Circulating microRNA Panels for Detection of Liver Cancers and Liver-Metastasizing Primary Cancers.

Malignant liver tumors, including primary malignant liver tumors and liver metastases, are among the most frequent malignancies worldwide. The disease carries a poor prognosis and poor overall survival, particularly in cases involving liver metastases. Consequently, the early detection and precise differentiation of malignant liver tumors are of paramount importance for making informed decisions regarding patient treatment. Significant research efforts are currently directed towards the development of diagnostic tools for different types of cancer using minimally invasive techniques. A prominent area of focus within this research is the evaluation of circulating microRNA, for which dysregulated expression is well documented in different cancers. Combining microRNAs in panels using serum or plasma samples derived from blood holds great promise for better sensitivity and specificity for detection of certain types of cancer.

Histologic changes of porcine portal vein anastomosis after electrochemotherapy with bleomycin.

Electrochemotherapy (ECT1) is used for treatment of unresectable abdominal malignancies. This study aims to show that ECT of porcine portal vein anastomosis is safe and feasible in order to extend the indications for margin attenuation after resection of locally advanced pancreatic carcinoma. No marked differences were found between the control group and ECT treated groups. Electroporation thus caused irreversible damage to the vascular smooth muscle cells in tunica media that could bedue to the narrow irreversible electroporation zone that may occur near the electrodes, or due to vasa vasorum thrombosis in the tunica externa. Based on the absence of vascular complications, and similar histological changes in lienal veinanastomosis, we can conclude that ECT of portal vein anastomosis is safe and feasible.

miR-200b, ZEB2 and PTPN13 Are Downregulated in Colorectal Carcinoma with Serosal Invasion.

Serosal invasion is an independent negative prognostic factor in certain cancers, including CRC. However, the mechanisms behind serosal invasion are poorly understood. We therefore assumed that epithelial-mesenchymal transition (EMT) might be involved. Our study included 34 patients with CRC, 3 stage pT2, 14 stage pT3 and 17 showing serosal invasion (stage pT4a according to TNM staging system). RNA isolated from formalin-fixed paraffin-embedded tissue samples was analysed for expression of the miR-200 family and their target genes CDKN1B, ONECUT2, PTPN13, RND3, SOX2, TGFB2 and ZEB2 using real-time PCR. We found upregulation of miR-200b and ONECUT2 in CRC pT3 and pT4a compared to normal mucosa, and downregulation of CDKN1B in CRC pT3. Moreover, we observed, downregulation of miR-200b, PTPN13 and ZEB2 in CRC with serosal invasion (pT4a) compared to pT3. Our results suggest the involvement of partial EMT in serosal invasion of CRC. In addition, PTPN13 seems to be one of the important regulators involved in serosal invasion, and ONECUT2 in tumour growth.

Neuroendocrine Tumor Arising within Mature Cystic Teratoma of the Pancreas: Literature Review and Case Report.

Cystic teratomas are germ cell tumors most commonly found in the ovaries and testes. The pancreas, however, is very rare as a site of occurrence. Moreover, only two cases of cystic teratoma with concomitant neuroendocrine tumor have been reported to date. We report the case of a 33-year-old female who presented with abdominal pain. Computed tomography and magnetic resonance imaging of the upper abdomen revealed an 85 mm cystic tumor in the head of the pancreas. Cystic teratoma and mucinous cystadenoma were suggested as differential diagnoses. Cytopathologic analysis of endoscopic ultrasound-guided fine needle aspiration was consistent with mucinous cystadenoma. Therefore, the patient underwent surgical resection. Histologic analysis revealed a mature cystic teratoma of the pancreas with a concomitant neuroendocrine tumor. The patient is in great condition at 8 months follow-up. Cystic teratoma of the pancreas with a concomitant neuroendocrine tumor is an extremely rare condition. Surgical resection remains the mainstay of treatment as it provides a definitive diagnosis and no recurrences have been reported to date.

Emerging Roles for Phase Separation of RNA-Binding Proteins in Cellular Pathology of ALS.

Liquid-liquid phase separation (LLPS) is emerging as a major principle for the mesoscale organization of proteins, RNAs, and membrane-bound organelles into biomolecular condensates. These condensates allow for rapid cellular responses to changes in metabolic activities and signaling. Nowhere is this regulation more important than in neurons and glia, where cellular physiology occurs simultaneously on a range of time- and length-scales. In a number of neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), misregulation of biomolecular condensates leads to the formation of insoluble aggregates-a pathological hallmark of both sporadic and familial ALS. Here, we summarize how the emerging knowledge about the LLPS of ALS-related proteins corroborates with their aggregation. Understanding the mechanisms that lead to protein aggregation in ALS and how cells respond to these aggregates promises to open new directions for drug development.

Acutely applied melatonin prevents CCl4-induced testicular lesions in rats: the involvement of the oxidative capacity and arginine metabolism

Abstract Carbon tetrachloride (CCl4) represents an organic chemical that causes reactive oxygen species derived organ disturbances including male infertility. Melatonin (MLT) is a neurohormone with strong antioxidant capacity, involved in numerous physiological processes. In this study we evaluated the capability of MLT, administered in a single dose of 50 mg/kg, to preserve the testicular tissue function after an acute administration of CCl4 to rats. The disturbance in testicular tissue and the effects of MLT after CCl4 exposure were estimated using biochemical parameters that enabled us to determine the tissue (anti)oxidant status and the intensity of arginine/nitric oxide metabolism. Also, the serum levels of testosterone and the histopathological analysis of tissue gave us a better insight into the occurring changes. A significant diminution in tissue antioxidant defences, arginase activity and serum testosterone levels, followed by the increased production of nitric oxide and extensive lipid and protein oxidative damage, was observed in the CCl4-treated group. The application of MLT after the CCl4 caused changes, clearly visible at both biochemical and histological level, which could be interpreted mainly as a consequence of general antioxidant system stimulation and a radical scavenger. On the other hand, the application of MLT exerted a limited action on the nitric oxide signalling pathway.

Aberrant Phase Separation of FUS Leads to Lysosome Sequestering and Acidification.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to the death of upper and lower motor neurons. While most cases of ALS are sporadic, some of the familial forms of the disease are caused by mutations in the gene encoding for the RNA-binding protein FUS. Under physiological conditions, FUS readily phase separates into liquid-like droplets in vivo and in vitro. ALS-associated mutations interfere with this process and often result in solid-like aggregates rather than fluid condensates. Yet, whether cells recognize and triage aberrant condensates remains poorly understood, posing a major barrier to the development of novel ALS treatments. Using a combination of ALS-associated FUS mutations, optogenetic manipulation of FUS condensation, chemically induced stress, and pH-sensitive reporters of organelle acidity, we systematically characterized the cause-effect relationship between the material state of FUS condensates and the sequestering of lysosomes. From our data, we can derive three conclusions. First, regardless of whether we use wild-type or mutant FUS, expression levels (i.e., high concentrations) play a dominant role in determining the fraction of cells having soluble or aggregated FUS. Second, chemically induced FUS aggregates recruit LAMP1-positive structures. Third, mature, acidic lysosomes accumulate only at FUS aggregates but not at liquid-condensates. Together, our data suggest that lysosome-degradation machinery actively distinguishes between fluid and solid condensates. Unraveling these aberrant interactions and testing strategies to manipulate the autophagosome-lysosome axis provides valuable clues for disease intervention.

Metastatic Gastric Signet Ring Cell Adenocarcinoma Presenting With Colonic Stenosis.

Metastases to the colon are rare and may mimic other diseases such as inflammatory bowel disease. This differential diagnosis is often overlooked by endoscopists which leads to unnecessary diagnostic delay or inappropriate treatment. We present a case of a 54-year-old woman who presented with ascites. Malignant cells were demonstrated on cytologic examination of ascitic fluid, but no primary tumour or metastases were seen on computed tomography of the abdomen. On colonoscopy, an impassable stenosis was found in the transverse colon with scattered patches of oedematous colonic mucosa through to the mid-descending colon. Histological examination revealed scattered signet ring cells and the diagnosis of gastric signet ring cell adenocarcinoma was confirmed with subsequent gastroscopy. The correct and timely diagnosis of metastatic lesions to the colon requires a high index of suspicion and adequate mucosal sampling with multiple biopsies.

Epithelial-Mesenchymal Transition-Related MicroRNAs and Their Target Genes in Colorectal Cancerogenesis.

MicroRNAs of the miR-200 family have been shown experimentally to regulate epithelial-mesenchymal transition (EMT). Although EMT is the postulated mechanism of development and progression of colorectal cancer (CRC), there are still limited and controversial data on expression of miR-200 family and their target genes during CRC cancerogenesis. Our study included formalin-fixed paraffin-embedded biopsy samples of 40 patients (10 adenomas and 30 cases of CRC with corresponding normal mucosa). Expression of miR-141, miR-200a/b/c and miR-429 and their target genes (CDKN1B, ONECUT2, PTPN13, RND3, SOX2, TGFB2 and ZEB2) was analysed using quantitative real-time PCR. Expression of E-cadherin was analysed using immunohistochemistry. All miRNAs were down-regulated and their target genes showed the opposite expression in CRC compared to adenoma. Down-regulation of the miR-200 family at the invasive front in comparison to the central part of tumour was observed as well as a correlation of expression of miR-200b, CDKN1B, ONECUT2 and ZEB2 expression to nodal metastases. Expression of the miR-200 family and SOX2 also correlated with E-cadherin staining. These results suggest that the miR-200 family and their target genes contribute to progression of adenoma to CRC, invasive properties and development of metastases. Our results strongly support the postulated hypotheses of partial EMT and intra-tumour heterogeneity during CRC cancerogenesis.

Case report and literature review: patient with gastroduodenal intussusception due to the gastrointestinal stromal tumor of the lesser curvature of the gastric body.

BACKGROUND: Intussusception in adult patient is rare. Gastroduodenal intussusception due to the gastrointestinal stromal tumors is infrequently described in the literature. Authors present a case of gastroduodenal intussusception due to the low-risk gastrointestinal stromal tumor of the lesser curvature of the gastric body with literature review. CASE PRESENTATION: Sixty-two-year-old male was admitted to our hospital with symptoms of acute gastric outlet obstruction. Imaging studies confirmed a lesion of the gastric wall producing gastroduodenal intussusception with pylorus obstruction. Upon laparotomy a tumor mass of the lesser curvature of the gastric body that invaginated through the pylorus into the duodenum was found. Desinvagination and resection of the tumor with the adequate resection margins were performed. Histology reveled a low-risk gastrointestinal stromal tumor. Due to favorable outcome only observation was suggested by the multidisciplinary team. CONCLUSIONS: Gastroduodenal intussusception due to the gastrointestinal stromal tumor of the gastric wall is a rare event. Surgical resection is the treatment of choice. In selected cases laparosopic resection of the tumor can be performed.

Bioinformatics Analysis Reveals Most Prominent Gene Candidates to Distinguish Colorectal Adenoma from Adenocarcinoma.

Colorectal cancer (CRC) is one of the leading causes of death by cancer worldwide. Bowel cancer screening programs enable us to detect early lesions and improve the prognosis of patients with CRC. However, they also generate a significant number of problematic polyps, e.g., adenomas with epithelial misplacement (pseudoinvasion) which can mimic early adenocarcinoma. Therefore, biomarkers that would enable us to distinguish between adenoma with epithelial misplacement (pseudoinvasion) and adenoma with early adenocarcinomas (true invasion) are needed. We hypothesized that the former are genetically similar to adenoma and the latter to adenocarcinoma and we used bioinformatics approach to search for candidate genes that might be potentially used to distinguish between the two lesions. We used publicly available data from Gene Expression Omnibus database and we analyzed gene expression profiles of 252 samples of normal mucosa, colorectal adenoma, and carcinoma. In total, we analyzed 122 colorectal adenomas, 59 colorectal carcinomas, and 62 normal mucosa samples. We have identified 16 genes with differential expression in carcinoma compared to adenoma: COL12A1, COL1A2, COL3A1, DCN, PLAU, SPARC, SPON2, SPP1, SULF1, FADS1, G0S2, EPHA4, KIAA1324, L1TD1, PCKS1, and C11orf96. In conclusion, our in silico analysis revealed 16 candidate genes with different expression patterns in adenoma compared to carcinoma, which might be used to discriminate between these two lesions.

Potentially inappropriate prescribing of drugs in elderly patients on chronic hemodialysis treatment
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PURPOSE: The aim of this study was to determine the prevalence of potentially inappropriate drug prescription (PIP) in older patients who were on chronic hemodialysis treatment and to explore the factors that lead to PIP. MATERIALS AND METHODS: The study was performed at the Department of Nephrology, Clinical Center Nis, Serbia. It included patients who were 65 years old and older who suffered from the end-stage of kidney failure and were treated by hemodialysis. Univariate and subsequent multivariate logistic regression was used to analyze risk factors for PIP or omission (PPO) according to the STOPP and START criteria. RESULTS: The study included 83 patients. According to the START criteria, PPO was found in 18 (22%) patients, and 32 (39%) patients experienced PIPs according to the STOPP criteria. The following factors were associated with PIP according to the START criteria: a number of comorbidities, reading the patient leaflet, and having the habit of drinking coffee. According to the STOPP criteria, polypharmacy was associated with PIP (OR = 1.287, p = 0.021): each additional drug increased the risk of potentially inadequate medications (PIM) by 28.7%. CONCLUSION: Adequate consideration of potential risk factors, as well as the implementation of valid criteria for assessment of PIP, are just some of the measures that would contribute to solving complex therapeutic problems and designing strategies for rational prescribing according to the individual characteristics of patients.
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Simultaneous occurrence of pancreatic mixed acinar-ductal adenocarcinoma and primary follicular lymphoma of the duodenum, accompanied by increased number of IgG4 plasma cells in tumor-free parenchyma as concomitant IgG4-related disease or reaction to tumor? A case report.

Mixed acinar-ductal carcinoma is rare among pancreatic cancers, as is duodenal involvement in follicular lymphoma (FL). Although usually a systemic disease, primary FL of the duodenum occurs, with superficial involvement of the intestinal wall and low risk of progression. We report on a unique case of mixed ductal-acinar carcinoma of the pancreatic head accompanied by low-grade duodenal FL and autoimmune pancreatitis-like changes in adjacent pancreatic parenchyma. To our knowledge this is the first report of concomitant pancreatic mixed acinar-ductal carcinoma and duodenal FL. Clinico-pathological features of this unusual case, possible relationship between the entities and differential diagnosis are discussed.

SOX18 Is a Novel Target Gene of Hedgehog Signaling in Cervical Carcinoma Cell Lines.

Although there is much evidence showing functional relationship between Hedgehog pathway, in particular Sonic hedgehog, and SOX transcription factors during embryonic development, scarce data are available regarding their crosstalk in cancer cells. SOX18 protein plays an important role in promoting tumor angiogenesis and therefore emerged as a promising potential target in antiangiogenic tumor therapy. Recently it became evident that expression of SOX18 gene in tumors is not restricted to endothelium of accompanying blood and lymphatic vessels, but in tumor cells as well.In this paper we have identified human SOX18 gene as a novel target gene of Hedgehog signaling in cervical carcinoma cell lines. We have presented data showing that expression of SOX18 gene is regulated by GLI1 and GLI2 transcription factors, final effectors of Hedgehog signaling, and that modulation of Hedgehog signaling activity in considerably influence SOX18 expression. We consider important that Hedgehog pathway inhibitors reduced SOX18 expression, thus showing, for the first time, possibility for manipulationwith SOX18 gene expression. In addition, we analyzed the role of SOX18 in malignant potential of cervical carcinoma cell line, and showed that its overexpression has no influence on cells proliferation and viability, but substantially promotes migration and invasion of cells in vitro. Pro-migratory effect of SOX18 suggests its role in promoting malignant spreading, possibly in response to Hedgehog activation.