Comprehensive Review of BAP1 Tumor Predisposition Syndrome

Health Professions - Clinical: 4th Place, Honorable Mention (The Ohio State University Denman Undergraduate Research Forum)BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a rapidly developing area of medical research. Germline mutations in this multifaceted tumor suppressor gene predispose families to the development of various malignancies. The molecular function of the gene as well as the clinical phenotype of the syndrome are still being clarified. We sought to conduct a complete review of all published research into BAP1-TPDS to more thoroughly understand the clinical implications of BAP1 mutations. This information, in conjunction with phenotypic characteristics such as age of onset, disease aggressiveness, and survival can aid in the management, diagnoses, prognoses, and therapy of these patients and their families. We found that germline BAP1 mutations predispose families to the development of uveal melanoma, renal cell carcinoma, mesothelioma, cutaneous melanoma, characteristic benign skin lesions and possibly a range of other cancers. These cancers tend to be more aggressive, have a propensity to metastasize, and onset earlier in life in patients with BAP1 mutations. Genetic counseling and clinic management for these patients and their families are recommended. Further research on families carrying BAP1 mutations is necessary; however, this is an important step toward clinical application of the published research on the topic.Patti Blow Research Fund in OphthalmologyAmerican Cancer SocietyOhio Lions Eye Research FoundationOcular Melanoma FoundationMelanoma Know More FoundationNational Eye InstituteNational Cancer InstituteThe Ohio State University Arts and Sciences Undergraduate Research ScholarshipAcademic Major: Molecular Genetic

Comprehensive Review of BAP1 Tumor Predisposition Syndrome

BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a recently identified hereditary cancer syndrome and a rapidly developing area of medical research. Germline mutations in this tumor suppressor gene predispose families to the development of various malignancies. The molecular functions of the gene as well as the clinical phenotype of the syndrome are still being clarified. The aim of this study is to conduct a comprehensive review of all published research into BAP1-TPDS to more thoroughly delineate the clinical implications of germline BAP1 mutations. Current evidence suggests that germline BAP1 mutations predispose families to uveal melanoma, malignant mesothelioma, cutaneous melanoma, renal cell carcinoma, characteristic benign skin lesions, and possibly a range of other cancers as well. Some of these cancers tend to be more aggressive, have a propensity to metastasize, and onset earlier in life in patients with BAP1 mutations. Survival in these patients is significantly decreased. Although further research is necessary, this information can aid in the management, diagnoses, prognoses, and therapy of these patients and their families, and highlights the importance of genetic counseling.National Cancer InstituteNational Eye InstituteMelanoma Know More FoundationOcular Melanoma FoundationOhio Lions Eye Research FoundationAmerican Cancer SocietyPatti Blow Research Fund in OphthalmologyThe Ohio State University Arts and Sciences Undergraduate Research ScholarshipA one-year embargo was granted for this item.Academic Major: Molecular Genetic

Mitral valve replacement in a 12 year old boy with Marfan syndrome and severe mitral regurgitation

A 12 year old boy with Marfan syndrome associated with severe mitral regurgitation underwent successful mitral valve replacement. Careful evaluation of the cardiovascular system and specific surgical intervention help long-term survival of  patients

Chronic Lymphocytic Leukemia Cells in a Lymph Node Microenvironment Depict Molecular Signature Associated with an Aggressive Disease

Chronic lymphocytic leukemia (CLL) cells survive longer in vivo than in vitro, suggesting that the tissue microenvironment provides prosurvival signals to tumor cells. Primary and secondary lymphoid tissues are involved in the pathogenesis of CLL, and the role of these tissue microenvironments has not been explored completely. To elucidate host-tumor interactions, we performed gene expression profiling (GEP) of purified CLL cells from peripheral blood (PB; n = 20), bone marrow (BM; n = 18), and lymph node (LN; n = 15) and validated key pathway genes by real-time polymerase chain reaction, immunohistochemistry and/or TCL1 trans-genic mice. Gene signatures representing several pathways critical for survival and activation of B cells were altered in CLL cells from different tissue compartments. Molecules associated with the B-cell receptor (BCR), B cell-activating factor/a proliferation-inducing ligand (BAFF/APRIL), nuclear factor (NF)-κB pathway and immune suppression signature were enriched in LN-CLL, suggesting LNs as the primary site for tumor growth. Immune suppression genes may help LN-CLL cells to modulate antigen-presenting and T-cell behavior to suppress antitumor activity. PB CLL cells overexpressed chemokine receptors, and their cognate ligands were enriched in LN and BM, suggesting that a chemokine gradient instructs B cells to migrate toward LN or BM. Of several chemokine ligands, the expression of CCL3 was associated with poor prognostic factors. The BM gene signature was enriched with antiapoptotic, cytoskeleton and adhesion molecules. Interestingly, PB cells from lymphadenopathy patients shared GEP with LN cells. In Eμ-TCL1 transgenic mice (the mouse model of the disease), a high percentage of leukemic cells from the lymphoid compartment express key BCR and NF-κB molecules. Together, our findings demonstrate that the lymphoid microenvironment promotes survival, proliferation and progression of CLL cells via chronic activation of BCR, BAFF/APRIL and NF-κB activation while suppressing the immune response

Tethered Spinal Cord due to Thoracic Spinal Cord Lipoma: Minimally Invasive Surgical Management Case Report and Literature Review

An unusual case of a thoracic spine lipoma presenting with profound progressive numbness along with difficult to interpret preoperative imaging is discussed. A uniquely minimally invasive surgical treatment approach with successful outcome and improved neurologic symptoms is presented. A literature review and discussion of the benefits and limitations of a minimally invasive surgical technique are provided. A male presented with several months of progressive bilateral lower extremity numbness that ascended to the mid-thoracic spine. Spine magnetic resonance imaging demonstrated a 9 mm intradural, thoracic spinal mass, which was thought preoperatively to represent an arachnoid cyst with an adhesion or a localized dural ectasia. Subsequent imaging demonstrated a band at the cranial margin of the mass appearing to tether the spinal cord to the dorsal-lateral spinal canal without an arachnoid cyst or osseous defect. Surgical exploration revealed an intradural exophytic, intramedullary fatty mass tethering the spinal cord to the dorsolateral dura. An abnormal patch of dura was observed overlying the fatty attachment but no dural defect was identified. Pathology demonstrated fragments of fibroconnective tissue, scattered mature adipocytes, and entrapped meningeal cells, yielding the diagnosis of a spinal cord lipoma. Follow up imaging demonstrated no residual tethering of the spinal cord

Fibrinolytic protease production by new Streptomyces sp. DPUA 1576 from amazon lichens

Background Streptomyces sp. DPUA 1576 from Amazon lichens was studied to protease and fibrinolytic production. A 22 factorial experimental design was applied to optimize its protease enzyme production using two independent variables, namely soybean flour and glucose concentrations. Results The optimal conditions to obtain high protease production (83.42 U/mL) were 1.26% soybean flour and 1.23% glucose concentration. A polynomial model was fitted to correlate the relationship between the two variables and protease activity. In relation to fibrinolytic activity, the highest activity of 706.5 mm2 was obtained at 1.7% soybean flour and 1.0% glucose concentration, which was 33% higher than plasmin. Fibrinolytic production was not optimized in the studied conditions. Conclusions These results show that the optimization of the culture medium can enhance protease production, thus becoming a good process for further research. In addition, Streptomyces sp. DPUA 1576, isolated from Amazon lichens, might be a potential strain for fibrinolytic protease production.The authors thank CAPES (National Council for the Improvement of Higher Education) for the scholarship and CNPq/RENORBIO (National Counsel of Technological and Scientific Development, N. 55146/2010-3) and FACEPE (Fundacao de Amparo a Ciencia e Tecnologia do Estado de Pernambuco, 0158-2.12/11) for the financial support

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

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

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