The spread of influenza A(H1N1)pdm09 in Victorian school children in 2009:iImplications for revised pandemic planning

Background Victoria was the first state in Australia to experience community transmission of influenza A(H1N1)pdm09. We undertook a descriptive epidemiological analysis of the first 1,000 notified cases to describe the epidemic associated with school children and explore implications for school closure and antiviral distribution policy in revised pandemic plans. Methods Records of the first 1,000 laboratory-confirmed cases of influenza A(H1N1)pdm09 notified to the Victorian Government Department of Health between 20 May and 5 June 2009 were extracted from the state’s notifiable infectious diseases database. Descriptive analyses were conducted on case demographics, symptoms, case treatment, prophylaxis of contacts and distribution of cases in schools. Results Two-thirds of the first 1,000 cases were school-aged (5–17 years) with cases in 203 schools, particularly along the north and western peripheries of the metropolitan area. Cases in one school accounted for nearly 8% of all cases but the school was not closed until nine days after symptom onset of the first identified case. Amongst all cases, cough (85%) was the most commonly reported symptom followed by fever (68%) although this was significantly higher in primary school children (76%). The risk of hospitalisation was 2%. The median time between illness onset and notification of laboratory confirmation was four days, with only 10% of cases notified within two days of onset and thus eligible for oseltamivir treatment. Nearly 6,000 contacts were followed up for prophylaxis. Conclusions With a generally mild clinical course and widespread transmission before its detection, limited and short-term school closures appeared to have minimal impact on influenza A(H1N1)pdm09 transmission. Antiviral treatment could rarely be delivered to cases within 48 hours of symptom onset. These scenarios and lessons learned from them need to be incorporated into revisions of pandemic plans

Effects of Ketosis and Hypocalcemia on The Biochemical Parameters and Subsequent Postpartum Reproductive Performance in Buffaloes

Water buffaloes (Bubalus bubalis) are mainly distributed in tropical and subtropical countries that include the Indian sub-continent and some Mediterranean countries such as Egypt. The transition period is the most stressful period for buffaloes, and it is considered as a turning point in the productive cycle from one lactation to the next and includes different metabolic, physiological, and nutritional changes. Metabolic disorders are common causes of lower productivity in buffaloes. Of these metabolic disorders, ketosis and hypocalcemia are most prevalent. This study aimed to study the ketosis- and hypocalcemia-related biochemical changes during the transition period and their impacts on the postpartum reproductive fertility in Buffaloes. Out of 120 total number of examined buffaloes, 40 buffaloes were used in this study; control group (n=10), hypocalcemia-affected (n=15), and ketosis-affected group (n=15). All buffaloes were subjected to thorough clinical and gynecological examination. Both urine and blood samples were collected from all groups. The amounts of ketone bodies were detected in urine. Biochemical parameters were evaluated including concentrations of glucose, triglycerides, cholesterol, non-esterified fatty acids (NEFA), calcium, phosphorus, sodium, potassium, albumin, total protein, urea and progesterone hormone (P4) in blood the following time-points (2-weeks prepartum, 1-week prepartum, partum, 1-week postpartum, and 2-weeks postpartum). Both hypocalcemia- and ketosis affected buffaloes had lower glucose, phosphorus, sodium and albumin and higher NEFA than control group. Hypocalcemia-affected buffaloes showed lower calcium and higher total protein than control group, while, ketosis-affected buffaloes showed lower cholesterol and total protein than control group. Moreover, metabolic disorders negatively affected the reproductive performance. Both ketosis and hypocalcemia significantly prolonged the duration to first estrus, increased both the number of days-open and the number of services per conceptio

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

HIV Delays IFN-α Production from Human Plasmacytoid Dendritic Cells and Is Associated with SYK Phosphorylation

Plasmacytoid dendritic cells (pDC) are the major producers of type I interferons (IFNs) in humans and rapidly produce IFN-α in response to virus exposure. Although HIV infection is associated with pDC activation, it is unclear why the innate immune response is unable to effectively control viral replication. We systematically compared the effect of HIV, Influenza, Sendai, and HSV-2 at similar target cell multiplicity of infection (M.O.I.) on human pDC function. We found that Influenza, Sendai, HSV-2 and imiquimod are able to rapidly induce IFN-α production within 4 hours to maximal levels, whereas HIV had a delayed induction that was maximal only after 24 hours. In addition, maximal IFN-α induction by HIV was at least 10 fold less than that of the other viruses in the panel. HIV also induced less TNF-α and MIP-1β but similar levels of IP-10 compared to other viruses, which was also mirrored by delayed upregulation of pDC activation markers CD83 and CD86. BDCA-2 has been identified as an inhibitory receptor on pDC, signaling through a pathway that involves SYK phosphorylation. We find that compared to Influenza, HIV induces the activation of the SYK pathway. Thus, HIV delays pDC IFN-α production and pDC activation via SYK phosphorylation, allowing establishment of viral populations

Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH -Mutant Molecular Profiles

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Protein ubiquitination is a dynamic and reversibleprocess of adding single ubiquitin molecules orvarious ubiquitin chains to target proteins. Here,using multidimensional omic data of 9,125 tumorsamples across 33 cancer types from The CancerGenome Atlas, we perform comprehensive molecu-lar characterization of 929 ubiquitin-related genesand 95 deubiquitinase genes. Among them, we sys-tematically identify top somatic driver candidates,including mutatedFBXW7with cancer-type-specificpatterns and amplifiedMDM2showing a mutuallyexclusive pattern withBRAFmutations. Ubiquitinpathway genes tend to be upregulated in cancermediated by diverse mechanisms. By integratingpan-cancer multiomic data, we identify a group oftumor samples that exhibit worse prognosis. Thesesamples are consistently associated with the upre-gulation of cell-cycle and DNA repair pathways, char-acterized by mutatedTP53,MYC/TERTamplifica-tion, andAPC/PTENdeletion. Our analysishighlights the importance of the ubiquitin pathwayin cancer development and lays a foundation fordeveloping relevant therapeutic strategies