The transcriptional landscape of Shh medulloblastoma

© The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.info:eu-repo/semantics/publishedVersio

Economic burden of cardiovascular diseases before and after Iran�s health transformation plan: evidence from a referral hospital of Iran

Background: Different countries have set different policies to control and decrease the costs of cardiovascular diseases (CVDs). Iran was aiming to reduce the economic burden of different disease by a recent reform from named as health transformation plan (HTP). This study aimed to examine the economic burden of CVDs before and after of HTP. Methods: This cross-sectional study was conducted on 600 patients with CVDs, who were randomly selected from a specialized cardiovascular hospital in the north-west of Iran. Direct and indirect costs of CVDs were calculated using the cost of illness and human capital approaches. Data were collected using a researcher-made checklist obtained from several sources including structured interviews, the Statistical Center of Iran, Iran�s Ministry of Cooperatives, Labor, and Social Welfare, the central bank of Iran, and the data of global burden of disease obtained from the Institute for Health Metrics and Evaluation to estimate direct and mortality costs. All costs were calculated in Iranian Rials (IRR). Results: Total costs of CVDs were about 5571 and 6700 billion IRR before and after the HTP, respectively. More than 62 of the total costs of CVDs accounted for premature death before (64.89) and after (62.01) the HTP. The total hospitalization costs of CVDs was significantly increased after the HTP (p = 0.038). In both times, surgical services and visiting had the highest and lowest share of hospitalization costs, respectively. The OOP expenditure decreased significantly and reached from 54.2 to 36.7. All hospitalization costs, except patients� OOP expenditure, were significantly increased after the HTP about 1.3 times. Direct non-medical costs reached from 2.4 to 3.3 billion before and after the HTP, respectively. Conclusion: Economic burden of CVDs increased in the north-west of Iran after the HTP due to the increase of all direct and indirect costs, except the OOP expenditure. Non-allocation of defined resources, which coincided with the international and national political and economic challenges in Iran, led to unsustainable resources of the HTP. So, no results of this study can be attributed solely to the HTP. Therefore, more detailed studies should be carried out on the reasons for the significant increase in CVDs costs in the region. © 2021, The Author(s)

Host Cell Cytotoxicity and Cytoskeleton Disruption by CerADPr, an ADP-Ribosyltransferase of <i>Bacillus cereus</i> G9241

<i>Bacillus cereus</i> G9241 was isolated from a welder suffering from an anthrax-like inhalation illness. <i>B. cereus</i> G9241 encodes two megaplasmids, pBCXO1 and pBC210, which are analogous to the toxin- and capsule-encoding virulence plasmids of <i>Bacillus anthracis</i>. Protein modeling predicted that the pBC210 LF homologue contained an ADP-ribosyltransferase (ADPr) domain. This putative bacterial ADP-ribosyltransferase domain was denoted CerADPr. Iterative modeling showed that CerADPr possessed several conserved ADP-ribosyltransferase features, including an α-3 helix, an ADP-ribosyltransferase turn–turn loop, and a “Gln-XXX-Glu” motif. CerADPr ADP-ribosylated an ∼120 kDa protein in HeLa cell lysates and intact cells. EGFP-CerADPr rounded HeLa cells, elicited cytoskeletal changes, and yielded a cytotoxic phenotype, indicating that CerADPr disrupts cytoskeletal signaling. CerADPr­(E431D) did not possess ADP-ribosyltransferase or NAD glycohydrolase activities and did not elicit a phenotype in HeLa cells, implicating Glu431 as a catalytic residue. These experiments identify CerADPr as a cytotoxic ADP-ribosyltransferase that disrupts the host cytoskeleton

The transcriptional landscape of Shh medulloblastoma

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention