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Colorectal cancer (CRC) patients with liver metastases usually obtain less benefit from immunotherapy, and the underlying mechanisms remain understudied. Here, we identify that fibrinogen-like protein 1 (FGL1), secreted from cancer cells and hepatocytes, facilitates the progression of CRC in an intraportal injection model by reducing the infiltration of T cells. Mechanistically, tumor-associated macrophages (TAMs) activate NF-ĸB by secreting TNFα/IL-1β in the liver microenvironment and transcriptionally upregulate OTU deubiquitinase 1 (OTUD1) expression, which enhances FGL1 stability via deubiquitination. Disrupting the TAM-OTUD1-FGL1 axis inhibits metastatic tumor progression and synergizes with immune checkpoint blockade (ICB) therapy. Clinically, high plasma FGL1 levels predict poor outcomes and reduced ICB therapy benefits. Benzethonium chloride, an FDA-approved antiseptics, curbs FGL1 secretion, thereby inhibiting liver metastatic tumor growth. Overall, this study uncovers the critical roles and posttranslational regulatory mechanism of FGL1 in promoting metastatic tumor progression, highlighting the TAM-OTUD1-FGL1 axis as a potential target for cancer immunotherapy. The suppressive immune microenvironment in colorectal cancer (CRC) liver metastasis remains to be explored. Here, the authors find tumor-associated macrophages in the liver microenvironment induces elevated secretion of FGL1 from cancer cells and hepatocytes which promotes CRC metastasis by suppressing the infiltration of T cells. [ABSTRACT FROM AUTHOR]

Objective: To assess the diagnostic value of spectral parameters in differentiating adrenal adenomas from metastases based on dual-layer detector spectral CT (DLSCT). Materials and methods: Patients with adenomas or metastases who underwent enhanced DLSCT of the adrenals were enrolled. The CT values of virtual non-contrast images (CTVNC), iodine density (ID) values, and Z-effective (Z-eff) values, the normalized iodine density (NID) values, slopes of spectral HU curves (s-SHC), and iodine-to-CTVNC ratios of the tumors were measured in each phase. Receiver operating characteristic (ROC) curves were used to compare the diagnostic values. Results: Ninety-nine patients with 106 adrenal lesions (63 adenomas, 43 metastases) were included. In the venous phase, all spectral parameters were significantly different between adenomas and metastases (all p < 0.05). The combined spectral parameters showed a better diagnostic performance in the venous phase than in other phase (p < 0.05). The iodine-to-CTVNC value had a larger area under the ROC curve (AUC) than the other spectral parameters in the differential diagnosis of adenomas and metastases, with a diagnostic sensitivity and specificity of 74.4% and 91.9%, respectively. In the differential diagnosis of lipid-rich adenomas, lipid-poor adenomas and metastases, the CTVNC value and s-SHC value also had a larger AUC than the other spectral parameters, with a diagnostic sensitivity of 97.7%, 79.1% and specificity of 91.2%, 93.1%, respectively. Conclusion: On DLSCT, the combined spectral parameters in the venous phase could help better distinguish adrenal adenomas from metastases. The iodine-to-CTVNC, CTVNC and s-SHC values had the highest AUC values in differentiating adenomas, lipid-rich adenomas and lipid-poor adenomas from metastases, respectively. [ABSTRACT FROM AUTHOR]

Purpose: Tumor spread through air space (STAS) is a novel pattern of invasion related to poor prognosis in non-small cell cancer (NSCLC). Nevertheless, little is known about the role of STAS in small cell lung cancer (SCLC). We sought to determine whether STAS has a significant effect on recurrence among SCLC patients. Methods: We collected clinical and follow-up information from 181 resected stage I–III SCLC patients and compared overall survival (OS) and disease-free survival (DFS) between the patients with or without STAS using the Kaplan‒Meier method. To explore the effect of STAS on recurrence, a competing-risk analysis was conducted. Results: Among 181 SCLC patients, STAS was observed in 56 (30.94%) patients, and 125 (69.06%) patients did not have STAS. Furthermore, 33 (18.23%) patients had recurrence, including 12 patients with brain metastases. Patients with STAS had worse DFS. The cumulative incidence of any recurrence was higher in patients with STAS than in those without STAS. Univariate and multivariate competing-risk regression analyses revealed that sublobar resection and STAS were independent risk factors for SCLC recurrence (p = 0.009 and p = 0.029 for multivariate analysis, respectively). Conclusion: SCLC patients with STAS have worse DFS than SCLC patients without STAS. STAS is an independent prognostic factor in SCLC patients. [ABSTRACT FROM AUTHOR]

Programmed cell death 6 (PDCD6), a Ca2+-binding protein, has been reported to be aberrantly expressed in all kinds of tumors. The aim of this study was to explore the role and mechanism of PDCD6 in hepatocellular carcinomas (HCCs). The expression levels of PDCD6 in liver cancer patients and HCC cell lines were analyzed using bioinformatics and Western blotting. Cell viability and metastasis were determined by methylthiazol tetrazolium (MTT) and transwell assays, respectively. And Western blotting was used to test related biomarkers and molecular pathway factors in HCC cell lines. LY294002, a PI3K inhibitor inhibiting AKT, was used to suppress the AKT/GSK3β/β-catenin pathway to help evaluate the role of this pathway in the HCC carcinogenesis associated with PDCD6. The analysis of The Cancer Genome Atlas Database suggested that high PDCD6 expression levels were relevant to liver cancer progression. This was consistent with our finding of higher levels of PDCD6 expression in HCC cell lines than in normal hepatocyte cell lines. The results of MTT, transwell migration, and Western blotting assays revealed that overexpression of PDCD6 positively regulated HCC cell proliferation, migration, and invasion. Conversely, the upregulation of PDCD6 expression in the presence of an AKT inhibitor inhibited HCC cell proliferation, migration, and invasion. In addition, PDCD6 promoted HCC cell migration and invasion by epithelial-mesenchymal transition. The mechanistic investigation proved that PDCD6 acted as a tumor promoter in HCC through the AKT/GSK3β/β-catenin pathway, increasing the expression of transcription factors and cellular proliferation and metastasis. PDCD6 has a tumor stimulative role in HCC mediated by AKT/GSK3β/β-catenin signaling and might be a potential target for HCC progression. [ABSTRACT FROM AUTHOR]

As a common malignant tumor, the morbidity and mortality of lung cancer have been rising in recent years. The concept of "premetastatic niche" may lead to a revolutionary change in antitumor metastasis therapeutic strategies. Traditional Chinese medicine with multitargets and lower poisonous agents may be a potentially effective means to intervene in the "premetastatic niche (PMN)" to prevent and treat tumor metastasis. Astragalus polysaccharide (APS) is a substance with strong immune activity in Astragalus membranaceus that has excellent biological activities such as immunomodulation, anti-inflammatory, and antitumor. In this study, we constructed a tumor lung metastasis animal model to explore the intervention mechanism of APS on the premetastatic niche. We found that APS inhibited the formation of the lung premetastatic niche and inhibited the recruitment of myeloid-derived suppressor cells (MDSCs) in the lung. Mechanistically, we showed that the proteins and gene expression of S1PR1, STAT3, and p-STAT3 in the S1PR1/STAT3 signaling pathway were suppressed by APS. In line with the above findings, our results confirmed that APS may inhibit the accumulation of MDSCs in the premetastatic niche through the intervention of the S1PR1-STAT3 signaling pathway to achieve the antitumor effect. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the most common malignancies in women worldwide. Triple‐negative breast cancer (TNBC) is a highly aggressive and metastatic subtype that has the characteristics of easy recurrence, poor prognosis as well as lack of targeted therapeutics. Snail1, a key factor regulating epithelial–mesenchymal transition (EMT) process, contributing to metastasis and chemoresistance in human cancers. However, the molecular mechanism of Snail1 stabilization in cancers is not fully understood. Here, we demonstrate that the deubiquitinating enzyme USP9X deubiquitinates and stabilizes Snail1, thereby promoting metastasis and chemoresistance. The depletion and pharmacological inhibition of USP9X by WP1130, an inhibitor of USP9X, downregulate endogenous Snail1 protein, inhibit cell migration, invasion, metastasis, and increase cellular sensitivity to cisplatin and paclitaxel both in vitro and in vivo, whereas the reconstitution of Snail1 in cells with USP9X depletion at least partially reverses these phenotypes. Overall, our study establishes the USP9X‐Snail1 axis as an important regulatory mechanism of breast cancer metastasis and chemoresistance and provides a rationale for potential therapeutic interventions in the treatment of TNBC. [ABSTRACT FROM AUTHOR]

The concept of the inflammatory pre‐metastatic niche (PMN) provides a new and promising direction for the prevention and treatment of metastasis. The excessive activation of the GAS‐STING signaling leads to augmented metastasis by promoting the formation of the inflammatory PMN. In this study, tumor‐derived microparticles (MP) were used to establish the PMN model both in vitro and in vivo, and pro‐inflammatory mediators were also employed to evaluate the effects of Icaritin (ICT). It was demonstrated that ICT could inhibit the pulmonary metastasis of B16BL6 melanoma cells in mice via interfering with PMN. The phosphorylation and dimerization of STING and its downstream signaling TBK1‐IFNβ were proved to be diminished in the presence of ICT. Furthermore, we revealed that ICT suppressed the generation of pro‐inflammatory PMN through conferring the inactivation of the STING signaling pathway. CETSA and DARTS assay also confirmed that STING tended to be a target for the action of ICT. Collectively, our findings highlight a new binding mechanism between STING and ICT for the inhibition of transduction of the STING signaling pathway, suggesting that pharmacological or therapeutic intervention of the STING‐TBK1‐IFNβ singling axis may serve as an effective strategy to prevent the progression of inflammatory PMN and lung metastasis. [ABSTRACT FROM AUTHOR]

Advanced breast cancer with recurrent and distal organ metastasis is aggressive and incurable. The current existing treatment strategies for advanced breast cancer are difficult to achieve synergistic treatment of recurrent tumors and distant metastasis, resulting in poor clinical outcomes. Herein, a synergistic therapy strategy composed of biomimetic tumor‐derived exosomes (TEX)‐Liposome‐paclitaxel (PTX) with lung homing properties and gold nanorods (GNR)‐PEG, was designed, respectively. GNR‐PEG, with well biocompatibility, cured recurrent tumors effectively by thermal ablation under the in situ NIR irradiation. Meanwhile, GNR‐mediated thermal ablation activated the adaptive antitumor immune response, significantly increased the level of CD8+ T cells in lungs and the concentration of serum cytokines (tumor necrosis factor‐α, interlekin‐6, and interferon‐γ). Subsequently, TEX‐Liposome‐PTX preferentially accumulated in lung tissues due to autologous tumor‐derived TEX with inherent specific affinity to lung, resulting in a better therapeutic effect on lung metastasis tumors with the assistance of adaptive immunotherapy triggered by GNR in vivo. The enhanced therapeutic efficacy in advanced breast cancer was a combination of thermal ablation, adaptive antitumor immunotherapy, and targeted PTX chemotherapy. Hence, the synergistic strategy based on GNR and TEX‐Liposome provides selectivity to clinical treatment of advanced breast cancer with recurrent and metastasis. [ABSTRACT FROM AUTHOR]

Hypoxia‐inducible factor 2α (HIF2α) plays a pivotal role in breast tumor growth and metastasis. However, the regulatory mechanisms of HIF2α protein stability remain poorly understood. The precise role of the deubiquitinase (DUB) ubiquitin‐specific peptidase 5 (USP5) in breast cancer and the underlying mechanism remains largely unknown. Here, we identified USP5 as a novel DUB for HIF2α. Physically, USP5 interacts with HIF2α and protects HIF2α from ubiquitin‐proteasome degradation, thereby promoting the transcription of HIF2α target genes, such as SLC2A1, PLOD2, P4HA1, and VEGFA. USP5 ablation impairs breast cancer cells proliferation, colony formation, migration, and invasion. Moreover, USP5 is highly expressed in breast cancer, and the protein levels of USP5 are positively correlated with HIF2α protein levels in human breast cancer tissues. Importantly, high levels of USP5 leads to poor clinical outcome in patients with breast cancer. Collectively, USP5 stabilizes HIF2α through its DUB activity and provides a potential therapeutic target for breast cancer. [ABSTRACT FROM AUTHOR]

Bcl2-associated athanogene 4 (BAG4) has been found to be aberrantly expressed in several types of human cancers. However, little is known about its expression, role, and clinical significance in gastric cancer (GC). In this study, we aimed to address these issues and to explore the underlying mechanisms. The expression level of BAG4, measured by immunohistochemistry, was significantly higher in GC tissues than in paired normal tissues. Elevated BAG4 expression was positively correlated with T stage, lymph node metastasis, and tumor size of GC and was associated with unfavorable outcomes of the patients. The overexpression of BAG4 promoted the in vitro invasion and in vivo metastasis of GC cells, and opposite results were observed after silencing of BAG4. Silencing of BAG4 significantly reduced the phosphorylation of PI3K, AKT, and p65, whereas overexpression of BAG4 markedly enhanced the phosphorylation of these molecules. At the same time, manipulating BAG4 expression resulted in the corresponding changes in p65 nuclear translocation and ZEB1 expression. Luciferase reporter and chromatin immunoprecipitation assays verified that p65 binds to the promoter of ZEB1 to upregulate its transcription. Our results demonstrate that BAG4 plays an oncogenic role in the invasion and metastasis of GC cells by activating the PI3K/AKT/NF-κB/ZEB1 axis to induce epithelial-mesenchymal transition. [ABSTRACT FROM AUTHOR]

Antimalarial drugs Dihydroartemisinin (DHA) and chloroquine phosphate (CQ) exhibit evident anti-cancer activity, particularly as combination therapy. DHA and CQ combination therapy has been proved to exhibit higher cytotoxic effect in tumor cells and lower toxicity to normal cells than combination of artemisinin derivatives (ARTs) and anticancer chemotherapy drugs. However, different physiochemical properties of DHA and CQ, leading to distinctive in vivo outcomes, considerably limited their synergistic effect in cancer treatment. Herein, we developed a lipid nanoparticle (LNP) for co-delivery of DHA and CQ to inhibit proliferation and metastasis of colorectal cancer. Considering the beneficial effects of acid/reactive oxide species (ROS)-sensitive phospholipids and targeting ligands for colorectal cancer cells, an RGD peptide-modified pH/ROS dual-sensitive LNP loaded with DHA and CQ (RLNP/DC) was prepared. It exhibited optimal cytotoxicity and suppression of invasion and metastasis in HCT116 cells in vitro , attributable to irreversible upregulation of intracellular ROS levels, downregulation of VEGF expression, and upregulation of paxillin expression. A mouse model of orthotopic metastasis of colorectal cancer was established to evaluate anti-proliferation and anti-metastasis effects of RLNP/DC in vivo. Thus, an optimized nanoplatform for DHA and CQ combination therapy was developed in this study that offered potential antitumor efficacy against colorectal cancer. [ABSTRACT FROM AUTHOR]

The incidence and associated mortality of lung cancer in tin miners in Gejiu County and farmers in Xuanwei Country, Yunnan Province have been very high in the world. Current published literatures on the molecular mechanisms of lung cancer initiation and progression in Gejiu and Xuanwei County are still controversial. Studies confirmed that microRNA-34a (miR-34a) functioned as a vital tumor suppressor in tumorigenesis and progression. However, the role and precise mechanisms of miR-34a and its regulatory gene network in initiation and progression of lung cancer in Gejiu and Xuanwei County, Yunnan Province, have not been elucidated. In the current study, we first found that miR-34a was downregulated in Gejiu lung squamous carcinoma YTMLC-90, Xuanwei lung adenocarcinoma XWLC-05, and other non-small cell lung carcinoma (NSCLC) cell lines, and miR-34a overexpression inhibited cell proliferation, migration and invasion, as well as induced cell apoptosis in YTMLC-90 and XWLC-05 cells. Our findings revealed that miR-34a is critical and cannot be considered as the area-specific non-coding RNA in initiation and progression of lung cancer in Gejiu and Xuanwei County. Next we revealed that miR-34a overexpression suppressed lung cancer growth and metastasis partially via increasing PTEN but reducing CDK6 expression that might lead to subsequent inactivation of PI3K/AKT pathway. Furthermore, our findings demonstrated that YY1 functioned as a tumor suppressor gene in initiation and progression of lung cancer in Gejiu and Xuanwei County. In conclusion, our findings in the study confirmed that miR-34a overexpression could simultaneously suppress tumor growth and metastasis and play a vital role in tumorigenesis and progression of NSCLC via increasing PTEN and YY1 expression, but decreasing CDK6. Most interestingly, our findings also raised doubts about the current ideas about these area-specific diseases. [ABSTRACT FROM AUTHOR]

Progression of hepatocellular carcinoma involves multiple genetic and epigenetic alterations that promote cancer invasion and metastasis. Our recent study revealed that hyperphosphorylation of ezrin promotes intrahepatic metastasis in vivo and cell migration in vitro. Celastrol is a natural product from traditional Chinese medicine which has been used in treating liver cancer. However, the mechanism of action underlying celastrol treatment was less clear. Here we show that ROCK2 is a novel target of celastrol and inhibition of ROCK2 suppresses elicited ezrin activation and liver cancer cell migration. Using cell monolayer wound healing, we carried out a phenotype-based screen of natural products and discovered the efficacy of celastrol in inhibiting cell migration. The molecular target of celastrol was identified as ROCK2 using celastrol affinity pull-down assay. Our molecular docking analyses indicated celastrol binds to the active site of ROCK2 kinase. Mechanistically, celastrol inhibits the ROCK2-mediated phosphorylation of ezrin at Thr567 which harnesses liver cancer cell migration. Our findings suggest that targeting ROCK2-ezrin signaling is a potential therapeutic niche for celastrol-based intervention of cancer progression in hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Background: The poor prognosis of patients with ovarian cancer is mainly due to cancer progression. γ-Synuclein (SNCG) has reported as a critical player in cancer metastasis. However, its biological roles and mechanism are yet incompletely understood in ovarian cancer, especially in high-grade serous ovarian cancer (HGSOC). Methods: This is a retrospective study of 312 patients with ovarian cancer at a single center between 2006 and 2016. Ovarian cancer tissues were stained by immunohistochemistry to analyze the relationship between SNCG expression and clinicopathologic factors. The clinical outcomes versus SNCG expression level were evaluated by Kaplan–Meier method and multiple Cox regression analysis. Next, systematical functional experiments were given to examine the proliferation and metastatic abilities of SNCG both in vitro and in vivo using loss- and gain- of function approaches. Furthermore, the mechanisms of SNCG overexpression were examined by human phospho-kinase array kit and western blot analysis. Results: Clinically, the expression of SNCG was significantly upregulated in ovarian cancer compared with the borderline and benign tumor, normal ovary, and fallopian tube. Notably, the high level of SNCG correlated with high-risk clinicopathologic features and showed poor survival for patients with HGSOC, indicating an independent prognostic factor for these patients. Functionally, we observed that overexpression of SNCG promoted cell proliferation, tumor formation, migration, and invasion both in vitro and in vivo. Mechanistically, we identified that SNCG promoted cancer cell metastasis through activating the PI3K/AKT signaling pathway. Conclusions: Our results reveal SNCG up-regulation contributes to the poor clinical outcome of patients with HGSOC and highlight the metastasis-promoting function of SNCG via activating the PI3K/Akt signaling pathway in HGSOC. [ABSTRACT FROM AUTHOR]

Epstein‐Barr virus (EBV) BamHI A rightward transcripts (BART) encoded microRNAs (EBV‐miR‐BARTs) are abnormally highly expressed in nasopharyngeal carcinoma (NPC). This study aims to investigate the diagnostic and prognostic performance of miR‐BART7‐3p and miR‐BART13‐3p. Plasma levels of EBV DNA, miR‐BART7‐3p, and miR‐BART13‐3p were examined by quantitative PCR in 483 treatment‐naïve NPC patients and 243 controls without NPC. The prognostic performance was examined by comparing plasma levels with rates of distant metastasis during follow‐up. The area under the receiver operating characteristic curve for diagnosing NPC was 0.926 for EBV DNA, 0.964 for plasma miR‐BART7‐3p, 0.973 for miR‐BART13‐3p, and 0.997 for all three indices. Among 465 NPC patients without distant metastasis, the above‐median miR‐BART7‐3p and EBV DNA were independent risk for shorter distant metastasis‐free survival (DMFS) (hazard ratio [HR] = 2.94, 95% confidence interval [CI], 1.44‐5.97, P =.003; HR = 2.27, 95% CI, 1.26‐4.10, P =.006) in multivariate Cox regression. Epstein‐Barr virus DNA, miR‐BART7‐3p, and miR‐BART13‐3p after radiotherapy were detectable in 28.6%, 17.6%, and 54.7% of patients, respectively. In multivariate Cox regression, detectable miR‐BART7‐3p and EBV DNA were independent risks for shorter DMFS (HR = 4.13, 95% CI, 1.89‐9.01, P <.001; HR = 2.14, 95% CI, 1.04‐4.42, P =.039). The 4‐year DMFS rate was 92.0% in subjects (n = 156) with neither detectable miR‐BART7‐3p nor EBV DNA, 80.0% in subjects (n = 65) with either detectable miR‐BART7‐3p or EBV DNA, and 52.9% in subjects (n = 24) with both detectable miR‐BART7‐3p and EBV DNA after radiotherapy (P <.001). Circulating levels of miR‐BART7‐3p and miR‐BART13‐3p show excellent diagnostic performance for NPC. The combination of plasma levels of miR‐BART7‐3p and EBV DNA at diagnosis and after radiotherapy could help stratify patients by risk of poor DMFS. [ABSTRACT FROM AUTHOR]

Background/Objectives: Oral maintenance chemotherapy can effectively prolong overall survival (OS) in many types of metastatic cancer, but its role in metastatic nasopharyngeal carcinoma (mNPC) is unclear. In this study, the efficacy of oral maintenance chemotherapy in mNPC and the effectiveness of circulating tumor EBV‐DNA for screening patients were evaluated. Methods: Between June 2016 and December 2017, 141 patients with mNPC who received platinum‐based systemic chemotherapy were included (median follow‐up time, 21 months). Patients were classified into two groups according to the administration of oral maintenance chemotherapy. Plasma samples were collected before, during, and after treatment for the measurement of circulating EBV DNA. Results: The 2‐year OS was higher for patients who received maintenance chemotherapy than for patients without maintenance chemotherapy (78.9% vs 62.7%, P =.016). Patients with undetectable posttreatment EBV‐DNA after 4‐6 cycles of systemic chemotherapy (n = 73) had a higher 2‐year OS than that of patients with detectable EBV‐DNA (n = 68) (82.16% vs 51.45%, P =.001). For patients with undetectable posttreatment EBV‐DNA, OS was better for those with maintenance chemotherapy than for those without (86.7% vs 73%, P =.027). For patients with detectable posttreatment EBV‐DNA, maintenance chemotherapy did not improve outcomes (49.5% vs 55.4%, P =.824). The most common acute events were hematological toxicity, and all were tolerable and curable. Conclusions: Oral maintenance chemotherapy with S1 or capecitabine can improve OS in mNPC. Posttreatment EBV‐DNA was not only an independent prognosis factor for mNPC but also can screen out beneficiaries of maintenance chemotherapy. [ABSTRACT FROM AUTHOR]

aims to investigate the risk factors of prelaryngeal lymph node metastasis in papillary thyroid carcinoma and its clinical application value. Methods: The clinical pathological features and metastatic risks were statistically analyzed by reviewing 254 patients with papillary thyroid carcinoma, who received their first operation and prelaryngeal lymph node dissection in our department. Results: The detection of prelaryngeal lymph nodes, tumor size and any paratracheal lymph node metastasis were correlated with the number of paratracheal lymph node metastasis (P< 0.05), but these were not correlated with age, gender, multiple foci, tumor size, any paratracheal lymph node metastasis, metastatic location, or foci location (P> 0.05). Conclusion: Paratracheal lymph node metastasis indicates a high possibility of prelaryngeal lymph node metastasis. Paratracheal lymph node dissection combined with prelaryngeal lymph node dissection should be simultaneously considered in operations for thyroid papilla carcinoma. [ABSTRACT FROM AUTHOR]

Primitive neuroectodermal tumor (PNET) is a rare and highly malignant neoplasm composed of small round cells, which frequently occurs in children and adolescents. PNET originating from the prostate is even rarer. We report a case of PNET of the prostate with notalgia and paraplegia as the initial symptoms. Positron emission tomography–computed tomography scanning showed hypodense and hypermetabolism on the prostate; subsequently, we ascertained the diagnosis by transrectal ultrasound-guided biopsy. The patient underwent local vertebral radiotherapy combined with five courses of systematic chemotherapy. Disease progressed after 11 months, and the overall survival was 17 months. [ABSTRACT FROM AUTHOR]

Purpose: To compare the diagnostic accuracies of MDCT and high-resolution MRI (HR-MRI) for regional nodal metastases with different short-axis diameter ranges in rectal cancer patients. Methods: Rectal adenocarcinoma patients who underwent both MDCT and HR-MRI before surgery were included. The maximum short-axis diameters of the nodes were measured, and were classified as benign or malignant on imaging findings. All of the nodes were subdivided as follows: ≤ 5 mm (Group A), > 5 mm and ≤ 10 mm (Group B) , and > 10 mm (Group C). The postoperative pathological reports were used as the standard, and the sensitivity, specificity, accuracy, ROC curve, and AUC value were calculated for each subgroup. Results: A total of 592 nodes were included in the node-to-node evaluation. In Group A, the specificity and accuracy of HR-MRI were significantly higher than those of MDCT (99.28% vs. 93.99%, P < 0.001; 95.78% vs. 89.56%, P = 0.010; respectively). In Group B, the specificity and accuracy of HR-MRI were also higher than those of MDCT (98.36% vs. 55.74%, P < 0.001; 80.45% vs. 66.17%, P < 0.001; respectively). For Groups A and B, the AUCs of MDCT were both 0.65, whereas those of HR-MRI were 0.76 and 0.82, respectively. In Group C, all nine malignant nodes were correctly diagnosed metastases on MDCT, whereas one was misjudged as benign on HR-MRI. Conclusions: The diagnostic value of HR-MRI is superior to that of MDCT, with higher specificity, accuracy, and AUC values for HR-MRI than for MDCT. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is characterized by elevated metastasis, low survival, and poor response to therapy. Although many specific and effective agents for treating TNBC have been investigated, promising therapeutic options remain elusive. Here, we screened the inhibitory activities of three main components of Lithospermum erythrorhizon Sieb. et Zucc (shikonin, acetylshikonin, and β,β-dimethylacrylshikonin) on TNBC cells. The results revealed that shikonin potently decreased the viabilities of TNBC MDA-MB-231 and 4T1 cells but showed less cytotoxicity to normal mammary epithelial MCF-12A cells. Additionally, shikonin reversed the epithelial-to-mesenchymal transition (EMT) in MDA-MB-231 and 4T1 cells. Shikonin depressed cell migration and invasion, upregulated E-cadherin levels, downregulated N-cadherin, vimentin, and Snail levels, and reorganized the cytoskeletal proteins F-actin and vimentin. Shikonin reversed EMT by inhibiting activation of β-catenin signaling through attenuating β-catenin expression, nuclear accumulation, binding to T-cell factor consensus oligos, and transcription of its targeted EMT-related genes. Moreover, shikonin upregulated glycogen synthase kinase 3β (GSK-3β) levels, leading to enhanced phosphorylation and decreased levels of β-catenin. Furthermore, shikonin administration significantly inhibited lung metastasis of MDA-MB-231 cells in NOD/SCID mice accompanied by low systemic toxicity. Histological analysis confirmed that shikonin elevated levels of E-cadherin, phosphorylated β-catenin, and GSK-3β, and decreased levels of vimentin and β-catenin in pulmonary metastatic foci. These results indicated that shikonin potently inhibits TNBC metastasis by targeting the EMT via GSK-3β-regulated suppression of β-catenin signaling, which highlights the importance of shikonin as a potential candidate for novel anticancer therapeutics against TNBC. [ABSTRACT FROM AUTHOR]

Objective: To identify whether whole-tumour histogram analysis of pharmacokinetic parameters from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) could predict T-stage and regional lymph node metastasis (LNM) of resectable oesophageal squamous cell carcinoma (SCC).Materials and Methods: Forty-two consecutive patients with confirmed oesophageal SCC underwent thoracic DCE-MRI. Histogram metrics (median, mean, standard deviation [SD], skewness, kurtosis and entropy) of whole-tumour pharmacokinetic parameters including endothelial transfer constant (Ktrans), reflux rate (Kep) and fractional extravascular extracellular space volume (Ve) were generated by the Omni-Kinetics software. Histogram datasets were interpreted using the Mann-Whitney U test and receiver operating characteristic (ROC) statistical analyses.Results: The Mann-Whitney U tests revealed that the median, mean and SD of Ktrans, the SD and entropy of Kep, and the median, mean and entropy of Ve of T1-2 stage oesophageal SCC were lower when compared with T3 stage (all Ps < 0.05); and the ROC analysis showed that the entropy of Ve could reliably distinguish T1-2 stage from T3 stage with an area under ROC (AUC) of 0.773. The Mann-Whitney U tests illustrated that the entropy of Ktrans, and the median, mean, SD and entropy of Kep were higher while the skewness of Kep was lower in tumours with LNM than without LNM (all Ps < 0.05); and the ROC analysis demonstrated that the SD of Kep could best identify tumours with LNM with an AUC of 0.702.Conclusion: Whole-tumour histogram analysis of pharmacokinetic parameters of oesophageal SCC on DCE-MRI could be used to predict T-stage and regional LNM. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to analyze MR imaging features of renal epithelioid angiomyolipoma (EAML).Methods: This study included 17 patients with histopathologically confirmed renal EAML who underwent renal MRI scanning before radical or partial nephrectomy. MR images were retrospectively reviewed and correlated with pathological findings.Result: Fifteen lesions (88.2%) appeared as round or oval. The tumor-kidney interface was round in 14 lesions (82.4%). Fifteen tumors (88.2%) presented mainly isointensity on T1WI, and eleven tumors (64.7%) presented mainly hypointensity on T2WI. Twelve lesions (70.6%) showed restricted diffusion on DWI, and the mean ADC value was 1.23 ± 0.28 × 10−3mm2/s. Minimal fat component was identified as loss of signal intensity on opposed-phase MR images in 6 cases (35.3%). Sixteen lesions (100%) demonstrated inhomogeneous enhancement, and 7 of 16 masses (43.8%) showed reticular enhancement. Rapid wash-in and wash-out enhancement was seen in 13 masses (81.3%). In the corticomedullary phase, the mass showed markedly enhancement in 14 cases (87.5%). The irregular vessels and hemorrhage were detected in 4 cases (23.5%) and 7 cases (41.2%), respectively. One patient (5.9%) had a lymph node involvement at initial diagnosis, and showed distant metastasis after operation. In the immunohistochemical analysis, 15 tumors (88.2%) were positive for melanocytic marker (HMB45 or Melan-A), and all cases (100%) were negative for epithelial-associated markers (CK or AE1/AE3).Conclusion: The presence of hypointensity on T2WI, restricted diffusion on DWI, round tumor-kidney interface, reticular, and marked enhancement (rapid wash-in and wash-out) should further raise suspicion for renal EAML. The diagnosis may be confirmed by pathological analysis. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

Background: Gallbladder cancer is an invasive cancer with a discouraging prognosis, and early detection and active intervention are of great value.Aims: To establish a more accurate and effective survival model to predict the prognosis of patients with non-metastatic gallbladder after surgical resection.Methods: A retrospective analysis was conducted in non-metastatic gallbladder cancer patients who were registered in the surveillance, epidemiology and end results database from 2010 to 2014. Univariate analysis and multivariate analysis were performed for the related factors that might affect the gallbladder cancer-specific survival. A prognostic gallbladder cancer-specific survival model was established using the nomogram tool. The discrimination test was measured by the c-index, and the conformance test was performed by a calibration curve.Results: In all, 1422 patients with non-metastatic gallbladder cancer were identified. The prognostic factors include age, gender, lymph node dissection, postoperative chemotherapy, tumor size, histological grading, pT stage and pN stage. The gallbladder cancer-specific survival model was established based on the prognostic factors. The model's c-index was 0.775, and the 7th AJCC staging c-index was 0.649. The calibration curves showed a good correlation between prediction and actual survival.Conclusions: This study established the gallbladder cancer-specific survival model successfully. Compared with the 7th AJCC stage, this model refined the contribution of the pT stage, pN stage and other related factors and was demonstrated to be more accurate and reliable. More importantly, this model may allow clinicians to screen patients with a poor prognosis for closer follow-up or adjuvant treatment. [ABSTRACT FROM AUTHOR]

Purpose Prostate circulating tumor cells escape into peripheral blood and enter bone marrow as disseminated tumor cells, representing an early step before conventionally detectable metastasis. It is unclear how frequently this occurs in localized disease and existing detection methods rely on epithelial markers with low specificity and sensitivity. We used multiple methodologies of disseminated tumor cell detection in bone marrow harvested at radical prostatectomy. Materials and Methods Bone marrow was harvested from 208 clinically localized cases, 16 controls and 5 metastatic cases with peripheral blood obtained from 37 metastatic cases. Samples were evaluated at 4 centers with 4 distinct platforms using antibody enrichment with the AdnaTest (Qiagen®) or VERSA (versatile exclusion based rare sample analysis), or whole sample interrogation with the RareCyte platform (Seattle, Washington) or HD-SCA (high definition single cell assay) using traditional epithelial markers and prostate specific markers. We investigated the sensitivity and specificity of these markers by evaluating expression levels in control and metastatic cases. Results EpCAM , NKX3.1 and AR were nonspecifically expressed in controls and in most samples using AdnaTest with no relation to perioperative variables. Only 1 patient with localized disease showed positive results for the prostate specific marker PSA . With the VERSA platform no localized case demonstrated disseminated tumor cells. With the RareCyte and HD-SCA platforms only a single patient had 1 disseminated tumor cell. Conclusions Evaluation across multiple platforms revealed that epithelial markers are nonspecific in bone marrow and, thus, not suitable for disseminated tumor cell detection. Using prostate specific markers disseminated tumor cells were typically not detected in patients with localized prostate cancer. [ABSTRACT FROM AUTHOR]

Introduction: Epithelial-mesenchymal transition (EMT) is regarded as a crucial process of invasion and metastasis, which contribute greatly to cancer-related relapse and death. Based on research results that hypoxia can trigger gastric cancer EMT and decreasing lactate production can selectively kill hypoxic cancer cells, we infer that lactate dehydrogenase A (LDH-A) transforming pyruvate into lactate is at least in part responsible for poor prognosis of gastric cancer. Materials and methods: We used siRNA to knock down LDH-A in intestinal-type gastric cancer (ITGC) cell lines SGC7901 and BGC823. Western blot and RT-PCR were applied to detect mRNA and protein expression of EMT-related genes, respectively. Transwell invasion assay and migration assay were applied to study invasive and migratory abilities, respectively. Survival analysis was used to evaluate prognostic values. Results and conclusion: The results of in vitro experiment demonstrated that LDH-A facilitates ITGC cells' invasion and migration by upregulating ZEB2. The positive correlation between LDH-A and ZEB2 was verified in 371 ITGC specimens. Survival analysis indicated that co-expression of LDH-A/ZEB2 had synergetic power to predict overall survival. Thus, we conclude that the close relationship between LDH-A and ZEB2 may offer a potential therapeutic strategy for ITGC. [ABSTRACT FROM AUTHOR]

The colorectal cancer ( CRC) is one of the leading causes of cancer-related death worldwide, but the pathogenesis of CRC remains not well-known. Increasing studies have highlighted the critical roles of long noncoding RNAs (lnc RNAs) in tumorigenesis and cancer cells metastasis, however, the expression pattern, biological roles of lnc RNAs, and the mechanisms responsible for their function in CRC remain elusive. In this study, we performed a genome-wide comprehensive analysis of lnc RNAs profiling and clinical relevance to identify novel lnc RNAs for the further study in CRC. RNA sequencing and microarray data obtained from The Cancer Genome Atlas ( TCGA) and Gene Expression Omnibus ( GEO) were annotated and analyzed to find differentially expressed lnc RNAs in CRC. Analysis of these datasets revealed that hundreds of lnc RNAs expression are dysregulated in CRC tissues when compared with normal tissues. By genomic variation analyses, we identified that some of these lnc RNAs dysregulation is associated with the copy number amplification or deletion. Moreover, many lnc RNAs expression levels are significantly associated with CRC patients overall and recurrence-free survivals, such as H19, LEF1- AS1, and RP11-296E3.2. Furthermore, we identified one liver metastasis-associated lnc RNA termed LUCAT1 in CRC by analyzing lnc RNAs expression profiles in the CRC tissues from patients with liver metastasis compared with the CRC tissues without metastasis. Finally, loss-of-function assays determined that knockdown of LUCAT1 could impair CRC cells invasion. Taken together, aberrantly expressed lnc RNAs may play critical roles in the development and liver metastasis of CRC, and our findings may provide useful resource for identification of novel biomarkers of CRC. [ABSTRACT FROM AUTHOR]

Background c-MET has recently been identified as a promising novel target in non-small cell lung cancer ( NSCLC). We detected the consistency of c-MET gene amplification in metastatic lymph nodes and tumor tissues of NSCLC patients and discuss the clinical application value of c-MET gene amplification in metastatic lymph nodes. Methods Real-time fluorescent quantitative PCR was used to test tumor tissues in 368 NSCLC patients and 178 paired metastatic lymph node samples. The amplification consistency in metastatic lymph nodes and tissue samples were compared and the correlation between c-MET gene amplification and the clinical characteristics of patients was analyzed. Results The c-MET gene amplification rate was 8.97% (33/368) in tumor tissues. Of the 178 paired cases, c-MET gene amplification was positive in 7.95% (15/178) of cancerous tissues and 18.54% (33/178) of metastatic lymph nodes. c-MET gene amplification was detected more frequently in metastatic lymph nodes than in primary cancerous tissue. When metastatic lymph nodes were used as surrogate samples of primary cancerous tissues, the sensitivity was 86.67% (13/15) and the specificity was 87.69% (143/163). Conclusions Screening for c-MET gene amplification in lymph node metastases could determine which patients are eligible for tyrosine kinase inhibitor therapy. Lymph node metastasis can predict c-MET gene amplification in a primary tumor and guide the clinical use of c-MET gene targeted drugs. [ABSTRACT FROM AUTHOR]