Progression Of Malignant Disease Research Articles

Circulating Plasma Gelsolin: A Predictor of Favorable Clinical Outcomes in Head and Neck Cancer and Sensitive Biomarker for Early Disease Diagnosis Combined with Soluble Fas Ligand

Head and neck cancer (HNC) accounts for more than 330,000 cancer deaths annually worldwide. Despite late diagnosis being a major factor contributing to HNC mortality, no satisfactory biomarkers exist for early disease detection. Cytoplasmic gelsolin (cGSN) was discovered to predict disease progression in HNC and other malignancies, and circulating plasma gelsolin (pGSN) levels are significantly correlated with infectious and inflammatory disease prognoses. Here, the plasma levels of five candidate biomarkers (circulating pGSN, squamous cell carcinoma antigen, cytokeratin 19 fragment, soluble Fas, and soluble Fas ligand (sFasL)) in 202 patients with HNC and 45 healthy controls were measured using enzyme-linked immunosorbent assay or Millipore cancer multiplex assay. The results demonstrated that circulating pGSN levels were significantly lower in patients with HNC than in healthy controls. Moreover, circulating pGSN outperformed other candidate biomarkers as an independent diagnostic biomarker of HNC in both sensitivity (82.7%) and specificity (95.6%). Receiver operating characteristic curves indicated that combined pGSN and sFasL levels further augmented this sensitivity (90.6%) for early disease detection. Moreover, higher pGSN levels predicted improved prognosis at both 5-year overall survival and progression-free survival. In conclusion, circulating pGSN could be an independent predictor of favorable clinical outcomes and a novel biomarker for the early HNC detection in combination with sFasL.

Noncoding RNAs in oral premalignant disorders and oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) has the highest mortality rate among all head and neck cancers and a relatively low five-year survival rate. Generally, the development of an oral mucosal malignancy represents a multistep process beginning with normal oral mucosa epithelium and culminating in OSCC after transitioning through intermediary oral premalignant disorders (OPMDs), during which dysplasia is often observed. Noncoding RNAs (ncRNAs) are RNAs that are not translated into proteins, but still can participate in regulating neoplastic cell behavior. Recently, data have emerged on the role of ncRNAs in the progression of oral mucosal malignant diseases, but the exact mechanisms through which ncRNAs are involved remain to be elucidated. Knowledge on ncRNAs has added an extra layer of complexity to our understanding of the malignant progression of oral mucosal diseases. The identification of ncRNAs in multiple body fluids as biomarkers may provide new diagnostic options that can be used for the diagnosis and prognosis of OPMDs and OSCC, respectively. Despite overall advances that have been made in cancer treatment, the treatment options for OPMDs and OSCC are still limited. Several studies have shown that ncRNA-based treatment regimens may hold promise as alternative methods for treating OPMDs and OSCC. The use of ncRNAs as therapeutic agents, including miR-155, miR-34 and lncRNA HOTAIR, appear promising.

The circular RNA circMAST1 promotes hepatocellular carcinoma cell proliferation and migration by sponging miR-1299 and regulating CTNND1 expression

Circular RNAs (circRNAs) are a class of non-coding RNAs with a loop structure; however, their functions remain largely unknown. Growing evidence suggests that circRNAs play a pivotal role in the progression of malignant diseases. However, the expression profiles and function of circRNAs in hepatocellular carcinoma (HCC) remain unclear. We investigated the expression of microtubule-associated serine/threonine kinase 1 (MAST1) circRNA (circMAST1) in HCC and healthy tissues using bioinformatics, quantitative real-time PCR (qRT-PCR), and fluorescence in situ hybridization. Luciferase reporter assays were performed to assess the interaction between circMAST1 and miR-1299. Proliferation assays, colony formation assays, flow cytometry, transwell assays, and western blotting were also performed. A mouse xenograft model was also used to determine the effect of circMAST1 on HCC growth in vivo. CircMAST1 was upregulated in HCC tissues and cell lines; silencing via small interfering RNA inhibited migration, invasion, and proliferation of HCC cell lines in vitro as well as tumor growth in vivo. Furthermore, the expression of circMAST1 was positively correlated with catenin delta-1 (CTNND1) and negatively correlated with microRNA (miR)-1299 in HCC clinical samples. Importantly, circMAST1 sponged miR-1299 to stabilize the expression of CTNND1 and promoted tumorigenic features in HCC cell lines. We found that circMAST1 may serve as a novel biomarker for HCC. Moreover, circMAST1 elicits HCC progression by sponging miRNA-1299 and stabilizing CTNND1. Our data provide potential options for therapeutic targets in patients with HCC.

A miR-205-LPCAT1 axis contributes to proliferation and progression in multiple cancers

In the past two decades, miRNAs have been demonstrated to play critical roles in development and progression of malignant diseases. To identify the role and mechanism of miRNA are urgent for the application of miRNA-based therapeutics in cancers. MiR-205 is a conserved miRNA from the invertebrate to mammalian species. Previous studies showed a large body of evidence to demonstrate the oncogenic or tumor suppressive role of it in different types of cancers. Our aim here is to clarify the role and novel mechanism of miR-205 in solid tumors. In the present study, we found that a high level of miR-205 is an independent biomarker for favorable prognosis in LIHC, HNSCC and LUSC. In the functional experiment, we stably expressed miR-205 in tumor cell lines derived from above mentioned cancers. The result showed that overexpression of miR-205 significantly inhibits cancer cell proliferation. Mechanistically, we identified that the lysophosphatidylcholine acyltransferase-1 (LPCAT1) is a novel target of miR-205 in multiple cancer cells. Furthermore, we found that LPCAT1 is required for sustained proliferation of cancer cells and a high level of it is closely associated with poor prognosis in clinical patients. Collectively, we revealed the important prognostic value of a miR-205-LPCAT1 axis in multiple cancers and highlighted an essential role of LPCAT1 in miR-205-regulated cancer cell proliferation. All these discoveries make a miR-205-LPCAT1 axis to shed light upon a potential therapeutic target in cancer treatment.

Risk factors in the prediction of long-term patency of Resonance metallic ureteric stent in malignant ureteric obstruction.

ObjectivesCancer is the second leading cause of death globally in 2018 with an estimated 9.6 million deaths. The costs of managing malignant ureteric obstruction (MUO) is a significant burden to any healthcare system. However, the management of MUO has long been a challenge for urologists. The standard options of percutaneous nephrostomy or polymer double J stents are fraught with problems. We report a large patient series with long‐term follow‐up in the use of Resonance metallic ureteric stents to relieve MUO, and identification of risk factors associated with stent failure.Patients and methodsAll patients with MUO who were arranged to have Resonance metallic ureteric stent insertion at two university hospitals were included in this cohort study, starting from June 2011 to July 2016. Data were retrieved retrospectively. The primary outcome was the total duration of stent patency before stent failure due to malignant disease progression. Stent failure was defined as ureteric obstruction identified on imaging (functional radioisotope scan or antegrade pyelogram), acute renal failure resolved by subsequent percutaneous nephrostomy, or any other cause requiring stent removal prematurely. Secondary outcomes were identification of factors associated with stent failure, grade III or above complication, and development of a risk‐adopted model to predict metallic ureteric stent patency rates in MUO patients. Median duration of functioning metallic ureteric stent was determined with Kaplan‐Meier survival curve.ResultsA total of 124 renal units in 95 patients with MUO were eligible for the study, with a median follow‐up period of 22.9 months. About 106 (85.5%) renal units had successful metallic stent insertion, of whom 41 (33.1%) renal units ultimately progressed to ureteric obstruction despite the metallic stents, and required subsequent insertion of nephrostomies. Median duration of functioning metallic ureteric stents was 25 months. Female gender (HR 3.0, 95% CI: 1.3‐7.2, P = .014) and suspicious bladder lesion (HR 2.9, 95% CI: 1.4‐6.2, P = .005) were independent risk factors for stent failure, respectively. Stratifying patients into low (0 risk factor), intermediate (1 risk factor), and high (2 risk factors) risk groups, we found that this could predict the duration of stent patency in MUO with the metallic stents. (Low risk: 30.3 months vs intermediate group: 17.8 months vs high risk: 4.9 months, P < .001).ConclusionResonance metallic ureteral stents are able provide a median of 25 months of ureteric drainage in patients with MUO. Determining whether a patient has one or both risks factors (female gender and bladder lesion) will allow one to estimate the duration of metallic stent patency, which in turn may aid in determining cost‐effectiveness in individual patients.

Expression of CLEC4G in liver disease and its correlation with hepatocellular carcinoma

Objective To investigate the expression level of C-type lectin domain family 4 member G (CLEC4G) in liver disease tissues and its correlation with the clinicopathological characteristics of hepatocellular carcinoma (HCC) patients. Methods The cancer tissue and the corresponding adjacent tissues (at least 2 cm from the edge of the cancer tissue), cut in surgeries from January to December in 2019, of 40 HCC patients in Zhuzhou Central Hospital, as well as 10 normal liver tissue samples (seen as far away as possible from the edge of the cancer tissue with naked eyes) and 10 liver cirrhosis samples were analyzed retrospectively. The tumor genome atlas (TCGA) database was used to screen the HCC transcriptome data sets, and bioinformatics methods were used to make expression heat maps and box maps which can help analyze the difference of CLEC4G in cancer and adjacent tissues. The mRNA expression level of CLEC4G was detected by conducting real-time fluorescence quantitative PCR (qRT-PCR), and the protein expression level of CLEC4G was detected by immunohistochemistry (IHC). The measurement data were expressed as mean±standard deviation (Mean±SD). Group t test was used for inter-group comparison. The counting information was expressed as a percentage (%). The χ2 test was adopted to analyze the correlation between CLEC4G expression level and the clinicopathological features of patients. Results The expression level of CLEC4G in cancer tissues was significantly decreased in heat map compared with that in adjacent tissues. In the box figure, the relative expression of CLEC4G mRNA in the cancer tissues was (82.5±18.9) and (3 354.4±296.2) in paracancer tissues, with statistically significant difference (P<0.001). Respectively, qRT-PCR and IHC showed that mRNA of CLEC4G were abundant in normal liver tissues (3 301.3±286.4), while they were very little in liver cancer tissues (63.6±32.9), significantly decreasing in liver cirrhosis (1 742.6±208.7) and paracancer tissues (1 553.2±249.9), with statistically significant difference (P<0.001). Moreover, low CLEC4G expression level was associated with tumor vascular metastasis in HCC patients. Conclusions CLEC4G is highly expressed in normal liver tissue, but with the progression of malignant liver disease, it is significantly decreased with little expression in HCC tissue. It can be expected to be a good marker for the pathological diagnosis of HCC. Key words: Carcinoma, hepatocellular; Liver cirrhosis; Neoplasms, vascular tissue; Liver tissue

Apatinib exhibits cytotoxicity toward leukemia cells by targeting VEGFR2-mediated prosurvival signaling and angiogenesis

ObjectiveVascular permeability contributes to disease progression and drug resistance in hematological malignancies, including AML. Thus, targeting angiogenic signaling is a promising treatment strategy, especially for relapsed and resistant AML. The aim of this study was to evaluate the efficacy of apatinib, a novel receptor tyrosine kinase inhibitor that selectively targets VEGFR2. MethodsSeveral AML cell lines were exposed to various concentrations of apatinib, and then CCK8 and Annexin V/PI assays were performed to determine IC50 values and apoptosis, respectively. The effect of apatinib against primary AML cells from 57 adult patients and 11 normal controls was also analyzed utilizing an apoptosis assay. Next, we tested the underlying mechanism of apatinib in AML using western blotting and mass cytometry (CyTOF). Finally, the activity of apatinib against tumor growth and angiogenesis was further evaluated in vivo in xenograft models. ResultsWe found apatinib significantly inhibited growth and promoted apoptosis in AML cell lines in vitro. Similarly, apatinib showed cytotoxicity against primary AML cells but didn't affect normal BMMCs. Its effect was highly correlated with several clinical features, such as NPM1 mutation, extramedullary infiltration, relapsed/refractory disease, and M2 and M5 FAB subtypes. In addition, apatinib suppressed AML growth and attenuated angiogenesis in xenograft models. Mechanistically, apatinib-induced cytotoxicity was closely associated with inhibition of the VEGFR2-mediated Src/STAT3 and AKT/mTOR pathways and induction of mitochondria-mediated apoptosis. ConclusionApatinib exerts antileukemia effects by targeting VEGFR2-induced prosurvival signaling and angiogenesis, thus providing a rationale for the application of apatinib in AML.

Malignant Restenosis and Progression of Disease in Psoriatic Patients Undergoing Coronary Interventions: Is it the Koebner's Phenomena to Blame?

Malignant Restenosis and Progression of Disease in Psoriatic Patients Undergoing Coronary Interventions: Is it the Koebner's Phenomena to Blame?

COT-12 CLINICAL MANAGEMENT AND TIMING OF SURGICAL TREATMENT FOR ASYMPTOMATIC GLIOMA

BACKGROUNDIn Japan, there are many cases where intracranial diseases are found accidentally due to the widespread use of MRI and brain check-up. Unruptured cerebral aneurysms and asymptomatic cerebral infarctions are often diagnosed, but asymptomatic glioma is rarely diagnosed. We analyzed the asymptomatic gliomas retrospectively among grade 2 or higher gliomas that had undergone diagnostic imaging or surgical treatment in our institution.MATERIAL AND METHODSOf 166 adults with grade 2 or higher grade glioma treated in our institution between 2007 and 2018, 15 cases were asymptomatic. Twelve cases were males and 3 were females, with an average age of 55.1 years (34–79 years). There were 7 cases found in brain check-up, 6 cases in the follow-up of other intracranial diseases, and 2 cases in migraine. Twelve patients, except 3 patients, have undergone surgical treatment, and the average time from an initial imaging to surgical treatment was 51.1 weeks (2 to 329 weeks). Eight patients were treated after radiological follow-up and 4 cases are treated within 2 months after the tumor was discovered. The pathological diagnosis was grade 2: 5 cases, grade 3: 2 cases, and grade 4: 5 cases. Three patients without surgical treatment were diagnosed as grade 2 on MRI. Six patients died during follow-up. The median survival time from the first surgical treatment for grade 3 and 4 glioma was 17 months.CONCLUSIONIncidence of asymptomatic glioma is very rare. Even for asymptomatic gliomas, the prognosis is not so good due to malignant transformation and disease progression. It is important to explain the natural course of disease and treatment strategy accurately.

Tumor-Associated Macrophages in Hematologic Malignancies: New Insights and Targeted Therapies.

The growth of hematologic malignant cells can be facilitated by other non-tumor cells within the same microenvironment, including stromal, vascular, immune and mesenchymal stem cells. Macrophages are an integral part of the human innate immune system and the tumor microenvironment. Complex interplays between the malignant hematologic cells and the infiltrating macrophages promote the formation of leukemia, lymphoma or myeloma-associated macrophages. These pro-tumorigenic macrophages in turn play an important part in facilitating tumor growth, metastasis and chemotherapeutic resistance. Previous reports have highlighted the association between tumor-associated macrophages (TAMs) and disease progression in hematologic malignancies. This review summarizes the role of TAMs in different subtypes of leukemia, lymphoma and myeloma, focusing on new insights and targeted therapies.

The neural regulation of cancer.

Cancers hijack mechanisms of neural plasticity to promote malignant disease progression

208 The Aryl hydrocarbon receptor (AhR) induces the expression of aldo-keto reductase (AKR) 1C3 in keratinocytes in a ligand-specific manner

The aldo-keto reductase 1C3 (AKR1C3) belongs to a superfamily of NAD(P)H-dependent oxidoreductases, which metabolize prostaglandins and steroid hormones. It is involved in the pathogenesis of various skin malignancies, such as atopic dermatitis (AD) and squamous cell carcinoma, which are triggered by polycyclic aromatic hydrocarbons and related environmental pollutants. These chemicals are able to bind to the aryl hydrocarbon receptor (AhR), a cytosolic transcription factor that, upon activation, rapidly translocates to the nucleus to induce the expression of target genes, for instance encoding for cytochrome P450 (CYP) 1A monooxygenases. In this study, we identified AKR1C3 as a target gene of the AhR in immortalized keratinocytes. Interestingly, activation of AhR by benzo(a)pyrene (BaP), but not by PCB126, a dioxin-like polychlorinated biphenyl, induced AKR1C3 expression. Chemical and genetic inhibition of AhR reversed the BaP-mediated expression of AKR1C3 and CYP1A1, providing evidence for an AhR-dependent effect. As the expression of CYP1A1 was induced by both ligands, we hypothesize that AKR1C3 is regulated by a non-canonical AhR signaling pathway. Upon ligand-binding, AhR undergoes conformational changes and c-Src, as an integral component of the cytosolic multiprotein complex, is released. This tyrosine kinase, in turn, activates EGFR-MEK-ERK signal transduction. Accordingly, chemical inhibition of either c-Src, EGFR and MEK abrogated the BaP-triggered induction of AKR1C3. SDS-PAGE/western blot analyses confirmed the AhR-dependent activation of this cascade in response to BaP treatment. Taken together, these data provide a new mechanism through which pollutants may regulate AKR1C3 expression and thereby contribute to the progression of inflammatory and malignant skin diseases.

A reliable Epstein-Barr Virus classification based on phylogenomic and population analyses

The Epstein-Barr virus (EBV) infects more than 90% of the human population, playing a key role in the origin and progression of malignant and non-malignant diseases. Many attempts have been made to classify EBV according to clinical or epidemiological information; however, these classifications show frequent incongruences. For instance, they use a small subset of genes for sorting strains but fail to consider the enormous genomic variability and abundant recombinant regions present in the EBV genome. These could lead to diversity overestimation, alter the tree topology and misinterpret viral types when classified, therefore, a reliable EBV phylogenetic classification is needed to minimize recombination signals. Recombination events occur 2.5-times more often than mutation events, suggesting that recombination has a much stronger impact than mutation in EBV genomic diversity, detected within common ancestral node positions. The Hierarchical Bayesian Analysis of Population Structure (hierBAPS) resulted in the differentiation of 12 EBV populations showed seven monophyletic and five paraphyletic. The populations identified were related to geographic location, of which three populations (EBV-p1/Asia/GC, EBV-p2/Asia II/Tumors and EBV-p4/China/NPC) were related to tumor development. Therefore, we proposed a new consistent and non-simplistic EBV classification, beneficial in minimizing the recombination signal in the phylogeny reconstruction, investigating geography relationship and even infer associations to human diseases. These EBV classifications could also be useful in developing diagnostic applications or defining which strains need epidemiological surveillance.

Causes of Elevated Troponin in Patients with Normal Coronary Angiography

Troponin rise indicates myocardial cell injury. However, elevated values of troponin are not always consequence of infarction or ischemia. In this paper, aim was to elucidate diverse etiologies of elevated troponin in patients with normal coronary angiography. At KBC Zagreb in 2014 there was 976 patients identified from catheterization database who underwent coronary angiography due to suspicion of acute coronary syndrome (ACS). We identified 30 (3.1%) patients who had alternative cause for myocyte injury other than coronary artery disease (CAD), meaning that there was less than 30 % coronary arterial luminal stenosis. The elevation of cardiac troponin T (cTnT) in patients with normal coronary angiography was attributed to diverse etiologies, including hypertensive crisis, Takotsubo syndrome, severe aortic stenosis, atrial fibrillation (AF), chronic obstructive pulmonary disease (COPD) exacerbation, advanced heart failure, hypertensive cardiomyopathy, acute pulmonary embolism, malignant disease progression, and cardiogenic shock. Apart from ACS, cTnT could be elevated in a number of different conditions, which should be considered according to clinical presentation, different diagnostic procedure, and still could reflect myonecrosis, even in the absence of significant angiographic CAD.

Abstract SY21-01: Analyzing tumor metabolism in patients

Abstract Metabolism is dynamic and responds to a wide range of cell-intrinsic and cell-extrinsic factors. Many human diseases involve perturbations of metabolism at the cellular level, and in many cases normalizing the metabolic state has proven to be therapeutically valuable. Cancer is one such disease, in which factors both intrinsic and extrinsic to the malignant cell impact tumor biology and disease progression. In cancer, cell-intrinsic influences on metabolism include somatically-acquired mutations in oncogenes and tumor suppressor genes, many of which regulate metabolic activity. Cell-extrinsic factors include nutrient access, which may become limiting due to inadequate vasculature and intense fuel utilization, and metabolic interactions with stromal and immune cells. A major challenge in cancer metabolism research is to understand how these various factors culminate in the metabolic phenotype of an intact tumor, and ultimately to identify which altered pathways represent potential therapeutic targets. Among the many metabolic pathways reprogrammed in cancer, nucleotide metabolism and responses to DNA damage are highly integrated with aberrant signaling and gene regulatory networks in cancer. We have taken two parallel approaches to understand metabolic complexity and identify potential therapeutic liabilities in human cancer. The first uses a combination of multi-parametric imaging and intraoperative stable isotope infusions to assess metabolic fluxes in patients with solid tumors, and to compare fluxes between tumors and adjacent tissue. Genomic, histological and metabolic analysis of tumor samples allows us to correlate various intrinsic and extrinsic factors to specific aspects of the metabolic phenotype. The second approach uses standardized culture conditions to assess cell-intrinsic heterogeneity of metabolic preferences and dependencies in large panels of human cancer cell lines. This approach has uncovered liabilities associated with specific molecular subtypes of non-small cell and small cell lung cancerm ncluding several related to nucleotide and nucleic acid metabolism. I will discuss the application of these approaches to metabolic heterogeneity in human cancer, with an emphasis on features relevant to intact tumors and therapeutic liabilities and the role of metabolic imaging in studying cancer metabolism. Citation Format: Ralph J. Deberardinis. Analyzing tumor metabolism in patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY21-01.

New tools for pathology: a user's review of a highly multiplexed method for in situ analysis of protein and RNA expression in tissue.

Tumor cell heterogeneity and tumor cell-stromal interactions are being explored as determinants of disease progression and treatment resistance in solid tumor and hematological malignancies. As such, tools simultaneously capable of highly multiplexed profiling of tissues' protein and RNA content, as well as interrogation of rare or single cells, are required to precisely characterize constituent tumor cell populations, infiltrating lymphocytes and stromal elements. Access to spatial relationships will enable more precise characterization of tumors, support patient stratification and may help to identify novel drug targets. Multiple platforms are being developed to address these critical unmet needs. The NanoString digital spatial profiling (DSP) platform enables highly multiplexed, spatial assessment of protein and/or RNA targets in tissues by detecting oligonucleotide barcodes conjugated via a photocleavable linker to primary antibodies or nucleic acid probes. Although this platform enables high-dimensional spatial interrogation of tissue protein and RNA expression, a detailed understanding of its composition, function and chemistry is advisable to guide experimental design and data interpretation. The purpose of this review is to provide an independent, comprehensive description of the DSP technology, including an overview of NanoString's capture and antibody barcode conjugation chemistries, experimental workflow, data output and analysis methods. The DSP technology will be discussed in the context of other highly multiplexed immunohistochemistry methods, including imaging mass cytometry and multiplexed ion beam imaging, to inform potential users of the advantages and limitations of each. Additional issues such as preanalytical variability, sampling and specimen adequacy will be considered with respect to the platforms to inform potential experimental design. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

RETRACTED ARTICLE: CircPSMC3 suppresses the proliferation and metastasis of gastric cancer by acting as a competitive endogenous RNA through sponging miR-296-5p

BackgroundCircular RNAs (circRNAs) are a class of non-coding RNAs with a loop structure, but its functions remain largely unknown. Growing evidence has revealed that circRNAs play a striking role as functional RNAs in the progression of malignant disease. However, the precise role of circRNAs in gastric cancer (GC) remains unclear.MethodsCircRNAs were determined by human circRNA array analysis and quantitative reverse transcription polymerase reaction. Luciferase reporter, RNA pull down, and fluorescence in situ hybridization assays were employed to test the interaction between circPSMC3 and miR-296-5p. Ectopic over-expression and siRNA-mediated knockdown of circPSMC3, proliferation, migration and invasion in vitro, and in vivo experiment of metastasis were used to evaluate the function of circPSMC3.ResultsCircPSMC3 rather than liner PSMC3 mRNA was down-regulated in GC tissues, corresponding plasmas from GC patients as well as GC cell lines compared to normal controls. Lower circPSMC3 expression in GC patients was correlated with higher TNM stage and shorter overall survival. Over-expression of circPSMC3 and miR-296-5p inhibitor could inhibit the tumorigenesis of gastric cancer cells in vivo and vitro whereas co-transfection of circPSMC3 and miRNA-296-5p could counteract this effect. Importantly, we demonstrated that circPSMC3 could act as a sponge of miR-296-5p to regulate the expression of Phosphatase and Tensin Homolog (PTEN), and further suppress the tumorigenesis of gastric cancer cells.ConclusionOur study reveals that circPSMC3 can serve as a novel potential circulating biomarker for detection of GC. CircPSMC3 participates in progression of gastric cancer by sponging miRNA-296-5p with PTEN, providing a new insight into the treatment of gastric cancer.

POH1 contributes to hyperactivation of TGF-β signaling and facilitates hepatocellular carcinoma metastasis through deubiquitinating TGF-β receptors and caveolin-1.

BackgroundHyper-activation of TGF-β signaling is critically involved in progression of hepatocellular carcinoma (HCC). However, the events that contribute to the dysregulation of TGF-β pathway in HCC, especially at the post-translational level, are not well understood.MethodsAssociations of deubiquitinase POH1 with TGF-β signaling activity and the outcomes of HCC patients were examined by data mining of online HCC datasets, immunohistochemistry analyses using human HCC specimens, spearman correlation and survival analyses. The effects of POH1 on the ubiquitination and stability of the TGF-β receptors (TGFBR1 and TGFBR2) and the activation of downstream effectors were tested by western blotting. Primary mouse liver tissues from polyinosinic:polycytidylic acid (poly I:C)- treated Mx-Cre+, poh1f/f mice and control mice were used to detect the TGF-β receptors. The metastatic-related capabilities of HCC cells were studied in vitro and in mice.FindingsHere we show that POH1 is a critical regulator of TGF-β signaling and promotes tumor metastasis. Integrative analyses of HCC subgroups classified with unsupervised transcriptome clustering of the TGF-β response, metastatic potential and outcomes, reveal that POH1 expression positively correlates with activities of TGF-β signaling in tumors and with malignant disease progression. Functionally, POH1 intensifies TGF-β signaling delivery and, as a consequence, promotes HCC cell metastatic properties both in vitro and in vivo. The expression of the TGF-β receptors was severely downregulated in POH1-deficient mouse hepatocytes. Mechanistically, POH1 deubiquitinates the TGF-β receptors and CAV1, therefore negatively regulates lysosome pathway-mediated turnover of TGF-β receptors.ConclusionOur study highlights the pathological significance of aberrantly expressed POH1 in TGF-β signaling hyperactivation and aggressive progression in HCC.

Extra-Anatomic Stents in Ureteric Obstruction: Our Experience.

To present our experience of the Detour extra-anatomic stent (EAS; Porges-Coloplast, Denmark) to bypass ureteric obstruction. Use of the EAS is indicated in patients with complex ureteric strictures or malignant disease, where long-term nephrostomy drainage is undesirable. Between December 2001 and October 2017, 20 Detour EAS were implanted into 13 patients. The primary indication was ureteric obstruction or injury secondary to metastatic malignancy, or from treatment for malignancy. Five patients required bilateral EAS, with two patients having bilateral EAS following initial unilateral insertion. In 11 patients, the stent was inserted into their bladder, with 2 diverted into a double-barreled stoma. The mean age at the time of implantation was 64 years (range: 50-83 years), and the median follow-up was 12 months (range: 1.5-42 months). Four patients required stent revision for urinary leaks, and two developed recurrent urinary tract infections in their stent requiring intravenous antibiotics. All EAS continued to drain successfully following treatment or revision. One patient died due to complications from dislodgement of the stent, leading to laparotomy and intra-abdominal sepsis. Seven patients died due to progression of metastatic malignant disease, and the Detour EAS was functioning in all seven at time of death. The remaining five patients are well with functioning Detour EAS. The Detour EAS system provides a suitable alternative option for urinary diversion, affording a good quality of life to carefully selected patients with multiple comorbidities and malignant disease.

CALR and CD47: An Insight into Their Roles in the Disease Progression of MDS and MPN

Myelodysplastic syndrome and myeloproliferative neoplasms are clonal myeloid disorders arising from haematopoietic stem cells that have the tendency to progress into acute myeloid leukaemia. Multiple prognostic scoring systems have been proposed and utilised in clinical practice to predict disease evolution, however none of them can predict treatment response. In solid tumours, the relationship between the pro-phagocytic calreticulin and the anti-phagocytic CD47 is repeatedly investigated. Overexpression of calreticulin has been documented to produce a pro-phagocytic signal in solid tumour and it is often counteracted by a concomitant expression of the anti-phagocytic CD47 as they act in response to one another, reflecting an apoptosis vs survival mechanism in response to chemotherapy. The role of both calreticulin and CD47 are currently poorly understood in myeloid malignancies including myelodysplastic syndrome and myeloproliferative neoplasms. The aim of this review is to elaborate on the current understanding round the roles and implications of calreticulin and CD47 signalling with in solid and haematological cancers, discuss potential roles for calreticulin and CD47 expression in transformation of myeloid cells in patients with MDS or MPN into AML and how these advances are starting to be used to design new therapeutic strategies to determine disease progression and treatment response in both solid cancer and myeloid malignancies.