tbuckley/cabot-search huggingface dataset:
MEDU-19. EZH2-REGULATED INHIBITION OF HIPK2 SUPPRESSES TREATMENT-INDUCED APOPTOSIS IN GROUP 3 MEDULLOBLASTOMA
Authors: Ismail Sola, Susan Fosmire, Sujatha Venkataraman, Ilango Balakrishnan, Diane Birks, Angela Pierce, Nicholas K Foreman, Rajeev Vibhakar
Journal: Neuro-Oncology (2019)

Our previous studies have shown that the epigenetic developmental regulator EZH2 is overexpressed in medulloblastoma (MB). EZH2 is known to repress developmental genes in embryonic stem cells to maintain their stem cell characteristics. To identify the role of EZH2 in medulloblastoma, we overexpressed EZH2 (EZH2Ox) in the C17.2 Myc immortalized cerebellar neural stem cell line. EZH2 overexpression in combination with Myc in the neural progenitor C17.2 cells generated orthotopic tumors that resembled clinical features of MYC-amplified group3 MB. To examine the mechanism of EZH2 mediated tumorigenesis we performed RNA-seq followed by Gene Set Enrichment Analysis (GSEA) of these EZH2 overexpressing neural stem cells. Transcriptomic analysis reveals that the gene sets associated with apoptosis were suppressed by EZH2 overexpression. Specifically, the p53 regulator and pro-apoptotic gene, HIPK2 was significantly suppressed by EZH2 overexpression. To examine the impact of EZH2 on apoptosis in Myc driven medulloblastoma cells we performed a CRISPR knock out of EZH2 in the D458 group 3 MB cell line. EZH2 deletion resulted in increased apoptosis leading to sensitization of cells to chemotherapy and radiation treatments. Further analysis of these CRISPR-edited EZH2 knockout cells showed a predominant upregulation in the HIPK2 expression compared to control D458 cells. While, overexpressing HIPK2 in D458 cells resulted in increased apoptosis after cisplatin or ionizing radiation, depleting HIPK2 in EZH2 CRISPR-KO cells rescued the proapoptotic phenotype. Treating mice with cisplatin resulted in significantly smaller orthotopic xenograft tumors of EZH2 knockout medulloblastoma cells compared to EZH2 sufficient medulloblastoma cells. Together, our results suggest that EZH2 contributes to treatment-resistance by inhibiting apoptosis via transcriptionally modulating HIPK2 expression in group 3 medulloblastoma. Therefore, targeting EZH2 will effectively sensitize tumors to standard therapies.
Oncolytic virotherapy for small-cell lung cancer induces immune infiltration and prolongs survival
Authors: Patrick Kellish, Daniil Shabashvili, Masmudur M. Rahman, Akbar Nawab, Maria V. Guijarro, Min Zhang, Chunxia Cao, Nissin Moussatche, Theresa Boyle, Scott Antonia, Mary Reinhard, Connor Hartzell, Michael Jantz, Hiren J. Mehta, Grant McFadden, Frederic J. Kaye, Maria Zajac-Kaye
Journal: Journal of Clinical Investigation (2019)

Oncolytic virotherapy has been proposed as an ablative and immunostimulatory treatment strategy for solid tumors that are resistant to immunotherapy alone; however, there is a need to optimize host immune activation using preclinical immunocompetent models in previously untested common adult tumors. We studied a modified oncolytic myxoma virus (MYXV) that shows high efficiency for tumor-specific cytotoxicity in small-cell lung cancer (SCLC), a neuroendocrine carcinoma with high mortality and modest response rates to immune checkpoint inhibitors. Using an immunocompetent SCLC mouse model, we demonstrated the safety of intrapulmonary MYXV delivery with efficient tumor-specific viral replication and cytotoxicity associated with induction of immune cell infiltration. We observed increased SCLC survival following intrapulmonary MYXV that was enhanced by combined low-dose cisplatin. We also tested intratumoral MYXV delivery and observed immune cell infiltration associated with tumor necrosis and growth inhibition in syngeneic murine allograft tumors. Freshly collected primary human SCLC tumor cells were permissive to MYXV and intratumoral delivery into patient-derived xenografts resulted in extensive tumor necrosis. We confirmed MYXV cytotoxicity in classic and variant SCLC subtypes as well as cisplatin-resistant cells. Data from 26 SCLC human patients showed negligible immune cell infiltration, supporting testing MYXV as an ablative and immune-enhancing therapy.
Abstract 13258: 3d Speckle Tracking Analysis of Left Ventricular Function after Transcatheter Aortic Valve Implantation
Authors: Christoph Hammerstingl, Robert Schueler, Jan Mallte Sinning, Nikos Werner, Alexander Ghanem, Eberhardt Grube, Georg Nickenig
Journal: Circulation (2012)

Background: The acute and long-term effects of transcatheter aortic valve implantation (TAVI) in patients with aortic valve stenosis (AVS) on left ventricular (LV) function are controversial. We ai...
GENE-09. MUTATION SIGNATURE ANALYSIS IN AN ULTRAHYPERMUTATED MEDULLOBLASTOMA PREDICTS UNDERLYING GERMLINE POLYMERASE PROOFREADING DEFICIENCY IN A CHILD WITH CLINICAL FEATURES OF CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME
Authors: Holly Lindsay, Sarah Scollon, Jacquelyn Reuther, Horatiu Voicu, Surya Rednam, Kevin Fisher, Murali Chintagumpala, D Will Parsons, Adekunle Adesina, Sharon Plon, Angshumoy Roy
Journal: Neuro-Oncology (2019)

BACKGROUND: Ultrahypermutation (>100 mutations/Mb) is rare in childhood cancer genomes and is primarily seen in patients with constitutional mismatch repair deficiency (cMMRD) caused by biallelic germline mutations in DNA mismatch repair (MMR) genes. We report a child with clinical features of cMMRD and an ultrahypermutated medulloblastoma found to harbor a germline mutation in DNA polymerase epsilon (POLE). CASE PRESENTATION: A 5-year-old female presented with clinical features of cMMRD including a malignant brain tumor, >100 hyperpigmented skin papules and café-au-lait macules, and axillary freckling. Additionally, she had a renal cyst, tibial osteochondroma, and 3 subcutaneous nodules. Pathology of the brain mass revealed non-WNT/non-SHH anaplastic medulloblastoma with tumor cells retaining MMR protein expression by immunohistochemistry. GENETIC ANALYSES: Germline genetic analysis of MMR genes revealed no pathogenic mutations. Targeted next-generation sequencing with a 124-cancer gene panel covering ≈1 Mb revealed an ultrahypermutated tumor genome (>150 mutations/Mb) and a mutation signature resembling “signature 10” (Campbell et al., Cell 2017), which is strongly associated with POLE exonuclease domain mutations. Analysis of matched tumor and blood DNA with an expanded 981-cancer gene panel demonstrated a germline heterozygous POLE missense variant (NM_006231.3:c.1366G>C; p.A456P) in the exonuclease domain, previously only reported as a somatic pathogenic variant in hypermutated cancers. The tumor additionally had a somatic heterozygous MSH6 nonsense variant (NM_000179.2:c.2722G>T; p.E908X). DISCUSSION: We report this early-onset brain tumor in a patient with phenotypic features of cMMRD, and a germline POLE p.A456P mutation. Heterozygous germline missense variants in the POLE exonuclease domain cause Polymerase Proofreading-associated Polyposis (PPAP), a cancer predisposition syndrome associated with colorectal polyposis and early-onset, microsatellite-stable colorectal cancer. Several brain tumors have been reported in patients with PPAP including pediatric astrocytoma. Dermatologic features and mutation signature analysis of hypermutated tumors may be associated with germline mutations in either the MMR or polymerase proofreading pathways.
Abstract 17705: Effects and Clinical Outcomes of Cardiac Progenitor Cell Infusion at Two Years in the Single Ventricle Cell Therapy Trials
Authors: Toshikazu Sano, Shuta Ishigami, Daiki Ousaka, Kenta Hirai, Takuya Goto, Shunji Sano, Hidemasa Oh
Journal: Circulation (2017)

Introduction: Single ventricle physiology is a fatal congenital heart disease and may develop to late-onset heart failure after staged palliations. Cardiosphere-derived cells (CDCs) have shown to i...
Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm
Authors: Naveen Pemmaraju, Andrew A. Lane, Kendra L. Sweet, Anthony S. Stein, Sumithira Vasu, William Blum, David A. Rizzieri, Eunice S. Wang, Madeleine Duvic, J. Mark Sloan, Sharon Spence, Shay Shemesh, Christopher L. Brooks, John Balser, Ivan Bergstein, Jeffrey E. Lancet, Hagop M. Kantarjian, Marina Konopleva
Journal: New England Journal of Medicine (2019)

Blastic plasmacytoid dendritic-cell neoplasm (BPDCN) is an aggressive hematologic cancer that is caused by transformed plasmacytoid dendritic cells that overexpress interleukin-3 receptor subunit alpha (IL3RA or CD123). Tagraxofusp (SL-401) is a CD123-directed cytotoxin consisting of human interleukin-3 fused to truncated diphtheria toxin.In this open-label, multicohort study, we assigned 47 patients with untreated or relapsed BPDCN to receive an intravenous infusion of tagraxofusp at a dose of 7 μg or 12 μg per kilogram of body weight on days 1 to 5 of each 21-day cycle. Treatment continued until disease progression or unacceptable toxic effects. The primary outcome was the combined rate of complete response and clinical complete response among patients who had not received previous treatment for BPDCN. A secondary outcome was the duration of response.Of the 47 patients, 32 were receiving tagraxofusp as first-line treatment and 15 had received previous treatment. The median age of the patients was 70 years (range, 22 to 84). Among the 29 previously untreated patients who received tagraxofusp at a dose of 12 μg per kilogram, the primary outcome occurred in 21 (72%), and the overall response rate was 90%; of these patients, 45% went on to undergo stem-cell transplantation. Survival rates at 18 and 24 months were 59% and 52%, respectively. Among the 15 previously treated patients, the response rate was 67%, and the median overall survival was 8.5 months. The most common adverse events were increased levels of alanine aminotransferase (64%) and aspartate aminotransferase (60%), hypoalbuminemia (55%), peripheral edema (51%), and thrombocytopenia (49%). Capillary leak syndrome was reported in 19% of the patients and was associated with one death in each of the dose subgroups.In adult patients with untreated or relapsed BPDCN, the use of tagraxofusp led to clinical responses. Serious adverse events included capillary leak syndrome; hepatic dysfunction and thrombocytopenia were common. (Funded by Stemline Therapeutics and the Leukemia and Lymphoma Society Therapy Acceleration Program; ClinicalTrials.gov number, NCT02113982.).
Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables
Authors: Andrew W. Roberts, Shuo Ma, Thomas J. Kipps, Steven E. Coutre, Matthew S. Davids, Barbara Eichhorst, Michael Hallek, John C. Byrd, Kathryn Humphrey, Lang Zhou, Brenda Chyla, Jacqueline Nielsen, Jalaja Potluri, Su Young Kim, Maria Verdugo, Stephan Stilgenbauer, William G. Wierda, John F. Seymour
Journal: Blood (2019)
NHS must tackle inequality to improve retention, says health secretary
Authors: Tom Moberly
Journal: BMJ (2019)

The NHS in England must deal with its problems concerning gender and racial inequality if it is to stem the flow of staff leaving the service, the health secretary, Matt Hancock, has said.

“Too often we’ve lost talented people from the NHS because we haven’t done enough to convince them to stay,” he said. “The most troubling statistic that I’ve seen is this: one in 11 NHS staff leave the NHS entirely every single year. It’s something we urgently need to address, and I believe a large number of those people leave because we haven’t done enough to make the NHS a great place to work.” …
2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death
Authors: Sana M. Al-Khatib, William G. Stevenson, Michael J. Ackerman, William J. Bryant, David J. Callans, Anne B. Curtis, Barbara J. Deal, Timm Dickfeld, Michael E. Field, Gregg C. Fonarow, Anne M. Gillis, Christopher B. Granger, Stephen C. Hammill, Mark A. Hlatky, José A. Joglar, G. Neal Kay, Daniel D. Matlock, Robert J. Myerburg, Richard L. Page
Journal: Journal of the American College of Cardiology (2018)
Activation of Mast-Cell-Expressed Mas-Related G-Protein-Coupled Receptors Drives Non-histaminergic Itch
Authors: James Meixiong, Michael Anderson, Nathachit Limjunyawong, Mark F. Sabbagh, Eric Hu, Madison R. Mack, Landon K. Oetjen, Fang Wang, Brian S. Kim, Xinzhong Dong
Journal: Immunity (2019)
Aneuploidy Enables Cross-Adaptation to Unrelated Drugs
Authors: Feng Yang, Flora Teoh, Alrina Shin Min Tan, Yongbing Cao, Norman Pavelka, Judith Berman
Journal: Molecular Biology and Evolution (2019)

Abstract Aneuploidy is common both in tumor cells responding to chemotherapeutic agents and in fungal cells adapting to antifungal drugs. Because aneuploidy simultaneously affects many genes, it has the potential to confer multiple phenotypes to the same cells. Here, we analyzed the mechanisms by which Candida albicans, the most prevalent human fungal pathogen, acquires the ability to survive both chemotherapeutic agents and antifungal drugs. Strikingly, adaptation to both types of drugs was accompanied by the acquisition of specific whole-chromosome aneuploidies, with some aneuploid karyotypes recovered independently and repeatedly from very different drug conditions. Specifically, strains selected for survival in hydroxyurea, an anticancer drug, acquired cross-adaptation to caspofungin, a first-line antifungal drug, and both acquired traits were attributable to trisomy of the same chromosome: loss of trisomy was accompanied by loss of adaptation to both drugs. Mechanistically, aneuploidy simultaneously altered the copy number of most genes on chromosome 2, yet survival in hydroxyurea or caspofungin required different genes and stress response pathways. Similarly, chromosome 5 monosomy conferred increased tolerance to both fluconazole and to caspofungin, antifungals with different mechanisms of action. Thus, the potential for cross-adaptation is not a feature of aneuploidy per se; rather, it is dependent on specific genes harbored on given aneuploid chromosomes. Furthermore, pre-exposure to hydroxyurea increased the frequency of appearance of caspofungin survivors, and hydroxyurea-adapted C. albicans cells were refractory to antifungal drug treatment in a mouse model of systemic candidiasis. This highlights the potential clinical consequences for the management of cancer chemotherapy patients at risk of fungal infections.
Environmental Styrene Exposure and Sensory and Motor Function in Gulf Coast Residents
Authors: Emily J. Werder, Dale P. Sandler, David B. Richardson, Michael E. Emch, Richard K. Kwok, Fredric E. Gerr, Lawrence S. Engel
Journal: Environmental Health Perspectives (2019)

Background: Although styrene is an established neurotoxicant at occupational exposure levels, its neurotoxicity has not been characterized in relation to general population exposures. Further, occupational research to date has focused on central nervous system impairment. Objective: We assessed styrene-associated differences in sensory and motor function among Gulf coast residents. Methods: We used 2011 National Air Toxics Assessment estimates of ambient styrene to determine exposure levels for 2,956 nondiabetic Gulf state residents enrolled in the Gulf Long-term Follow-up Study, and additionally measured blood styrene concentration in a subset of participants 1 to 2 y after enrollment (n=310). Participants completed an enrollment telephone interview and a comprehensive test battery to assess sensory and motor function during a clinical follow-up exam 2 to 4 y later. Detailed covariate information was ascertained at enrollment via telephone interview. We used multivariate linear regression to estimate continuous differences in sensory and motor function, and log-binomial regression to estimate prevalence ratios for dichotomous outcomes. We estimated associations of both ambient and blood styrene exposures with sensory and motor function, independently for five unique tests. Results: Those participants in the highest 25% vs. lowest 75% of ambient exposure and those in the highest 10% vs. lowest 90% of blood styrene had slightly diminished visual contrast sensitivity. Mean vibrotactile thresholds were lower among those in the highest vs. lowest quartile of ambient styrene and the highest 10% vs. lowest 90% of blood styrene (−0.13 log microns; 95% CI: −0.23, −0.03 and −0.39 log microns; 95% CI: −0.72, −0.05, respectively). The highest vs. lowest quartile of ambient styrene was associated with significantly poorer postural stability, and (unexpectedly) with significantly greater grip strength. Discussion: We observed associations between higher styrene exposure and poorer visual, sensory, and vestibular function, though we did not detect associations with reduced voluntary motor system performance. Associations were more consistent for ambient exposures, but we also found notable associations with measured blood styrene. https://doi.org/10.1289/EHP3954
Type I interferon in anti‐MDA5 dermatomyositis
Authors: S.H. Zhang, Y. Zhao, Q.B. Xie, Y. Jiang, Y.K. Wu, B. Yan
Journal: British Journal of Dermatology (2019)

Dermatomyositis (DM) is a rare condition which causes inflammation in the skin and muscles. There are different subtypes of DM, which are defined by genetic differences. One subtype of DM, characterised by a gene called anti‐melanoma differentiation‐associated gene 5 (anti‐MDA5 DM), is linked to an extremely high risk of interstitial lung disease (ILD). In Asia, 10‐48% of DM patients have this type of DM. This study, from China, aimed to explore the role of certain proteins, together known as the type 1 interferon system, in development of this type of DM. Patients with anti‐MDA5 DM were studied and compared with patients who suffered from other variations of DM. The levels of specific proteins in the blood (inflammatory cytokines, B cell activating factor or ‘BAFF’, Krebs von den Lungen‐6) and in skin lesions (STAT1, ISG15 and MxA) were tested. The levels of the protein plasma IFN‐α was much higher in anti‐MDA5 DM patients than those of other DM subtypes. Skin biopsies from anti‐MDA5 DM patients were characterized by the strong expressions of (presence of) STAT1, ISG15, and MxA proteins. In the anti‐MDA5 DM/ILD patients with high IFN‐α production, there was a relationship between IFN‐α and BAFF levels. In addition, the higher levels of BAFF paralleled to the higher concentrations of KL‐6. This study confirms the abnormal activation of type I IFN protein system in anti‐MDA5 DM. Overproduction of IFN‐α linked with BAFF may be implicated in the development of ILD.
Fit notes for benefit claimants: medical bodies “did not agree” advice to GPs
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The BMA and the Royal College of General Practitioners have disputed claims by the UK Department for Work and Pensions that they agreed the wording of advice issued by the government to doctors on how to administer “fit notes” for severely ill and disabled benefit claimants.

The House of Commons Work and Pensions Committee ordered an inquiry into the issue in response to a series of distressing media reports about people dying as they awaited the result of assessments to determine their eligibility for the Personal Independence Payment (PIP) and Employment and Support Allowance.

The MPs said that they had acted amid concern that the advice form sent to GPs after …
Recombinant phospholipase A1 from Polybia paulista (Hymenoptera: Vespidae) for specific diagnosis and immunotherapy of venom allergy
Authors: A. Perez-Riverol, A. Musacchio Lasa, L. G. Romani Fernandes, J. R. Dos Santos-Pinto, M. Luiz Bazon, M. S. Palma, R. De Lima Zollner, M. R. Brochetto-Braga
Journal: Allergy (2017)
Mannose Phosphate Isomerase and Mannose Regulate Hepatic Stellate Cell Activation and Fibrosis in Zebrafish and Humans
Authors: Charles DeRossi, Kathryn Bambino, Joshua Morrison, Isabel Sakarin, Carlos Villacorta‐Martin, Changwen Zhang, Jillian L. Ellis, M. Isabel Fiel, Maria Ybanez, Youngmin A. Lee, Kuan‐lin Huang, Chunyue Yin, Takuya F. Sakaguchi, Scott L. Friedman, Augusto Villanueva, Jaime Chu
Journal: Hepatology (2019)

The growing burden of liver fibrosis and lack of effective antifibrotic therapies highlight the need for identification of pathways and complementary model systems of hepatic fibrosis. A rare, monogenic disorder in which children with mutations in mannose phosphate isomerase (MPI) develop liver fibrosis led us to explore the function of MPI and mannose metabolism in liver development and adult liver diseases. Herein, analyses of transcriptomic data from three human liver cohorts demonstrate that MPI gene expression is down‐regulated proportionate to fibrosis in chronic liver diseases, including nonalcoholic fatty liver disease and hepatitis B virus. Depletion of MPI in zebrafish liver in vivo and in human hepatic stellate cell (HSC) lines in culture activates fibrotic responses, indicating that loss of MPI promotes HSC activation. We further demonstrate that mannose supplementation can attenuate HSC activation, leading to reduced fibrogenic activation in zebrafish, culture‐activated HSCs, and in ethanol‐activated HSCs. Conclusion: These data indicate the prospect that modulation of mannose metabolism pathways could reduce HSC activation and improve hepatic fibrosis.
HGG-25. TARGETING THE EPIGENETIC MODIFIER HMGA2 IN DIPG AND HIGH GRADE GLIOMAS INHIBITS PROLIFERATION, INVASION AND TUMORIGENICITY
Authors: Harpreet Kaur, Huizi Guo, Sepehr Akhtarkhavari, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2019)

Diffuse intrinsic pontine glioma (DIPG) and glioblastoma (GBM) are infiltrative and lethal brain tumors. Identifying and targeting novel molecular markers is urgently needed. Although DIPG and GBM have different epigenetic drivers, we found increased expression of an epigenetic modifier and stem cell factor HMGA2 in a subset of both tumors and multiple patient-derived cell lines by immunohistochemistry and western blotting. HMGA2 is a DNA minor-groove binding protein that regulates transcription in normal and cancer stem cells. We hypothesized that HMGA2 contributes to high grade glioma tumorigenicity by altering the transcription of many genes. Lentiviral short hairpin RNA (shRNA)-mediated reduction of HMGA2 in DIPG and GBM cells significantly reduced invasion (transwell assay) and proliferation (BrdU incorporation), and increased apoptosis (cleaved caspase-3, shHMGA2 vs. shControl, P < 0.01). Mice bearing orthotopic GBM xenograft cells transduced with HMGA2 shRNA lived longer (median survival = 108 days) compared to control shRNA (67.5 days, P < 0.0001 by log-rank analysis). Pharmacological inhibition of HMGA proteins using the DNA minor-groove binding drug quinacrine caused dose-dependent reduction in proliferation (BrdU), and increase in apoptosis (cleaved caspase-3) of DIPG neurospheres (P<0.01). Quinacrine had no effect on growth of normal hindbrain cells. Quinacrine has a well-known safety profile, is brain penetrable and we can achieve therapeutically efficacious micromolar concentration of quinacrine in mouse and zebrafish brain after oral administration without overt toxicity. To investigate the mechanism of HMGA2-mediated malignancy, we discovered high levels of CD44 (a known mediator of invasion and stemness) that correlated with high HMGA2 expression in DIPG and GBM tumors. Suppression of HMGA2 led to decreased CD44 protein expression. Knockdown of CD44 in HMGA2-high glioma neurospheres reduced invasion (P<0.01). Our results identify HMGA2 as a potential therapeutic target and suggest that minor groove binding agents like quinacrine may be effective therapeutics for pediatric high-grade gliomas.