tbuckley/cabot-search huggingface dataset:
TMIC-18. ELECTRICAL CIRCUIT INTEGRATION OF GLIOMA THROUGH NEURON-GLIOMA SYNAPSES AND POTASSIUM CURRENTS
Authors: Humsa Venkatesh, Wade Morishita, Anna Geraghty, Dana Silverbush, Shawn Gillespie, Marlene Arzt, Lydia Tam, Anitha Ponnuswami, Lijun Ni, Pamelyn Woo, Kathryn Taylor, Amit Agarwal, Aviv Regev, David Brang, Hannes Vogel, Shawn Hervey-Jumper, Dwight Bergles, Mario Suvà, Robert Malenka, Michelle Monje
Journal: Neuro-Oncology (2019)

Abstract High-grade gliomas are a lethal group of cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors into the tumor microenvironment represents part of the mechanism by which neuronal activity influences glioma growth, but this alone is insufficient to explain the magnitude of the effect that activity exerts on glioma progression. Here, we report that neuron-glioma interactions include electrochemical communication through both bona fide synapses and activity-dependent potassium flux. Single cell transcriptomic analyses revealed unambiguous expression of synaptic genes by malignant glioma cells, and neuron to glioma synaptic structures were evident by electron microscopy. Whole cell patch clamp electrophysiology demonstrated AMPAR-mediated excitatory neurotransmission between pre-synaptic neurons and post-synaptic glioma cells. Millisecond timescale excitatory post-synaptic currents (EPSCs) were found in a subpopulation of glioma cells, reminiscent of the axon-glial synapses between neurons and normal oligodendrocyte precursor cells (OPCs). Neuronal activity also evokes a second, non-synaptic electrophysiological response characterized by a prolonged (&gt;1 sec) depolarization in a subpopulation of glioma cells. These longer duration currents are blocked by tetrodotoxin or barium and induced by potassium, indicating neuronal activity-dependent potassium flux reminiscent of astrocyte currents. The amplitude of the prolonged currents is reduced by gap junction inhibitors, supporting the concept that gap junction-mediated tumor interconnections can function to amplify evoked potassium currents in an electrically coupled network. As membrane depolarization of normal neural precursor cells can regulate proliferation, differentiation and survival, and glioma cells exhibit two distinct mechanisms of neuronal activity-evoked membrane depolarization, we tested the hypothesis that membrane depolarization promotes glioma growth. Using in vivooptogenetic techniques to depolarize xenografted glioma cells, we found that glioma membrane depolarization robustly promoted proliferation, while pharmacologically or genetically blocking electrochemical signaling inhibited glioma xenograft growth and extended mouse survival. Together, these findings indicate that electrical circuit integration promotes glioma progression.
CBMT-10. MUTANT ISOCITRATE DEHYDROGENASE 1 INHIBITION INDUCES A UNIQUE MRS-DETECTABLE METABOLIC SIGNATURE IN LOW-GRADE GLIOMAS
Authors: Abigail Molloy, Aliya Lakhani, Chloé Najac, Elavarasan Subramani, Anne Marie Gillespie, Russell O Pieper, Pavithra Viswanath, Sabrina Ronen
Journal: Neuro-Oncology (2019)

Abstract Mutations in isocitrate dehydrogenase 1/2 (IDHmut) are reported in 70–90% of low-grade gliomas and secondary glioblastomas. IDHmut catalyzes the reduction of a-ketoglutarate (a-KG) to 2-hydroxyglutarate (2-HG), an oncometabolite that drives tumorigenesis. Inhibition of IDHmut is therefore a rapidly emerging therapeutic approach and IDHmut inhibitors such as AG-120 and AG-881 have shown promising results in phase 1 and 2 clinical studies. The goal of this study was to identify early non-invasive metabolic biomarkers of IDHmut inhibition that can serve to moniter response to these therapies. We used 1H and 13C magnetic resonance spectroscopy (MRS) to investigate the response of two genetically-engineered IDHmut cell lines (U87-based and normal human astrocyte-based) to AG-120 and AG-881 treatment. As expected, in both cell lines, our 1H-MRS data indicated that AG-120 and AG-881 induced a significant decrease in 2-HG. Interestingly however, we also observed a significant increase in phosphocholine and glutamate, pointing to broader changes in the metabolism of treated cells and a unique MRS signature. To further investigate the increase in glutamate induced by AG-120 and AG-881 in our models, we used 13C-MRS and quantified the flux of [1-13C] glucose and [3-13C] glutamine to 13C-labeled glutamate. Our results indicate that both AG-120 and AG-881 significantly increase the flux of 13C-labeled glutamine to 13C glutamate, while the flux of 13C-labeled glucose to 13C glutamate remained unchanged. Further studies are currently underway to explore the utility of using hyperpolarized [1-13C]-glutamine and hyperpolarized [1-13C]-a-KG for monitoring flux to glutamate and 2-HG, and to validate these probes as additional biomarkers of response to IDHmut inhibition. Taken together, our studies indicate that IDHmut inhibition induces a unique MRS-detectable metabolic profile that can potentially be exploited for early non-invasive, clinically translatable detection of response to emerging IDHmut inhibitors.
Phase I/II Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Dexamethasone As Targeted Therapy for Patients with t(11;14) Relapsed/Refractory Multiple Myeloma
Authors: Jonathan L. Kaufman, Cristina Gasparetto, Fredrik H. Schjesvold, Philippe Moreau, Cyrille Touzeau, Thierry Facon, Lawrence H. Boise, Stefanie Alzate, Tammy Macartney, John Pesko, Ahmed Hamed Salem, Jeremy A. Ross, Wan-Jen Hong, Paulo C. Maciag, James M. Pauff, Shaji K. Kumar
Journal: Blood (2019)
The neurotransmitter receptor Gabbr1 regulates proliferation and function of hematopoietic stem and progenitor cells
Authors: Lijian Shao, Adedamola Elujoba-Bridenstine, Katherine E. Zink, Laura M. Sanchez, Brian J. Cox, Karen E. Pollok, Anthony L. Sinn, Barbara J. Bailey, Emily C. Sims, Scott H. Cooper, Hal E. Broxmeyer, Kostandin V. Pajcini, Owen J. Tamplin
Journal: Blood (2020)
Evaluation of the Fibrin Assay for Venous Thromboembolism Exclusion in Cancer Patients: Subanalysis of a Prospective Assessment (FSET STUDY)
Authors: Isabelle Mahe, Jean Chidiac, Sadji Djennaoui, Nicolas Javaud, Benjamin Planquette, Edith Peynaud-Debayle, Laurent Sofiane Baccar, Bénédicte Dumont, Guy Meyer, Geneviève Contant, Francois Depasse, Virginie Siguret, Hélène Helfer
Journal: Blood (2019)
Risk Factors and Outcomes of Klebsiella Pneumoniae Infection before and after Allogeneic Hematopoietic Cell Transplantation
Authors: Eleni Gavriilaki, Ioanna Sakellari, Thomas Chatziconstantinou, Despina Mallouri, Ioannis Batsis, Eleni Katsifa, Stergios Papadimitriou, Alkistis Panteliadou, Eirini Baldoumi, Christos Demosthenous, Zoi Bousiou, Varnavas Constantinou, Damianos Sotiropoulos, Achilles Anagnostopoulos
Journal: Blood (2019)
Loss of BAP1 in Pheochromocytomas and Paragangliomas Seems Unrelated to Genetic Mutations
Authors: Valeria Maffeis, Rocco Cappellesso, Lorenzo Nicolè, Vincenza Guzzardo, Chiara Menin, Lisa Elefanti, Francesca Schiavi, Maria Guido, Ambrogio Fassina
Journal: Endocrine Pathology (2019)
Proximal Tubule–Derived Amphiregulin Amplifies and Integrates Profibrotic EGF Receptor Signals in Kidney Fibrosis
Authors: Eirini Kefaloyianni, Manikanda Raja Keerthi Raja, Julian Schumacher, Muthu Lakshmi Muthu, Vaishali Krishnadoss, Sushrut S. Waikar, Andreas Herrlich
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Sustained activation of EGF receptor (EGFR) in proximal tubule cells (PTCs) is a hallmark of fibrotic CKD, but the molecular mechanism(s) involved are unknown. Here, we show that the injury-upregulated, low-affinity EGFR ligand amphiregulin (AREG) amplifies its own signaling in PTCs and integrates signals of other moderately injury-upregulated EGFR ligands by inducing the transcriptional regulator Yes-associated protein 1 (YAP1). In vivo , AREG is necessary and sufficient to induce kidney fibrosis after injury, as AREG PTC-knockout mice exhibit protection and soluble AREG injection suffices to reverse protection in mice that cannot release EGFR ligands from PTCs. Our results identify AREG as a critical driver of the transition of kidney injury to fibrosis. Background Sustained activation of EGF receptor (EGFR) in proximal tubule cells is a hallmark of progressive kidney fibrosis after AKI and in CKD. However, the molecular mechanisms and particular EGFR ligands involved are unknown. Methods We studied EGFR activation in proximal tubule cells and primary tubular cells isolated from injured kidneys in vitro . To determine in vivo the role of amphiregulin, a low-affinity EGFR ligand that is highly upregulated with injury, we used ischemia-reperfusion injury or unilateral ureteral obstruction in mice with proximal tubule cell–specific knockout of amphiregulin. We also injected soluble amphiregulin into knockout mice with proximal tubule cell–specific deletion of amphiregulin’s releasing enzyme, the transmembrane cell-surface metalloprotease, a disintegrin and metalloprotease-17 (ADAM17), and into ADAM17 hypomorphic mice. Results Yes-associated protein 1 (YAP1)–dependent upregulation of amphiregulin transcript and protein amplifies amphiregulin signaling in a positive feedback loop. YAP1 also integrates signals of other moderately injury-upregulated, low-affinity EGFR ligands (epiregulin, epigen, TGF α ), which also require soluble amphiregulin and YAP1 to induce sustained EGFR activation in proximal tubule cells in vitro . In vivo , soluble amphiregulin injection sufficed to reverse protection from fibrosis after ischemia-reperfusion injury in ADAM17 hypomorphic mice; injected soluble amphiregulin also reversed the corresponding protective proximal tubule cell phenotype in injured proximal tubule cell–specific ADAM17 knockout mice. Moreover, the finding that proximal tubule cell–specific amphiregulin knockout mice were protected from fibrosis after ischemia-reperfusion injury or unilateral ureteral obstruction demonstrates that amphiregulin was necessary for the development of fibrosis. Conclusions Our results identify amphiregulin as a key player in injury-induced kidney fibrosis and suggest therapeutic or diagnostic applications of soluble amphiregulin in kidney disease.
A Molecular Revolution in the Treatment of Hemophilia
Authors: John S.S. Butterfield, Kerry M. Hege, Roland W. Herzog, Radoslaw Kaczmarek
Journal: Molecular Therapy (2019)

For decades, the monogenetic bleeding disorders hemophilia A and B (coagulation factor VIII and IX deficiency) have been treated with systemic protein replacement therapy. Now, diverse molecular medicines, ranging from antibody to gene to RNA therapy, are transforming treatment. Traditional replacement therapy requires twice to thrice weekly intravenous infusions of factor. While extended half-life products may reduce the frequency of injections, patients continue to face a lifelong burden of the therapy, suboptimal protection from bleeding and joint damage, and potential development of neutralizing anti-drug antibodies (inhibitors) that require less efficacious bypassing agents and further reduce quality of life. Novel non-replacement and gene therapies aim to address these remaining issues. A recently approved factor VIII-mimetic antibody accomplishes hemostatic correction in patients both with and without inhibitors. Antibodies against tissue factor pathway inhibitor (TFPI) and antithrombin-specific small interfering RNA (siRNA) target natural anticoagulant pathways to rebalance hemostasis. Adeno-associated virus (AAV) gene therapy provides lasting clotting factor replacement and can also be used to induce immune tolerance. Multiple gene-editing techniques are under clinical or preclinical investigation. Here, we provide a comprehensive overview of these approaches, explain how they differ from standard therapies, and predict how the hemophilia treatment landscape will be reshaped.
Therapeutic Applications of a Unique Calcium Channel Blocker to Target SF3B1 MDS
Authors: Sunisa Kongkiatkamon, Anand Tiwari, Vera Adema, Cassandra M Kerr, Bartlomiej Przychodzen, Hassan Awada, Jibran Durrani, Yvonne Parker, Drew Adams, Yuriy Fedorov, Hetty E. Carraway, Chao-Yie Yang, Mikkael A. Sekeres, Daniel J. Lindner, James G Phillips, Jaroslaw P. Maciejewski, Valeria Visconte
Journal: Blood (2019)
Nicotine Absorption Profile Among Regular Users of a Pod-Based Electronic Nicotine Delivery System
Authors: Jessica M. Yingst, Shari Hrabovsky, Andrea Hobkirk, Neil Trushin, John P. Richie, Jonathan Foulds
Journal: JAMA Network Open (2019)

JUUL is a popular electronic nicotine delivery system (ENDS)1 that contains a liquid with a high nicotine concentration (59 mg/mL). While there are concerns about the rapid increase in use of this potentially addictive product,2 there are no independent published data, to our knowledge, on its blood nicotine absorption profile. This case series aimed to characterize nicotine absorption among regular adult users of this product and to evaluate subjective effects associated with use.
Primary Mediastinal Large B-Cell Lymphoma (PMBL) Outcome Is Significantly Improved by the Addition of Rituximab to Dose Adjusted (DA)-EPOCH and Overcomes the Need for Radiation.
Authors: Kieron Dunleavy, Stefania Pittaluga, John Janik, Nicole Grant, Seth Steinberg, Louis Staudt, Elaine Jaffe, Wyndham H. Wilson
Journal: Blood (2005)
RDNA-11. LOW MITOCHONDRIAL DNA CONTENT INDUCES TREATMENT RESISTANCE AND CONFERS POOR PROGNOSIS IN GLIOBLASTOMA
Authors: Palavalasa Sravya, Vidya Nimbalkar, Nandaki Kanuri, Harsha Sugur, Shilpa Rao, Sampath Somanna, Paturu Kondaiah, Arivazhagan Arimappamagan, Vani Santosh
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Investigation of mitochondrial DNA (mtDNA) content in glioblastoma has gathered speed in recent years. Our study focusses on the effect of mtDNA content depletion on treatment response in glioblastoma. MATERIALS AND METHODS The study consists of a survival cohort (n=130), a recurrent cohort (32 pairs) and 35 non neoplastic control brain tissues. Malignant glioma cell lines, U87 and LN229 were utilized for radiation biology experiments. Patient tumor tissue was molecularly characterized for IDH, ATRX and TERT promoter mutations, MGMT promoter methylation and EGFR amplification using established methods. Relative quantification of mtDNA content was performed using quantitative real time PCR. Ethidium bromide was used to deplete mtDNA in U87 and LN229 cells. Clonogenic assay and MTT assay were performed to assess sensitivity to radiation and chemotherapy. RESULTS mtDNA content was lower in glioblastoma than in controls. Lower range of mtDNA copy number was associated with poor overall survival (p=0.033) and with markers of tumor aggressiveness like wild type IDH (p=0.02), unmethylated MGMT promoter, amplified EFGR and mutated TERT promoter. Out of 32 recurrent GBM patients, only 19 had received radiation treatment (RT) between the two surgeries and in these patients, mtDNA content was significantly higher in the recurrent tumor when compared to the primary tumor(p=0.01). U87 and LN229 cells showed a higher mtDNA copy number post irradiation (p=0.002). mtDNA depleted U87 and LN229 cells showed higher survival fraction post radiation exposure when compared to parent lines. The IC50 of TMZ was also higher for mtDNA depleted U87 and LN229 cells. CONCLUSION Low mtDNA content is associated with poor survival and aggressive tumor markers in glioblastoma. Lowering the mtDNA content in GBM cells induces radiation resistance as well as resistance to chemotherapy. Irradiation leads to increase in mitochondrial DNA content in both patient samples as well as malignant glioma cell lines.
ACTR-62. PHASE I TRIAL OF TG02 PLUS DOSE-DENSE OR METRONOMIC TEMOZOLOMIDE FOR RECURRENT HIGH-GRADE ASTROCYTOMA IN ADULTS
Authors: Jing Wu, Christine Bryla, Yu-Ting Su, Ewa Grajkowska, Ann McCoy, Lisa Boris, Ramya Antony, Nancy Garren, Christine Siegel, Christine Cordova, Orwa Aboud, Elizabeth Vera, Tracy Lawhon, Marta Penas-Prado, Brett Theeler, Tito Mendoza, Terri Armstrong, Ying Yuan, Mark Gilbert
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Therapies targeting multiple survival pathways are desirable for high-grade gliomas. TG02 (Zotiraciclib), a CDK9 inhibitor, regulates transcription and metabolism of tumor cells and synergizes with temozolomide. A phase I/II trial was launched to test the TG02/temozolomide combined treatment in recurrent high-grade astrocytomas. Phase I results are reported here. METHODS Adults with recurrent high-grade astrocytoma, KPS≥60, adequate organ function, &lt; 2 prior relapses were enrolled. Primary endpoint was dose limiting toxicity (DLT) in cycle1 in each arm. Bayesian optimal interval design was employed to determine the maximum tolerated dose (MTD) with the target DLT rate of 35% and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days1,12,15, and 26) and temozolomide, either as a dose-dense (DD; 125mg/m2/d, 7on/7off, Arm1) or metronomic (MN; 50mg/m2/d, Arm2) dosing schedule on a 28-day cycle. RESULTS Thirty-eight patients were evaluable; median age 50.7, KPS 90. Of 18 evaluable patients in Arm1, at TG02 dose-level 200mg, 1/6 had a DLT: Gr3 diarrhea; at dose-level 250mg, 3/12 had DLTs: Gr4 neutropenia for over 5 days, Gr3 elevated ALT, and Gr3 fatigue. Of 20 evaluable patients in Arm2, at TG02 dose-level 200mg, 1/6 had a DLT: recurrent Gr3 neutropenia; at dose-level 250mg, 5/12 had a DLT: Gr3 elevated ALT, Gr3 fatigue, and Gr4 neutropenia; at dose-level 300mg,1 of 2 had a DLT: Gr4 febrile neutropenia, Gr4 elevated ALT, Gr4 elevated AST. TG02 dose-level of 250mg was declared as the MTD in both Arms. Using the MDASI-BT, patients with high symptom burden had increased symptoms during cycle1 but became stable as they continued treatment. CONCLUSION The combination of TG02 at the MTD of 250mg with DD or MN temozolomide was tolerated. Cohort expansion continues at the MTD in both arms. Objective responses have been observed, suggesting activity of this regimen and supporting continued investigation.
The health of the nation.
Authors: D. W. Vorster
Journal: BMJ (1992)

James O'Brien and colleagues' approach was too simplistic.'The premise that primary treatment of the symptoms of stress, urge, and mixed incontinence is simple is unfounded.In controlled trials the objective cure rate after pelvic floor exercise in women with genuine stress incontinence is low2; similarly, in women with detrusor instability bladder retraining is associated with a high long term relapse rate.3In O'Brien and colleagues' study patients were treated on the basis of symptoms alone and no attempt was made to diagnose the cause of incontinence.As the correlation between urinary symptoms and urodynamic diagnosis is poor4 many patients will have been incorrectly treated, resulting in an apparent reduction in the efficacy of treatment.It is not surprising that patients with mixed symptoms had the poorest outcome, with only half reporting symptomatic improvement.Patients who remain incontinent will become disillusioned and may seek no further medical advice, thinking that nothing can be done to help them.It is already difficult to convince patients that most of them can be cured, or their incontinence can at least be improved, by appropriate investigation and management.The nature and duration of follow up were inadequate; no objective measures of severity of leakage were used, and no assessment of the results of treatment was continued beyond 12 weeks.We believe that, with few exceptions (notably elderly people), incontinent patients require some basic investigation, often including urodynamic assessment, before treatment.Outcome should be carefully monitored and assessed objectively whenever possible.
Abstract 1035: Functional Polymorphism of the Matrix Metalloproteinase 1 Gene Promoter (-1607 1G/2G) Predicts Carotid Intra-plaque Hemorrhage in Patients Submitted to Endarterectomy
Authors: Katia G. Santos, Luciane Narvaes, Daiane Silvello, Luciano Albuquerque, Luis Rohde
Journal: Circulation (2007)

Introduction: Carotid intraplaque hemorrhage is a marker of atheroma instability. Matrix metalloproteinase (MMP)-1 and -3 are proteolytic enzymes that degrade extracellular matrix components, leading to structural instability of vulnerable plaques. Hypothesis: We hypothesize that funcional polymorphisms of the MMP-1 and MMP-3 genes could identify patients prone to atheroma bleeding in the carotid artery. Methods : Consecutive patients submitted to carotid endarterectomy underwent high-resolution magnetic resonance imaging (MRI) - to evaluate the presence of a hyperintense signal on the T1-weighted sequence - and histological analysis - to assess the presence of intraplaque bleeding (stained by hematoxylineosin and Mallory trichromic). Genotyping of MMP-1 polymorphisms at nucleotide -1607 (1G/2G) and of MMP-3 at nucleotide -1612 (5A/6A) was performed by polymerase chain reaction with restriction fragment length polymorphism analysis. Results: We evaluated 48 predominantly male (63%) and hypertensive (88%) patients (66 ± 9 years-old). Intraplaque hemorrhage was identified in 30 (62.5%) patients by histology and classified as acute in 17 (35.4%), recent in 11 (22.9%) and late in 2 (4.2%) patients. There was an excellent agreement between acute or recent hemorrhage on histology and the presence of a hyperintense signal at MRI (kappa coefficient of 0.91, 95% confidence interval of 0.75–1.00). MMP-1 genotypes were 1G/1G in 7 (15%) subjects, 1G/2G in 30 (62%) and 2G/2G in 11 (23%) patients. MMP-3 genotypes were 5A/5A in 6 (12%) subjects, 5A/6A in 30 (63%) and 6A/6A in 12 (25%) patients. No significant association between MRI findings and MMPs genotypes was observed. However, carriers of the 2G allele, responsible for a greater proteolyic activity of MMP-1, were more prevalent in plaques with signs of hemorrhage on hystology compared to patients without intraplaque bleeding (28 out 30 [93%] versus 13 out of 18 [72%], respectively, p = 0.045). No interaction was observed between MMP-3 genotypes and carotid intraplaque hemorrhage (all p values &gt; 0.2). Conclusions - In conclusion, our data indicate that genetically mediated variability in MMP-1 activity may be involved in the events that lead to intraplaque hemorrhage.
NHS trust pays £30m to boy branded “naughty” after behaviour is linked to birth injury
Authors: Clare Dyer
Journal: BMJ (2019)

A 7 year old boy who has spent most of his life being branded naughty and disruptive has won a settlement of more than £30m (€35m; $39m) after it was discovered that he had sustained a brain injury after negligent delays in his delivery at University College Hospital in London.

The settlement is thought to be one of only a handful of NHS clinical negligence payouts to exceed £30m.

The boy, who is subject to an anonymity …