tbuckley/cabot-search huggingface dataset:
Evaluation of Rooming-in Practice for Neonates Born to Mothers With Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Italy
Authors: Andrea Ronchi, Carlo Pietrasanta, Maurizio Zavattoni, Martina Saruggia, Federico Schena, Maria Teresa Sinelli, Massimo Agosti, Chryssoula Tzialla, Felicia Filomena Varsalone, Lea Testa, Claudia Ballerini, Stefania Ferrari, Giovanna Mangili, Maria Luisa Ventura, Simona Perniciaro, Elena Spada, Giovanna Lunghi, Antonio Piralla, Fausto Baldanti, Fabio Mosca, Lorenza Pugni
Journal: JAMA Pediatrics (2020)

The management of mother-infant dyads during the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic constitutes a major issue for neonatologists. In mothers with SARS-CoV-2 infection, current recommendations suggest either to separate the dyad or encourage protected rooming-in under appropriate precautions. No data are available regarding the risk of mother-to-infant transmission of SARS-CoV-2 during rooming-in.To evaluate the risk of postnatal transmission of SARS-CoV-2 from infected mothers to their neonates following rooming-in and breastfeeding.A prospective, multicenter study enrolling mother-infant dyads from March 19 to May 2, 2020, followed up for 20 days of life (range, 18-22 days), was performed. The study was conducted at 6 coronavirus disease 2019 maternity centers in Lombardy, Northern Italy. Participants included 62 neonates born to 61 mothers with SARS-CoV-2 infection who were eligible for rooming-in practice based on the clinical condition of the mother and infants whose results of nasopharyngeal swabs were negative at birth.Mothers with SARS-CoV-2 infection were encouraged to practice rooming-in and breastfeeding under a standardized protocol to minimize the risk of viral transmission.Clinical characteristics and real-time reverse transcriptase-polymerase chain reaction for SARS-CoV-2 on neonatal nasopharyngeal swabs at 0, 7, and 20 days of life.Of the 62 neonates enrolled (25 boys), born to 61 mothers (median age, 32 years; interquartile range, 28-36 years), only 1 infant (1.6%; 95% CI, 0%-8.7%) was diagnosed as having SARS-CoV-2 infection at postbirth checks. In that case, rooming-in was interrupted on day 5 of life because of severe worsening of the mother's clinical condition. The neonate became positive for the virus on day 7 of life and developed transient mild dyspnea. Ninety-five percent of the neonates enrolled were breastfed.The findings of this cohort study provide evidence-based information on the management of mother-infant dyads in case of SARS-CoV-2 maternal infection suggesting that rooming-in and breastfeeding can be practiced in women who are able to care for their infants.
Subcellular Organization of the cAMP Signaling Pathway
Authors: Manuela Zaccolo, Anna Zerio, Miguel J. Lobo
Journal: Pharmacological Reviews (2020)

The field of cAMP signaling is witnessing exciting developments with the recognition that cAMP is compartmentalized and that spatial regulation of cAMP is critical for faithful signal coding. This realization has changed our understanding of cAMP signaling from a model in which cAMP connects a receptor at the plasma membrane to an intracellular effector in a linear pathway to a model in which cAMP signals propagate within a complex network of alternative branches and the specific functional outcome strictly depends on local regulation of cAMP levels and on selective activation of a limited number of branches within the network. In this review, we cover some of the early studies and summarize more recent evidence supporting the model of compartmentalized cAMP signaling, and we discuss how this knowledge is starting to provide original mechanistic insight into cell physiology and a novel framework for the identification of disease mechanisms that potentially opens new avenues for therapeutic interventions. <h3>Significance Statement</h3> cAMP mediates the intracellular response to multiple hormones and neurotransmitters. Signal fidelity and accurate coordination of a plethora of different cellular functions is achieved via organization of multiprotein signalosomes and cAMP compartmentalization in subcellular nanodomains. Defining the organization and regulation of subcellular cAMP nanocompartments is necessary if we want to understand the complex functional ramifications of pharmacological treatments that target G protein–coupled receptors and for generating a blueprint that can be used to develop precision medicine interventions.
QOL-05. TUMOR LOCATION IS LESS LIKELY INFLUENCE ON COGNITIVE DYSFUNCTION IN CHILDREN
Authors: Riho Nakajima, Masashi Kinoshita, Shingo Tanaka, Mitsutoshi Nakada
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Though several factors are known to influence on long-term cognitive function in children with brain tumor, the impact of tumor localization to specific cognitive function was not well known. Here we investigated the influence of local brain resection by surgery on postoperative cognitive outcome in school-aged children. METHODS Participants were seven pediatric patients who underwent craniotomy for tumor resection in our hospital (mean age, 13.9 years). Their diagnosis were WHO grade 1 or 2 glioma (n=6) and hemangioma (n=1). Tumor were mainly located in following regions; frontal, n=2; parietal, n=2; temporal, n=3 (These lesions included hippocampus or were located very close to it). Temporal assessments for cognitive function of several functional domains were performed according to tumor location until post-op 1 year. Based on MRI, we estimated cognitive dysfunctions and compared them to observational symptoms. RESULTS Preoperative cognitive function was normal in all patients. Cognitive dysfunctions estimated from resected area were as follows (cumulative total number); memory or working memory disorder, n=4; visuospatial cognitive disorder, n=3; disorder of processing speed, n=2; facial or topographical agnosia, n=2; Gerstman syndrome, n=1. Just after surgery, cognitive function was declined in two functional domains of two patients, which were only 16.7% of estimated deficit from resected region. They recovered completely until 3 months postoperatively, and returned to school without any deficits. CONCLUSIONS In pediatric lower-grade tumor, focal cognitive symptom was unlikely to be induced by local resection.
ATRT-09. IDENTIFICATION OF HUB GENES IN ATYPICAL TERATOID/RHABDOID TUMORS BY MULTIPLE-MICROARRAY ANALYSIS
Authors: Wei Liu, Yi Chai, Junhua Wang, Yuqi Zhang
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (ATRT) are rare, highly malignant neoplasms arising in infants and young children. However, the biological basis of ATRTs remains poorly understood. In the present study, we employed integrated bioinformatics to investigate the hub genes and potential molecular mechanism in ATRT. METHODS Three microarray datasets, GSE35943, GSE6635 and GSE86574, were downloaded from Gene Expression Omnibus (GEO) which contained a total of 79 samples including 32 normal brain tissue samples and 47 ATRT samples. The RobustRankAggreg method was employed to integrate the results of these gene expression datasets to obtain differentially expressed genes (DEGs). The GO function and KEGG pathway enrichment analysis were conducted at the Enrichr database. The hub genes were screened according to the degree using Cytoscape software. Finally, transcription factor (TF) of hub genes were obtained by the NetworkAnalyst algorithm. RESULTS A total of 297 DEGs, consisting of 94 downregulated DEGs and 103 upregulated DEGs were identified. Functional enrichment analysis revealed that these genes were associated with cell cycle, p53 signaling pathway and DNA replication. Protein-protein interaction (PPI) network analysis revealed that CDK1, CCNA2, BUB1B, CDC20, KIF11, KIF20A, KIF2C, NCAPG, NDC80, NUSAP1, PBK, RRM2, TPX2, TOP2A and TTK were hub genes and these genes could be regulated by MYC, SOX2 and KDM5B according to the results of TF analysis. CONCLUSIONS Our study will improve the understanding of the molecular mechanisms and provide novel therapeutic targets for ATRT.
EXTH-45. DELTA-24-RGDOX ACTIVATION OF THE IDO-KYN-AHR CASCADE IN GLIOBLASTOMA: OLD TARGETS FOR A NEW THERAPY
Authors: Teresa Nguyen, Dong Ho Shin, Hong Jiang, Derek Wainwright, Sagar Sohoni, Sumit Gupta, Ashley Ossimetha, Frederick Lang, Marta M Alonso, Juan Fueyo, Candelaria Gomez-Manzano
Journal: Neuro-Oncology (2020)

Abstract Immune enhancement of virotherapy by reshaping the tumor immune landscape may improve its success rates. IDO, an IFNγ inducible tryptophan catabolizing enzyme, is upregulated in glioblastoma, correlating with poor prognoses. IDO-mediated tryptophan depletion in the tumor-microenvironment decreases proliferation and induces apoptosis of surrounding effector T-cells. Kynurenine, a metabolite of tryptophan, induces T-cell differentiation into immunosuppressive Tregs. Excess kynurenine elicits AhR-mediated lymphocyte dysfunction and immunosuppression. The immune stimulating effect of oncolytic-virus, Delta-24-RGDOX, triggers IFNγ production contributing to a positive IDO-Kynurenine-AhR feedback loop. We hypothesized that combining Delta-24-RGDOX with IDO inhibitors will synergize to effectively treat glioblastoma. We characterized IDO and AhR in Delta-24-RGDOX infected cancers using immunofluorescence, qRT-PCR, and flow cytometry and found increased expression of both proteins in vitro and in vivo. We also observed induction of AhR in CD4+ and CD8+ T-cells by Delta-24-RGDOX in vivo. Delta-24-RGDOX also increased activity of AhR in cancer cells as indicated by an AhR responsive elements transcription assay. We used a murine glioblastoma model to test the efficacy of combining Delta-24-RGDOX with IDO inhibitor, 1MT/indoximod; the combination produced 30% more long-term survivors compared Delta-24-RGDOX alone (P=0.03), which we showed, through lymphocytic depletion studies, was dependent on CD4+ T-cell activation. We observed 100% survival in the re-challenged long-term glioblastoma survivors, indicating the establishment of immune memory by the combination. Functional studies showed significant increases in anti-tumor activity of splenocytes from combination-treated mice compared to Delta-24-RGDOX-treated mice (P=0.009). Flow cytometry studies revealed that combination-treated mice yielded the highest levels of chronically activated T-cells and lowest levels of Tregs and myeloid derived suppressor cells compared to Delta-24-RGDOX single treatment (P≤0.05). This microenvironment remodeling correlated with complete tumor elimination. Altogether, Delta-24-RGDOX activates the IDO-Kyn-AhR cascade in gliomas, identifying new targets, which when inhibited have the potential to enhance the anti-glioma effect of oncolytic-viruses by reversing tumor immunosuppression.
MODL-27. MEK INHIBITION WITH TRAMETINIB SLOWS PROGRESSION OF MEDULLOBLASTOMA AND ATYPICAL TERATOID RHABDOID TUMOR IN ORTHOTOPIC XENOGRAFT MURINE MODEL
Authors: Sujata Mushrif, Long Hung, Sakunthala Muthugounder, Shahab Asgharzadeh
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Combination of surgery, chemotherapy, autologous transplantation, irradiation constitutes treatment of CNS embryonal-cell tumors (Medulloblastoma-MBL, atypical teratoid rhabdoid tumor-AT/RT). Targeted agents to improve survival and decrease side effects are necessary. We hypothesize that inhibiting MAPK pathway in MBL and AT/RT may be beneficial. METHODS IHC(pERK) was performed on clinical tumors. Trametinib(MEK inhibitor) was tested on MBL(UW228, D283, DAOY); AT/RT(CHLA06, BT12) cell-lines. Luminescent cell-viability assay was done(72 hrs) and with crystal violet assay(10 days). Orthotopic, xenografts of MBL and AT/RT were made in NOD-Scid gamma mice. Mice were given Trametinib daily by gavage for 6 weeks(0.6mg/kg b.w). Western blot was performed on protein from cell lines and tumor xenografts incubated with Trametinib. H&amp;E staining was done on murine tumors. RESULTS AT/RT(48%) and MBL(57%); Anaplastic(50%), Desmoplastic(40%), Classic(38%); Group 4(66%), Group 3(20%), SHH(55%), WNT(0%) showed presence of pERK(clinical samples). In-vitro, Trametinib completely abrogated the phosphorylation of ERK at 125nM in AT/RT and 50nM in MBL. The IC50 after 10 days exposure was 10nM for AT/RT and 35nM for MBL. Trametinib treated mice showed delay in tumor growth and significant survival advantage in both AT/RT (p=0.00336) and MBL (p=0.0069). Murine tumors showed decreased proliferation (H&amp;E). CONCLUSION Trametinib decreased cell proliferation, increased survival in our murine model in both MBL and AT/RT. Pre-clinical results indicate benefits in subgroups of AT/RT and MBL with active MAPK pathway.
1, 4-bis (4-(1H-benzo[d]imidazol-2-yl-phenyl)) piperazine (BIPP) induces apoptosis in leukemia cells
Authors: Josiah Sampson
Journal: Cancer Research (2007)

1912  The agent, 1, 4-bis (4-(1H-benzo[d]imidazol-2-yl-phenyl)) piperazine (BIPP) is a newly synthesized piperazine derivative. Piperazines are normally used as anti-helmintic or antibiotic agents for treatment of parasitic worm or microbial infections. The increased solubility, stability, and potency of delivery that the piperazine base provides have led us to believe that it may also be a novel anticancer agent. We have compared the effect of BIPP on two leukemia cell lines (U937, monocytic leukemia and K562, erythroleukemia) against the HDAC inhibitor sodium butyrate. We provide evidence that BIPP induces an apoptotic response by inducing Annexin V binding, caspase activation, loss of mitochondrial membrane potential (MMP), and decrease in ATP levels. In addition, we investigated whether like butyrate; BIPP causes leukemia cell death via intrinsic or extrinsic apoptotic pathways. Using several techniques, we have shown that BIPP induces dose-responsive cell death in U937 and K562 leukemia cell lines by intrinsic apoptosis mechanisms. Maximum apoptotic effect of BIPP on cell viability was observed between 3.2 and12.8 uM while butyrate elicited its maximum effect at 10 to 25 mM. We performed caspase enzymatic assays in cells treated with varying doses of BIPP using untreated cells as negative control. We noted that BIPP induces differential dose-response activation of caspases 3, 8 and 9. Again, the optimum activation of these caspases was attained at 3.2 to 12.8 uM of BIPP. Caspase activation profiles induced by BIPP were similar to those caused by butyrate in that both differentially activate caspases 3, 8 ad 9 in these cells. However, BIPP failed to activate caspase 2 and had an inhibitory effect on caspase 10. The differential response seen in initiator caspase activity (caspases-2, -8, -10) combined with the increased activity of effector caspases (caspases-3 and -9) and the loss of MMP suggest and intrinsic mechanism in the initiation of apoptosis and that BIPP causes leukemia cell death by these intrinsic apoptotic mechanisms. Also, our data suggests that BIPP triggers induction of leukemia cell death and that this drug could be considered as a potential therapeutic agent for human monocytic and erythroblastic leukemia. NHLBI T32 and SCORE grants
ATRT-21. RHABDOID PREDISPOSITION SYNDROME: REPORT OF MOLECULAR PROFILES AND TREATMENT APPROACH IN THREE CHILDREN WITH SYNCHRONOUS ATYPICAL TERATOID/RHABDOID TUMOR AND MALIGNANT RHABDOID TUMOR
Authors: Margaret Shatara, Ajay Gupta, Mohamed H Abu Arja, Suzanne E Conley, Priyal Patel, Daniel R Boué, Christopher R Pierson, Diana L Thomas, Erin K Meyer, Summit H Shah, Jeremy Jones, Lisa Martin, Aaron McAllister, Kathleen M Schieffer, Elizabeth A Varga, Kristen Leraas, Tara Lichtenberg, Stephanie LaHaye, Katherine E Miller, Vincent Magrini, Richard K Wilson, Catherine E Cottrell, Elaine R Mardis, Jennifer H Aldrink, Jeffery J Auletta, Jonathan Pindrik, Jeffrey R Leonard, Diana S Osorio, Jonathan L Finlay, Mark Ranalli, Mohamed S AbdelBaki
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Rhabdoid predisposition syndrome is characterized by germline alterations in SMARCB1 or SMARCA4, leading to synchronous or metachronous central nervous system (CNS) and extra-CNS rhabdoid tumors. Rare survivors have been reported to date. METHODS We describe the molecular profiling and treatment regimen of three patients with synchronous atypical teratoid/rhabdoid tumor (ATRT) and malignant rhabdoid tumor of the kidney (MRT-K). All patients underwent radical nephrectomy of the kidney, and gross total resection of the primary CNS tumor was achieved for two patients. An intensive chemotherapy regimen was administered; an induction phase based on the modified Third Intergroup Rhabdomyosarcoma Study (IRS-III) for ATRT followed by a consolidation phase with three cycles of high-dose chemotherapy and autologous hematopoietic progenitor cell rescue, without irradiation. All three patients were enrolled on an institutional comprehensive genomic profiling protocol. RESULTS A germline focal 22q deletion, including SMARCB1, was detected in two patients, while the third patient had a maternally-inherited heterozygous frameshift variant in SMARCB1. Somatic loss of heterozygosity of 22q was identified in all patients, resulting in biallelic inactivation of SMARCB1. Divergent tumor subgroups were described using DNA methylation. The three MRT-K samples were classified as MYC subtype. One ATRT was classified as SHH while the other as TYR. One patient is currently three years off-therapy without evidence of disease, while the other two patients have completed the consolidation phase without recurrent disease. CONCLUSION Molecular profiling of CNS and extra-CNS rhabdoid tumors revealed different epigenetic subgroups. An intensive multimodal therapeutic approach without irradiation may achieve prolonged survival.
Unexpected Vertebral Bodies Trapping of 99mTc–Macroaggregated Albumin During Lung Perfusion Scintigraphy in a Patient With Collateral Paravertebral Venous System
Authors: Matthieu Dietz, Salim Si-Mohamed, Agathe Deville, Jeremie Tordo, Caroline Moreau-Triby
Journal: Clinical Nuclear Medicine (2020)

A 35-year-old woman was referred to our nuclear medicine center for a ventilation and perfusion (VQ) pulmonary scintigraphy to detect pulmonary embolism. She was treated with low-molecular-weight heparin following a proximal venous thrombosis of the right upper limb and had a previous history of an infiltrating ductal carcinoma of the right breast. Surprisingly, the VQ scintigraphy showed uptake of 99mTc-MAA in several superior vertebrae. A contrast-enhanced CT scan revealed a dilated collateral paravertebral venous system due to the deep vein thrombosis extended from superior vena cava to brachiocephalic trunk. 99mTc-MAA was trapped through the dilated vertebral venous system.
Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance
Authors: Philipp Koehler, Matteo Bassetti, Arunaloke Chakrabarti, Sharon C A Chen, Arnaldo Lopes Colombo, Martin Hoenigl, Nikolay Klimko, Cornelia Lass-Flörl, Rita O Oladele, Donald C Vinh, Li-Ping Zhu, Boris Böll, Roger Brüggemann, Jean-Pierre Gangneux, John R Perfect, Thomas F Patterson, Thorsten Persigehl, Jacques F Meis, Luis Ostrosky-Zeichner, P Lewis White, Paul E Verweij, Oliver A Cornely
Journal: The Lancet Infectious Diseases (2020)
Abstract 14018: Stroke Risk After Incidental Diagnosis of Papillary Fibroelastoma
Authors: Kunal Jha, Mamatha Pinninti, Erin Vanenkevort, Lokendra Thakur, Terry D Bauch
Journal: Circulation (2019)

Introduction: Papillary fibroelastoma (PFE) is a rare and benign primary cardiac tumor. It usually involves cardiac valves and it has embolic potential that can lead to stroke. The purpose of this ...
PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury
Authors: Evangelos Triantafyllou, Cathrin L.C. Gudd, Marie-Anne Mawhin, Hannah C. Husbyn, Francesca M. Trovato, Matthew K. Siggins, Thomas O’Connor, Hiromi Kudo, Sujit K. Mukherjee, Julia A. Wendon, Christine Bernsmeier, Robert D. Goldin, Marina Botto, Wafa Khamri, Mark J.W. McPhail, Lucia A. Possamai, Kevin J. Woollard, Charalambos G. Antoniades, Mark R. Thursz
Journal: Journal of Clinical Investigation (2020)

Patients with acute liver failure (ALF) have systemic innate immune suppression and increased susceptibility to infections. Programmed cell death 1 (PD-1) expression by macrophages has been associated with immune suppression during sepsis and cancer. We therefore examined the role of the programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) pathway in regulating Kupffer cell (KC) inflammatory and antimicrobial responses in acetaminophen-induced (APAP-induced) acute liver injury. Using intravital imaging and flow cytometry, we found impaired KC bacterial clearance and systemic bacterial dissemination in mice with liver injury. We detected increased PD-1 and PD-L1 expression in KCs and lymphocyte subsets, respectively, during injury resolution. Gene expression profiling of PD-1+ KCs revealed an immune-suppressive profile and reduced pathogen responses. Compared with WT mice, PD-1-deficient mice and anti-PD-1-treated mice with liver injury showed improved KC bacterial clearance, a reduced tissue bacterial load, and protection from sepsis. Blood samples from patients with ALF revealed enhanced PD-1 and PD-L1 expression by monocytes and lymphocytes, respectively, and that soluble PD-L1 plasma levels could predict outcomes and sepsis. PD-1 in vitro blockade restored monocyte functionality. Our study describes a role for the PD-1/PD-L1 axis in suppressing KC and monocyte antimicrobial responses after liver injury and identifies anti-PD-1 immunotherapy as a strategy to reduce infection susceptibility in ALF.
MBRS-27. EXOSOMES CARRY DISTINCT miRNAs THAT DRIVE MEDULLOBLASTOMA PROGRESSION
Authors: Hannah K Jackson, Franziska Linke, Ian Kerr, Beth Coyle
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Extracellular vesicles (EVs) represent an ideal source of functional biomarkers due to their role in intercellular communication and their ability to protect cargo, including RNA, from degradation. The most investigated EV’s are exosomes, nanovesicles secreted by all cell types and able to cross the blood-brain-barrier. Here we characterised the RNA of exosomes isolated from medulloblastoma cell lines, with the aim of investigating exosomal RNA cargo as potential functional biomarkers for medulloblastoma. METHODS Exosomes derived from a panel of matched (original tumour and metastasis) medulloblastoma cell lines were isolated and characterised by NanoSight, electron microscopy, western blotting and Nanoscale flow cytometry. Exosomal miRNA and mRNA from our matched cell lines and foetal neuronal stem cells, which were used as a normal control, were analysed by RNA-sequencing technology. RESULTS Based on hierarchical clustering, malignant derived exosomes were distinctly separated from normal control exosomes. miRNA profiling revealed several established oncomiRs identified in our malignant derived exosomes compared to control samples. Using interaction pathway analysis, we identified that our malignant exosomes carry numerous miRNAs implicated in migration, proliferation, cellular adhesion and tumour growth. Several previously identified oncomiRs were also identified to be present at higher levels in metastatic exosomes compared to primary and normal, including hsa-miR-455-3p and hsa-miR-92a-3p. CONCLUSION This study shows that exosomes from MB cells carry a distinct miRNA cargo which could enhance medulloblastoma progression. The use of circulating exosomes as markers of metastatic disease could be an innovative and powerful non-invasive tool.