis and luciferase assay. Transfection of the cells with small interfering RNA for AXL (siAXL) increased the apoptosis ratio of the MHCC-97L cell line. Transfection with siAXL led to similar biological behaviors in the MHCC-97L cells to those induced by ectopic expression of miRNA-34a-5p. Thus, it was concluded that miRNA-34a-5p enhanced the sensitivity of the cells to chemotherapy by targeting AXL in hepatocellular carcinoma. In addition, low expression of miRNA-34a-5p in HCC tissues yielded an unfavorable prognosis for patients with HCC that received radical surgery, due to the promotion of proliferation and an increase in chemoresistance in HCC cells.

Immune and non-immune factors in cryopreserved tissues.

BACKGROUND: Although cryopreserved tissues are used clinically, the effects of cryopreservation on antigenicity leading to immune and non-immune responses are not well known. METHODS: We investigated the change of inflammatory effects of cryopreserved tissue by using spleen and aortic allografts from Class I antigen-disparate B6.C-H-2(bm1) (bm1; K(bm1), IA(b), D(b)), Class II antigen-disparate B6.C-H-2(bm12) (bm12; K(b), IA(bm12), D(b)) and Class I and Class II antigen-disparate (bm1 x bm12)F1 (K(bm1 x b), IA(b x bm12), D(b)) mice against C57BL/6 Cr Slc (B6; H-2(b)) mice. Cryopreservation was done in a programmed freezer and cryopreserved tissues were kept in the vapor phase of liquid nitrogen for 2 weeks and thawed at room temperature. RESULTS: Cryopreserved B6 spleen cells expressed almost the same levels of Class I (K(b) and D(b)) and Class II (IA(b)) antigens as observed in fresh B6 spleen cells. Cryopreserved bm1 and bm12 spleen cells had the same stimulator activities in mixed-lymphocyte reaction (MLR) and cytotoxic T-lymphocyte (CTL) assays compared with fresh bm1 and bm12 spleen cells, respectively. To elucidate the effects of cryopreserved tissues on immune response of recipients, descending aortas of (bm1 x bm12)F1 mice were implanted into the right common carotid artery of B6 (H-2(b)) mice with the cuff technique and the reactivities of recipient B6 mice against Class I antigen-disparate bm1 antigens and Class II antigen-disparate bm12 antigens were examined 4 weeks after implantation. In both MLR and CTL assays against bm1 or bm12 antigens, anti-donor reactivities were augmented and there was no significant difference between B6 mice grafted with fresh aortic allografts and those grafted with cryopreserved ones. Histologic analysis showed that mild infiltration of mononuclear cells into the adventitia was observed in both fresh and cryopreserved aortic allografts. The fibrous change was observed more strongly in cryopreserved aortic allografts compared with fresh aortic allografts. CONCLUSIONS: Cryopreservation has no effect on eliciting immune responses to Class I or Class II alloantigens, but has some effect on promoting fibrous change.