tbuckley/cabot-search huggingface dataset:
EXTH-42. SPIDER VENOM COMPONENTS DECREASE GLIOBLASTOMA CELL MIGRATION AND INVASION THROUGH RHOA-ROCK AND NA+/K+-ATPASE β2: POTENTIAL MOLECULAR ENTITIES TO TREAT INVASIVE BRAIN CANCER
Authors: Catarina Raposo, Natalia Barreto dos Santos, Marcus Caballero, Amanda Bonfanti, Thomaz A A da Rocha-e-Silva, Rafael Sutti, Liana Verinaud
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GB) cells have the ability to migrate and infiltrate the normal parenchyma, leading to the formation of recurrent tumors often adjacent to the surgical extraction site. We recently showed that Phoneutria nigriventer spider venom (PnV) has anticancer effects mainly on the migration of human GB cell lines (NG97 and U-251). The present work aimed to investigate the effects of isolated components from the venom on migration, invasiveness, morphology and adhesion of GB cells. The involvement of RhoA-ROCK signaling and Na+/K+-ATPase β2 (AMOG) was also evaluated. Human (NG97) GB cells were treated with twelve subfractions (SFs - obtained by HPLC from PnV). Migration and invasion were evaluated by scratch wound heling and transwell assays, respectively. Cell morphology and actin cytoskeleton were shown by GFAP and phalloidin labeling. The assay with fibronectin coated well plate was made to evaluate cell adhesion. Western blotting demonstrated ROCK and AMOG levels and a ROCK inhibitor was used to verify the involvement of this pathway. Two (SF1 and SF11) of twelve SFs decreased migration and invasion compared to untreated control cells. Both SFs also altered actin cytoskeleton, changed cell morphology and reduced adhesion. SF1 and SF11 increased ROCK expression and the inhibition of this protein abolished the effects of both subfractions on migration, morphology and adhesion (but not on invasion). SF11 also increased Na+/K+-ATPase β2. All components of the venom were evaluated and two SFs were able to impair human glioblastoma cells. The RhoA effector, ROCK, was shown to be involved in the mechanisms of both PnV components. It is possible that AMOG mediates the effect of SF11 on the invasion. Further investigations to isolate and biochemically characterize the molecules are underway. Support: FAPESP #2015/04194-0; CNPq #431465/2016–9.
Face masks and COVID-19: don’t let perfect be the enemy of good
Authors: Benjamin J Cowling, Gabriel M Leung
Journal: Eurosurveillance (2020)

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CBIO-21. H3F3A G34R/V MUTATIONS INDUCE CHROMOSOMAL INSTABILITY AND PROMOTE PEDIATRIC HIGH-GRADE GLIOMA FORMATION
Authors: Charles Day, Florina Grigore, Alyssa Langfald, James Robinson, Edward Hinchcliffe
Journal: Neuro-Oncology (2020)

Abstract Histone H3.3 G34R/V mutations are drivers of pediatric high-grade glioma (pHGG). However, the mechanism(s) responsible for G34R/V induced tumorigenesis are unclear. We observed that pHGG cells with H3.3 G34 mutations have significantly reduced phosphorylation at H3.3 S31 as compared to H3.3 WT cell lines. And, in vitro, G34 mutation completely blocks H3.3 S31 phosphorylation by Chk1 – the kinase responsible for S31 phosphorylation. During early mitosis, phospho-S31 is enriched in the chromosomal pericentromere; which plays a vital structural role in chromosome segregation. Over-expression of GFP-H3.3 G34R or non-phosphorylatable GFP-H3.3 S31A in chromosomally stable cell lines results in a significant increase in chromosome mis-segregations. Likewise, H3.3 G34V pHGG derived cells showed a higher frequency of mis-segregation than H3.3 WT cells. During cell division, phospho-S31 is lost in late anaphase. However, when chromosome missegregation occurs, phospho-S31 spreads to the chromosome arms where it stimulates p53 accumulation in G1 – thus acting as a sensor to suppress the proliferation of aneuploid cells. Here we show that cells expressing mutant G34 fail to arrest following mis-segregation, despite having WT p53. Taken together this work demonstrates that the H3.3 G34R/V mutations are sufficient to transform normal, diploid cells into proliferative, chromosomally instable cells. To determine if this process contributes to tumorigenesis, we expressed WT H3.3, H3.3-G34R or H3.3-S31A in a mouse model of pHGG. H3.3 WT controls developed low-grade tumors and all survived 80 days. Mice with H3.3-G34R or H3.3-S31A developed low- and high-grade tumors. And 78% and 50% of H3.3-G34R and H3.3-S31A mice, respectively, survived to 80 days. Our work suggests that H3.3 G34R/V drives chromosomal instability through the suppression of H3.3 S31 phosphorylation AND that chromosomal instability is a contributing driver of glioma formation in G34 mutant tumors.
NCMP-07. TREATMENT-INDUCED CEREBRAL NECROSIS IN GLIOMAS: THE OHIO STATE UNIVERSITY COMPREHENSIVE CANCER CENTER (OSUCCC) EXPERIENCE
Authors: Appaji Rayi, Iyad Alnahhas, Joshua Palmer, Raju Raval, Wayne Slone, Shirley Ong, Pierre Giglio, Vinay Puduvalli
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Treatment-induced cerebral necrosis (TN) is a challenging complication encountered in neuro-oncology. Diagnosis and treatment of TN remains poorly defined. METHODS In this single institution, retrospective study, consecutive patients with gliomas and TN between 01/01/2012 and 04/20/2020 at the OSUCCC were identified. Details of the tumor treatment, molecular markers, radiological and pathological findings of TN, as well as treatment, recurrence rate and management upon recurrence were collected. RESULTS Of the 53 patients analyzed, 37 had glioblastoma, 7 had anaplastic oligodendroglioma and 9 had grade II or III astrocytoma. MGMT promoter hypermethylation was present in 31/50 (59%) and IDH mutation in 17/53 (32%). Diagnosis of TN was based on histology in 43/53 (81%) or clinical/radiographic features in 10/53 (19%). Worsening of focal weakness (36%), seizures (9%) or being (30%) were common presentations at TN diagnosis. Patient with right compared to left hemisphere involvement were more symptomatic at TN diagnosis. (p=0.049). Bevacizumab (BEV) (51%), resection (28%), steroids only (9%) or Laser Interstitial Thermal Therapy (6%) were used to treat TN. Steroids were weaned off in 20/27 (74%) after receiving BEV. Among all treatments, BEV was significantly associated with a better outcome (resolution or partial improvement of enhancement in 84.6%) (p=0.0006, Bonferroni corrected p&amp;lt; 0.005). TN Recurrence occurred in 36%, 70% and 100% of the patients treated with BEV, resection and LITT respectively. The median duration to TN recurrence was 10 weeks (range: 3–70 weeks). Initial treatment used for TN, MGMT methylation and IDH mutation status did not predict TN recurrence. (p=0.074; p=0.819; p=0.607 respectively). CONCLUSIONS BEV appears to be a superior treatment to control TN overall. Recurrence of TN in patients previously treated with BEV was 36%. There was no difference in the risk of developing recurrent TN based on MGMT or IDH status.
DDRE-29. SMOOTHENED-ACTIVATING LIPIDS DRIVE RESISTANCE TO CDK4/6 INHIBITION IN HEDGEHOG-ASSOCIATED MEDULLOBLASTOMA
Authors: Vikas Daggubati, Jordan Hochstelter, Ani Bommireddy, Abrar Choudhury, Alexis Krup, Pervinder Kaur, Pakteema Tong, Amy Li, Libin Xu, Jeremy Reiter, David Raleigh
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Medulloblastoma is an aggressive pediatric brain tumor that is associated with misactivation of the Hedgehog (HH) pathway. Our lab has shown that CDK6, a critical activator of the cell cycle, is a direct transcriptional target of oncogenic HH signaling, and that inhibiting CDK6 blocks the growth of HH-associated medulloblastoma in mice. A clinical trial exploring the efficacy of CDK6 inhibition in medulloblastoma patients is underway, but prior attempts to target the HH pathway in medulloblastoma have been encumbered by resistance to molecular monotherapy. Thus, we sought to identify mechanisms of resistance to CDK6 inhibition in HH-associated medulloblastoma. METHODS We performed orthogonal CRISPR and CRISPR interference screens in HH-associated medulloblastoma cells treated with pharmacologic inhibitors of CDK6 in vitro, and RNA-sequencing of HH-associated medulloblastomas with genetic deletion of CDK6 in vivo. Mechanistic and functional validation of resistance pathways was performed using CRISPR interference, immunoblotting, immunofluorescence, genetics, and pharmacology. Lipid quantification was carried out by ultra-high performance liquid chromatography-tandem mass spectrometry. RESULTS Our results reveal that decreased ribosomal protein expression underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, leading to endoplasmic reticular (ER) stress and activation of the unfolded protein response (UPR). We show that ER stress and the UPR increase the activity of enzymes producing Smoothened-activating sterol lipids that sustain oncogenic HH signaling in medulloblastoma despite CDK6 inhibition. These discoveries suggest that combination molecular therapy against CDK6 and HSD11ß2, an enzyme producing Smoothened-activating lipids, may be an effective treatment for HH-associated medulloblastoma. In support of this hypothesis, we demonstrate that concurrent genetic deletion or pharmacological inhibition of CDK6 and HSD11ß2 additively blocks the growth of multiple models of HH-associated medulloblastoma in mice. CONCLUSIONS Smoothened-activating lipid biosynthesis underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, revealing a novel combination therapy to treat the most common malignant brain tumor in children.
THER-08. SGT53 – A NOVEL p53 NANOMEDICINE INDUCES SIGNIFICANT RESPONSES IN CHILDREN WITH RECURRENT MEDULLOBLASTOMA AND CHOROID PLEXUS CARCINOMA: A REPORT OF TWO CASES
Authors: Eugene Hwang, Lindsay Kilburn, Lauren Hancock, Kathleen Pirollo, Chris Leung, Roger Packer, Esther Chang
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Abnormal p53 function commonly defines high-risk CNS tumors, but functional restoration has eluded investigators. SGT-53 is a targeted nanomedicine encapsulating a plasmid DNA encoding wild-type human p53 with a transferrin receptor-targeting scFv on the nanocomplex surface resulting in efficient delivery across the BBB and robust tumor binding/uptake. Data generated by collaborators demonstrated synergy with irradiation and chemotherapy. REPORT: Two children with recurrent CNS malignancies have been treated with SGT-53, each receiving greater than 50 infusions in combination with irradiation and chemotherapy with no grade 3/4 AEs positively attributed to SGT-53. The first was an 11yo male with recurrent disseminated p53+ SHH medulloblastoma, with bulky intracranial/thoracolumbar disease. He received irradiation followed by biweekly doses of SGT-53 and temozolomide, bevacizumab and irinotecan given one week out of four. This patient exhibited a complete response of all disease on his first follow-up scan 8 weeks after therapy initiation and remained in remission for 8 months. The second patient was a 3yo male with disseminated recurrent choroid plexus carcinoma. He received CSI with SGT-53, followed by SGT-53, temozolomide and irinotecan as described above, again with no related grade 3/4 AEs. He experienced a partial response to all sites of disease and completed therapy after six months, progressing 7.8 months after initiating treatment. CONCLUSIONS SGT-53 was well tolerated in two heavily-pretreated patients despite aggressive combinatorial strategies. The majority of the AEs experienced were mild and manageable. Each patient had significant responses, suggesting that SGT-53 should be evaluated in a clinical trial for similar patients.
David Ivor Maurice Siegler
Authors: Patrick O’Donnell
Journal: BMJ (2020)

Something of a star pupil, at University College Hospital Medical School David Ivor Maurice Siegler won the Fellowes silver medal in clinical medicine, the senior undergraduate prize for medicine, the FT Roberts prize, the McGrath scholarship, and was then appointed house physician to the professorial medical unit under Professor Lord Rosenheim at University College Hospital. Three years later he was appointed registrar to the same unit.

His path set on obtaining a consultancy in medicine, David undertook further training with stints at the Royal Free Hospital, University College Hospital, and the Royal Brompton Hospital. In 1975 he completed a research fellowship in pulmonary physiology …
Association of high profile football matches in Europe with traffic accidents in Asia: archival study
Authors: Kai Chi Yam, Joshua Conrad Jackson, Jenson Lau, Xin Qin, Christopher M Barnes, Juin-Kuan Chong
Journal: BMJ (2020)

Abstract Objective To investigate the association between popular football games played in Europe and the incidence of traffic accidents in Asia. Design Study based on 41 538 traffic accidents involving taxis in Singapore and 1 814 320 traffic accidents in Taiwan, combined with 12 788 European club football games over a seven year period. Setting Singapore and Taiwan. Participants The largest taxi company in Singapore, with fine grained traffic accident records in a three year span; all traffic accident records in Taiwan in a six year span. Exposure Days when high profile football games were played or not played. Main outcome measure Number of traffic accidents. Results Regression based and time series models suggest that days with high profile European football matches were more positively associated with traffic accidents than days with less popular European football matches. For an approximate €134.74m (£120.25m; $159.76m) increase in average market value for matches played on a given day, approximately one extra accident would occur among Singapore taxi drivers, and for an approximate €7.99m increase in average market value of matches, approximately one extra accident would occur among all drivers in Taiwan. This association remained after control for weather conditions, time of the year, weekend versus weekday effects, driver demographics, and underlying temporal trends. It was also stronger for daytime traffic accidents than for night time traffic accidents, suggesting that the association between high profile football matches and traffic accidents cannot be attributed to night time celebration or attention deficits while watching and driving. Annually, this increased rate of traffic accidents may translate to approximately 371 accidents among taxi drivers in Singapore and approximately 41 079 accidents among the Taiwanese public, as well as economic losses of approximately €821 448 among Singapore taxi drivers and approximately €13 994 409 among Taiwanese drivers and insurers. The total health and economic impact of this finding is likely to be much higher because GMT+8 is the most populous time zone, encompassing 24% of the world’s population. Conclusions Days featuring high profile football matches in Europe were associated with more traffic accidents in Taiwan and Singapore than were days with lower profile football matches. A potential causal mechanism may be Asian drivers losing sleep by watching high profile European matches, which are often played in the middle of the night in Asia.
Single-cell analyses reveal YAP/TAZ as regulators of stemness and cell plasticity in glioblastoma
Authors: Martina Castellan, Alberto Guarnieri, Atsushi Fujimura, Francesca Zanconato, Giusy Battilana, Tito Panciera, Hanna Lucie Sladitschek, Paolo Contessotto, Anna Citron, Andrea Grilli, Oriana Romano, Silvio Bicciato, Matteo Fassan, Elena Porcù, Antonio Rosato, Michelangelo Cordenonsi, Stefano Piccolo
Journal: Nature Cancer (2020)
Ulipristal Acetate for Treatment of Premenstrual Dysphoric Disorder: A Proof-of-Concept Randomized Controlled Trial
Authors: Erika Comasco, Helena Kopp Kallner, Marie Bixo, Angelica L. Hirschberg, Sara Nyback, Haro de Grauw, C. Neill Epperson, Inger Sundström-Poromaa
Journal: American Journal of Psychiatry (2020)

Objective: Premenstrual dysphoric disorder (PMDD) is a common mood disorder, characterized by distressing affective, behavioral, and somatic symptoms in the late luteal phase of the menstrual cycle. The authors investigated continuous treatment with a selective progesterone receptor modulator, ulipristal acetate (UPA), as a potential treatment for PMDD. Methods: The authors conducted an investigator-initiated, multicenter, double-blind, randomized, parallel-group clinical trial in which women with PMDD (N=95) were treated with either 5 mg/day of UPA or placebo during three 28-day treatment cycles. The primary outcome was the change in premenstrual total score on the Daily Record of Severity of Problems (DRSP) from baseline to end of treatment. DRSP scores were captured by daily ratings using a smartphone application and were analyzed with linear mixed models for repeated measures. Results: The mean improvement in DRSP score after 3 months was 41% (SD=18) in the UPA group, compared with 22% (SD=27) in the placebo group (mean difference −18%; 95% CI=−29, −8). Treatment effects were also noted for the DRSP depressive symptom subscale (42% [SD=22] compared with 22% [SD=32]) and the DRSP anger/irritability subscale (47% [SD=21] compared with 23% [SD=35]), but not for the DRSP physical symptom subscale. Remission based on DRSP score was attained by 20 women in the UPA group (50.0%) and eight women in the placebo group (21.1%) (a statistically significant difference). Conclusions: If these results are replicated, UPA could be a useful treatment for PMDD, particularly for the psychological symptoms associated with the disorder.
IMMU-07. IMMUNE EFFECTOR CELL ASSOCIATED NEUROTOXICITY (ICANS) AMONG PEDIATRIC AND AYA PATIENTS: MD ANDERSON CANCER CENTER EXPERIENCE
Authors: Brandon Brown, Paolo Tambaro, Kris Mahadeo, Sajad Khazal, Priti Tewari, Demetrios Petropoulos, John Slopis, Zsila Sadighi
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Immune effector cell associated neurotoxicity (ICANS) and cytokine release syndrome (CRS) are potentially life-threatening complications associated with immune effector cell (IEC) therapies. We characterize ICANS in pediatric and adult young adolescent (AYA) patients receiving IEC therapy at our institution. METHODS We reviewed clinical characteristics and severity (based on ASTCT Consensus Criteria) in pediatric and AYA patients with IEC products from 2018–2019 at MDACC. RESULTS Nine patients, median age 15.5 (range: 3–25) years received chimeric antigen receptor (CART) IEC therapy. Four (44%) developed ICANS within median of 8 (range: 3–27) days of CAR T cell infusion and median 6 (range: 2–7) days after CRS. Primary diagnoses were pre-B cell acute lymphoblastic leukemia (8) and mediastinal large B-cell lymphoma (1). Median CRS and ICANS severity grade was 2 (range 1–4). Symptoms included altered mental status (AMS) (5), seizure (1), aphasia (2), impaired ability to write a standard sentence (4). Neuroimaging did not correlate to ICANS symptoms or severity. EEG was performed in 3 and 1 had background slowing correlating with aphasia. CSF was obtained in two revealing lymphocytosis. All received prophylactic anti-epileptic medication and tocilizumab for concomitant CRS. Three received steroids. CONCLUSION ICANS may present in almost half of pediatric patients within one week of receiving CART products associated with CRS. CAR-T trafficking into the CSF may explain pleocytosis in the CSF. Prospective studies may clarify. Impaired ability to write a standard sentence and the Cornell Assessment of Pediatric Delirium (CAPD) may be early indicators of ICANS in pediatric/AYA patients.
Phospholemman Phosphorylation Regulates Vascular Tone, Blood Pressure, and Hypertension in Mice and Humans
Authors: Andrii Boguslavskyi, Sergiy Tokar, Oleksandra Prysyazhna, Olena Rudyk, David Sanchez-Tatay, Hamish A.L. Lemmey, Kim A. Dora, Christopher J. Garland, Helen R. Warren, Alexander Doney, Colin N.A. Palmer, Mark J. Caulfield, Julia Vlachaki Walker, Jacqueline Howie, William Fuller, Michael J. Shattock
Journal: Circulation (2020)

Although it has long been recognized that smooth muscle Na/K ATPase modulates vascular tone and blood pressure (BP), the role of its accessory protein phospholemman has not been characterized. The aim of this study was to test the hypothesis that phospholemman phosphorylation regulates vascular tone in vitro and that this mechanism plays an important role in modulation of vascular function and BP in experimental models in vivo and in humans.In mouse studies, phospholemman knock-in mice (PLM3SA; phospholemman [FXYD1] in which the 3 phosphorylation sites on serines 63, 68, and 69 are mutated to alanines), in which phospholemman is rendered unphosphorylatable, were used to assess the role of phospholemman phosphorylation in vitro in aortic and mesenteric vessels using wire myography and membrane potential measurements. In vivo BP and regional blood flow were assessed using Doppler flow and telemetry in young (14-16 weeks) and old (57-60 weeks) wild-type and transgenic mice. In human studies, we searched human genomic databases for mutations in phospholemman in the region of the phosphorylation sites and performed analyses within 2 human data cohorts (UK Biobank and GoDARTS [Genetics of Diabetes Audit and Research in Tayside]) to assess the impact of an identified single nucleotide polymorphism on BP. This single nucleotide polymorphism was expressed in human embryonic kidney cells, and its effect on phospholemman phosphorylation was determined using Western blotting.Phospholemman phosphorylation at Ser63 and Ser68 limited vascular constriction in response to phenylephrine. This effect was blocked by ouabain. Prevention of phospholemman phosphorylation in the PLM3SA mouse profoundly enhanced vascular responses to phenylephrine both in vitro and in vivo. In aging wild-type mice, phospholemman was hypophosphorylated, and this correlated with the development of aging-induced essential hypertension. In humans, we identified a nonsynonymous coding variant, single nucleotide polymorphism rs61753924, which causes the substitution R70C in phospholemman. In human embryonic kidney cells, the R70C mutation prevented phospholemman phosphorylation at Ser68. This variant's rare allele is significantly associated with increased BP in middle-aged men.These studies demonstrate the importance of phospholemman phosphorylation in the regulation of vascular tone and BP and suggest a novel mechanism, and therapeutic target, for aging-induced essential hypertension in humans.
Clinical, virological and imaging profile in patients with prolonged forms of COVID-19: A cross-sectional study
Authors: Dominique Salmon-Ceron, Dorsaf Slama, Thomas De Broucker, Marina Karmochkine, Juliette Pavie, Emmanuel Sorbets, Nicolas Etienne, Dominique Batisse, Gabriela Spiridon, Valérie Le Baut, Jean-François Meritet, Eric Pichard, Florence Canouï-Poitrine
Journal: Journal of Infection (2020)