Blastic plasmacytoid dendritic cell neoplasm: Genomics mark epigenetic dysregulation as a primary therapeutic target

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy for which there is still no effective B therapy. In order to identify genetic alterations useful for a new treatment design, we used whole-exome sequencing to analyze 14 BPDCN patients and the patient-derived CAL-1 cell line. The functional enrichment analysis of mutational data reported the epigenetic regulatory program to be the most significantly undermined (P<0.0001). In particular, twenty-five epigenetic modifiers were found mutated (e.g. ASXL1, TET2, SUZ12, ARID1A, PHF2, CHD8); ASXL1 was the most frequently affected (28.6% of cases). To evaluate the impact of the identified epigenetic mutations at the gene-expression and Histone H3 lysine 27 trimethylation/acetylation levels, we performed additional RNA and pathology tissue-chromatin immunoprecipitation sequencing experiments. The patients displayed enrichment in gene signatures regulated by methylation and modifiable by decitabine administration, shared common H3K27-acetylated regions, and had a set of cell-cycle genes aberrantly up-regulated and marked by promoter acetylation. Collectively, the integration of sequencing data showed the potential of a therapy based on epigenetic agents. Through the adoption of a preclinical BPDCN mouse model, established by CAL-1 cell line xenografting, we demonstrated the efficacy of the combination of the epigenetic drugs 5’-azacytidine and decitabine in controlling disease progression in vivo

Common features between neoplastic and preneoplastic lesions of the biliary tract and the pancreas

The bile duct system and pancreas show many similarities due to their anatomical proximity and common embryological origin. Consequently, preneoplastic and neoplastic lesions of the bile duct and pancreas share analogies in terms of molecular, histological and pathophysiological features. Intraepithelial neoplasms are reported in biliary tract, as biliary intraepithelial neoplasm (BilIN), and in pancreas, as pancreatic intraepithelial neoplasm (PanIN). Both can evolve to invasive carcinomas, respectively cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary neoplasms arise in biliary tract and pancreas. Intraductal papillary neoplasm of the biliary tract (IPNB) share common histologic and phenotypic features such as pancreatobiliary, gastric, intestinal and oncocytic types, and biological behavior with the pancreatic counterpart, the intraductal papillary mucinous neoplasm of the pancreas (IPMN). All these neoplastic lesions exhibit similar immunohistochemical phenotypes, suggesting a common carcinogenic process. Indeed, CCA and PDAC display similar clinic-pathological features as growth pattern, poor response to conventional chemotherapy and radiotherapy and, as a consequence, an unfavorable prognosis. The objective of this review is to discuss similarities and differences between the neoplastic lesions of the pancreas and biliary tract with potential implications on a common origin from similar stem/progenitor cells

Using Neural Networks for Relation Extraction from Biomedical Literature

Using different sources of information to support automated extracting of relations between biomedical concepts contributes to the development of our understanding of biological systems. The primary comprehensive source of these relations is biomedical literature. Several relation extraction approaches have been proposed to identify relations between concepts in biomedical literature, namely, using neural networks algorithms. The use of multichannel architectures composed of multiple data representations, as in deep neural networks, is leading to state-of-the-art results. The right combination of data representations can eventually lead us to even higher evaluation scores in relation extraction tasks. Thus, biomedical ontologies play a fundamental role by providing semantic and ancestry information about an entity. The incorporation of biomedical ontologies has already been proved to enhance previous state-of-the-art results.Comment: Artificial Neural Networks book (Springer) - Chapter 1

DACH1 suppresses breast cancer as a negative regulator of CD44.

Dachshund homolog 1 (DACH1), a key cell fate determination factor, contributes to tumorigenesis, invasion, metastasis of human breast neoplasm. However, the exact molecular mechanisms for the anti-tumor roles of DACH1 in breast carcinoma are still lack of extensive understanding. Herein, we utilized immunohistochemistry (IHC) staining and public microarray data analysis showing that DACH1 was higher in normal breast, low-grade and luminal-type cancer in comparison with breast carcinoma, high-grade and basal-like tumors respectively. Additionally, both correlation analysis of public databases of human breast carcinoma and IHC analysis of mice xenograft tumors demonstrated that DACH1 inversely related to cancer stem cells (CSCs) markers, epithelial-mesenchymal transition (EMT) inducers and basal-enriched molecules, while cluster of differentiation 44 (CD44) behaved in an opposite manner. Furthermore, mice transplanted tumor model indicated that breast cancer cells Met-1 with up-regulation of DACH1 were endowed with remarkably reduced potential of tumorigenesis. Importantly, meta-analysis of 19 Gene Expression Omnibus (GEO) databases of breast cancer implicated that patients with higher DACH1 expression had prolonged time to death, recurrence and metastasis, while CD44 was a promising biomarker predicting worse overall survival (OS) and metastasis-free survival (MFS). Collectively, our study indicated that CD44 might be a novel target of DACH1 in breast carcinoma

RAB family gene expression in breast cancer cells under influence of paclitaxel

The aim of this study was to investigate the role of paclitaxel on RAB family of genes in primary breast cancer cell lines. The cancer breast cells obtained from 40 women during mastectomy were used to address this issue. The group included patients with intraductal breast cancer - lesions in I or II advancement level by TNM classification and G1-G2 by Bloom classification. (tumor dimensions up to 2.0 cm without metastases to lymph nodes). Cytostatic drugs before surgery were not administered to these patients. The cultures were conducted in 25 cm^2^ plastic containers at RPMI medium with addiction of 10% fetal bovine serum (FBS) at the standard conditions. After reaching concentration levels of 10 000/ml of the cells, the cultures were treated with 60 ng/ml and 300 ng/ml doses of paclitaxel. The concentrations were calculated in relation to therapeutic doses of paclitaxel, applied in polytherapy in patients with breast cancer. The cell cultures untreated for cytostatic were used as a control group. Analysis was conducted for RAB family of genes: RAB3D, RAB5B, RAB5C, RAB7, RAB7L1, RAB9P1, RAB10. RAB11A, RAB311B, RAB13, RAB18, RAB22A, RAB23, RAB26, RAB27A, RAB27B, RAB28, RAB30, RAB31, RAB33A, RAB3D6, RAB 38, RABL2B Total RNA was extracted from the harvest control group and the treated cells, and this was followed by cDNA synthesis, which was used for hybridization assays using arrays. A lower dose of paclitaxel (60 ng/ml) treatment resulted in an increase (2-4 fold- statistically significant), whereas a higher dose (300 ng/ml) caused a decrease (2-fold - statistically insignificant) in expression of examined oncogenes, compared to that of the control group.In summary, this data indicates that 60 ng/ml paclitaxel dose induced the RAB gene expression in an up-regulated pathway. A higher concentration of cytostatic (300 ng/ml) is a toxic dose for primary breast cells in vitro

Cancer in Ancient Human Populations: Methods and Practice in Bioarchaeology and Paleopathology

Best Undergraduate Writing in Anthropology Award, 2019-2020Despite its prevalence in contemporary public health, research on the paleopathology of cancer is still extremely limited. Successful methods have been employed to identify cancer in human remains which show a very small fraction of the existing archaeological record to contain signs of cancer. This current evidence would indicate that cancer was much rarer in antiquity than it is now, and this would suggest that cancer is a product of modern day environments and lifestyles. However, this conclusion is based upon very narrow research utilizing a methodology that is limited in its reach. Current methods rely solely on gross observation of skeletal material, which fails to account for the wide range of factors that influence the growth and development of carcinomas. This methodology is insufficient in providing a detailed history of the growth and development of cancer in human antiquity. This project aims to determine an interdisciplinary methodology for the study of ancient human cancers, incorporating approaches employed in bioarcheology, epidemiology, and more contemporary cancer genomics.No embargoAcademic Major: Anthropological SciencesAcademic Major: Englis

Is porto sinusoidal vascular disease to be actively searched in patients with portal vein thrombosis?

Porto sinusoidal vascular liver disease (PSVD) and portal vein thrombosis (PVT) are distinct vascular liver diseases characterized, respectively, by an intrahepatic and a prehepatic obstacle to the flow in the liver portal system. PVT may also occur as a complication of the natural history of PSVD, especially if a prothrombotic condition coexists. In other cases, it is associated to local and systemic pro-thrombotic conditions, even if its cause remains unknown in up to 25% despite an active search. In our opinion, the presence of PSVD should be suspected in patients with PVT especially in those with PVT "sine causa" and the active search of this condition should be included in their diagnostic work-out. However, sometimes the diagnosis of pre-existing PSVD is very hard. Biopsy cannot be fully discriminant as similar histological data have been described in both conditions. Liver stiffness may help as it has been shown to be higher in PSVD than in "pure" PVT, due to the presence of sclerosis in the portal venous radicles observable in PSVD patients. Nevertheless, comparing liver stiffness between PVT and PSVD has until now been restricted to very limited series of patients. In conclusion, even if it is still totally hypothetical, our point of view may have clinical consequences, especially when deciding to perform a liver biopsy in patients with a higher liver stiffness and suspending the anticoagulation in patients with PVT and no detectable prothrombotic factors

Ancient Schwannoma of the Cauda Equina: our experience and review of the literature

Ancient schwannomas (AS) are exceedingly rare variant of common schwannomas (CS). Only two cases involving the cauda equina region have been previously reported in literature. AS are typically associated with a higher histological degree of degenerative changes (Antoni B areas). It is of peculiar importance, according to our opinion, to outline that, because of their extremely slow growth (which explains the increase of the degenerative changes in respect to the CS) and their typical soft consistency in respect to their standard counterparts, AS usually imply an even better prognosis