tbuckley/cabot-search huggingface dataset:
ATRT-18. SHH-SUBTYPE ATYPICAL TERATOID/RHABDOID TUMORS ARE SELECTIVELY SENSITIVE TO GEMCITABINE TREATMENT
Authors: Dennis Metselaar, Michaël Hananja Meel, Joshua Goulding, Piotr Waranecki, Mark de Gooijer, Marjolein Breur, Sophie Veldhuizen van Zanten, Marianna Bugiani, Pieter Wesseling, Gertjan Kaspers, Esther Hulleman
Journal: Neuro-Oncology (2020)

Abstract Atypical Teratoid Rhabdoid Tumors (ATRT) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. ATRT can be divided into three molecular subgroups of which the Sonic Hedgehog (SHH) subgroup is most prevalent. In this study, we developed and validated a novel patient-derived ATRT model, which we used along a panel of other primary ATRT models for large scale drug discovery assays. We found that ATRTs are selectively sensitive to the nucleoside analogue gemcitabine, with SHH-subtype ATRTs being the most sensitive subgroup. Gene expression profiles and protein analysis indicated that gemcitabine treatment causes degradation of Sirtuin 1 (SIRT1), which causes ATRT specific cell-death through NF-kB and p53 activation. Furthermore, we found that this gemcitabine induced loss of SIRT1 results in a nucleus-to-cytoplasm shift of the SHH signaling activator Gli, explaining the additional gemcitabine sensitivity in SHH-subtype ATRT. Treatment of SHH-subgroup ATRT xenograft-bearing mice resulted in a &amp;gt;40% increase in median survival (p&amp;lt;0.01, log-rank test) and long-term survivors in two independent models. To prepare translation of our findings to the clinic, we investigated potential gemcitabine induced resistance mechanisms by conducting kinome-wide CRISPR/Cas9 knockout screens in primary ATRT cells. Through these experiments we found that low-dose gemcitabine treatment combined with inhibition of protein kinase C zeta (PKCζ) prevents regrowth of resistant ATRT subclones. Together, these findings show that ATRT are highly sensitive to gemcitabine treatment; and as such we suggest that gemcitabine may be rapidly incorporated into future treatment regimens for SHH-ATRT.
Selegiline may be toxic in presence of increased dopamine concentrations
Authors: P H Yu, C T Lai, A A Boulton
Journal: BMJ (1996)

whole, P values at interim analyses would have to be considerably less than 0-01 to achieve significance with any of the common group se- quential designs.3Similarly, confidence intervals reported should be greater than 95%.Thus it is not clear that reports of significance are valid.Finally, levodopa was given to all patients at a daily dose of 375 mg rather than adjusted according to clinical need.Microdialysis studies show that selegiline significantly increases brain dopamine concentrations in rodents after administration of levodopa.4In our study, patients treated with selegiline required significantly less levodopa than patients taking levodopa alone.During the British study the median dose of levodopa was increased to 625 mg in the levodopa group but did not have to be changed in the patients taking levodopa plus selegiline despite their having comparable clinical benefits and increased dopaminergic side effects.Thus patients taking selegiline may have received much more levodopa than necessary, a factor that was related to increased mortality in the Prado study.5We take the British report seriously and will continue to monitor mortality in our patients.Because of the reassuring findings of our study and the increasing evidence of possible neuroprotective benefits related to selegiline, however, we do not recommend that patients should stop taking selegiline on the basis of the results of the British study alone.
BIOM-23. MOLECULAR PROFILING IDENTIFIES NOVEL BIOMARKERS IN A RURAL COHORT OF PATIENTS WITH GLIOBLASTOMA
Authors: Rebecca Bystrom, Wendy Craig, Jens Rueter, Christine Lu-Emerson
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The rural state of Maine has one of the highest incidences of primary malignant brain cancer in the United States. We sought to investigate the genomic landscape of glioblastoma (GBM) in Maine. METHODS Targeted next generation sequencing of 209 cancer related genes was performed on tumor samples from 60 patients diagnosed with GBM at our institution between 2014 and 2019. We compared mutation frequencies between patients grouped according to the published median overall survival for GBM: &amp;lt; 14 months (n = 14) and ≥ 14 months (n = 43, including 23 patients still alive). We excluded patients who were alive but diagnosed less than 14 months prior to analysis (n = 3). RESULTS Across all groups frequent molecular markers included EGFR (49%), TP53 (38%), CDKN2A (17.5%), PIK3R1 (15.8%), PDGFRA (12.2%), PIK3CA (10.5%), PTEN (19%), NF1 (10.5%) and IDH1/2 (10%); frequencies did not differ significantly between groups. MGMT methylation was similar between groups (6/14 (42.9%) in shorter survivors and 18/41 (43.9%) in longer survivors). FANC group mutations were more frequent in longer survivors (13/43 [30%] versus 0/14 [0%], p = 0.025). Among shorter survivors CDKN2A deletions were slightly more frequent (5/14 (45%) versus 5/43 (11%), p = 0.099). FES, KIAA1524, FLT (all 5/43,11.6%) and EPH (6/43, 14.0%) were only observed in longer survivors. These mutations co-occurred with 4/5 CDKN2A deletions in longer survivors. After excluding those 4 cases, CDKN2A deletions were significantly associated with shorter survival (5/14 [35.7%] versus 1/39 [2.6%]), p=0.004. CONCLUSION FANC group mutations may be a novel prognostic biomarker for longer survival in a rural cohort with GBM. CDKN2A deletions may be associated with shorter survival, but this may be ameliorated by co-occurring FES, KIAA1524, FLT, and EPH mutations.
Recovery from disorders of consciousness: mechanisms, prognosis and emerging therapies
Authors: Brian L. Edlow, Jan Claassen, Nicholas D. Schiff, David M. Greer
Journal: Nature Reviews Neurology (2020)

Substantial progress has been made over the past two decades in detecting, predicting and promoting recovery of consciousness in patients with disorders of consciousness (DoC) caused by severe brain injuries. Advanced neuroimaging and electrophysiological techniques have revealed new insights into the biological mechanisms underlying recovery of consciousness and have enabled the identification of preserved brain networks in patients who seem unresponsive, thus raising hope for more accurate diagnosis and prognosis. Emerging evidence suggests that covert consciousness, or cognitive motor dissociation (CMD), is present in up to 15–20% of patients with DoC and that detection of CMD in the intensive care unit can predict functional recovery at 1 year post injury. Although fundamental questions remain about which patients with DoC have the potential for recovery, novel pharmacological and electrophysiological therapies have shown the potential to reactivate injured neural networks and promote re-emergence of consciousness. In this Review, we focus on mechanisms of recovery from DoC in the acute and subacute-to-chronic stages, and we discuss recent progress in detecting and predicting recovery of consciousness. We also describe the developments in pharmacological and electrophysiological therapies that are creating new opportunities to improve the lives of patients with DoC. In this Review, the authors discuss recent progress in the detection and prediction of recovery of consciousness in patients with disorders of consciousness caused by severe brain injuries. They describe the ongoing development of pharmacological and electrophysiological therapies designed to enhance recovery.
A germline mutation in the platelet‐derived growth factor receptor beta gene may be implicated in hereditary progressive mucinous histiocytosis
Authors: A. Onoufriadis, B. Boulouadnine, G. Dachy, T. Higashino, H.Y. Huang, C.K. Hsu, M.A. Simpson, K. Bork, J.B. Demoulin, J.A. McGrath
Journal: British Journal of Dermatology (2020)
Abstract 12186: The Outcomes of Catheter Ablation for Hemodialysis Patients With Atrial Fibrillation
Authors: Yuki Shimizu, Yasuaki Tanaka, Takamitsu Takagi, Jun Nakajima, Kenji Okubo, Katsumasa Takagi, Hiroyuki Hikita, Atsushi Takahashi
Journal: Circulation (2019)

Background: The prevalence of atrial fibrillation (AF) is reportedly to be high in hemodialysis (HD) patients and can lead to hemodynamic instability, causing difficulty in continuing dialysis. Cat...
The covid-19 yearbook: world leaders edition
Authors: Mun-Keat Looi
Journal: BMJ (2020)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following The covid-19 yearbook: world leaders edition Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
NCOG-37. NATURAL LANGUAGE ASSESSMENT CORRELATES WITH HEALTH-RELATED QUALITY OF LIFE IN ADULT GLIOMA PATIENTS
Authors: Simon Ammanuel, Nyle Almeida, Garret Kurteff, Sofia Kakaizada, Annette Molinaro, Mitchel Berger, Edward Chang, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Impairments of speech are common in glioma patients and negatively impact health-related quality of life. The benchmark for clinical assessments is task-based measures that miss essential components of quality of life status. In this study, we test the hypothesis that variations in natural language (NL) correlate with health-related quality of life status. MATERIALS AND METHODS Natural language use was assessed using audio samples from 18 patients with newly diagnosed low- and high-grade gliomas collected unobtrusively. NL measures were correlated with the Quality of Life in Neurological Disorders (Neuro-QoL) outcomes at baseline. Spearman’s rank-order correlation was used to determine relationships between Neuro-QoL scores and NL measures. RESULTS Speech rate negatively correlated with functional domains of the Neuro-QoL (satisfaction with social roles: rho=-0.62, p=0.007; participate in social roles: rho=-0.74, p&amp;lt; 0.001;) while positively correlated with impairment domains(fatigue: rho=0.58, p=0.009). CONCLUSIONS Assessments of baseline natural language may be a useful tool in the context of treatment planning and monitoring outcomes.
PATH-02. CHARACTERIZATION OF FUNCTIONAL NETWORK EFFECTS IN THE CEREBRAL CORTEX DURING BRAIN TUMORIGENESIS IN THE MOUSE
Authors: Samuel Cramer, Laurentiu Popa, Samuel Haley, Sanjay Dhawan, Russell Carter, Jianfang Ning, Justin Aronson, Suhasa Kodandaramaiah, Timothy Ebner, Clark Chen
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Neuro-cognitive decline is near universal in glioblastoma patients and negatively impacts the quality of life for afflicted patients. Yet, there is little information on longitudinal effects of brain tumor growth on cerebral cortical function and network connectivity. OBJECTIVE To address this knowledge gap, we examined in vivo Ca2+ flux imaging in a transgenic murine glioblastoma model. METHODS Mesoscopic Ca2+ imaging was performed after implant of GL261 glioblastoma cells into a transgenic mice strain (Thy1-GCaMP6f) that expresses the fast calcium indicator GCaMP6f in Layer II/III and Layer V pyramidal neurons. Independent component analysis (ICA), correlation matrix and graph theory approaches were used to assess changes in network connectivity. RESULTS ICA defined canonical cerebral network consisting of nodal convergence and connectivity between nodes. The overall network structure remained unaltered after tumor implant. A decrease in the strength of connectivity was observed immediately following tumor implant. This temporary suppression was followed by progressive, global increase in the strength of nodal connectivity (p &amp;lt; 0.0001). By two weeks post-tumor implant, 50% of the nodes exhibited increased connectivity compared to baseline. Progressive activation of select nodes was also observed in the weeks following tumor implant (p &amp;lt; 0.01). In aggregate, these results suggest that activation of select network nodes as well as enhanced connectivity as means to compensate for the deleterious effects of glioblastoma growth. CONCLUSIONS Our results indicate that focal brain tumor growth induces a reorganization of both local and remote cortical activity. The finding bear pertinence to the pathogenesis of neuro-cognitive decline and tumor associated epilepsy.
CTNI-19. PHASE I TRIAL OF DAY101 IN PEDIATRIC PATIENTS WITH RADIOGRAPHICALLY RECURRENT OR PROGRESSIVE LOW-GRADE GLIOMA (LGG)
Authors: Karen Wright, Emily Krzykwa, Lianne Greenspan, Susan Chi, Kee Kiat Yeo, Michael Prados, Sabine Mueller, Daphne Haas-Kogan
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND We report phase I data examining pharmacokinetics, safety and preliminary efficacy of the dimeric, pan-RAF inhibitor DAY101 (formerly TAK-580/MLN2480) in pediatric patients with radiographically recurrent/progressive LGGs harboring MEK/ERK pathway alterations. METHODS Oral DAY101 was administered weekly to patients &amp;lt; 18 years of age with radiographically recurrent/progressive LGG for 4-week cycles up to a maximum of 2 years. The starting DAY101 dosage was 280 mg/m2. Dose limiting toxicities were determined after one cycle. RESULTS We treated nine eligible patients at 280, 350, and 420 mg/m2. Seven patients had KIAA1549:BRAF fusions, one a novel SRGAP3-RAF1 gene fusion and one with NF1 mutation. PK parameters following weekly administration of DAY101 in children mirrored the adult data, with dose-proportional increases in Cmax and AUC observed. There were no DLTs. The most common toxicity was skin rash followed by achromotrichia and nevi formation. There was only one grade 3 elevation is CPK and no grade 4 adverse events. A 2.2-fold mg/kg exposure difference was observed with respect to weight-based dosing and suggested a correlation to independent, centrally reviewed best radiographic RANO responses of 2 complete responses, 2 partial responses, 3 stable disease, and 2 progressive disease. Median time to response was 10.5 weeks (range: 8–32 weeks). CONCLUSIONS These phase 1 data provide initial pharmacokinetic parameters outlining oral weekly dosing of DAY101 in pediatric patients with radiographically recurrent and progressive LGG. Plasma exposures of DAY101 are similar in children and adults. Oral weekly DAY101 is well-tolerated and shows anti-tumor activity. The amended protocol explores differential dosing to achieve similar responses across a variety of body surface areas.
LGG-40. NATURAL COURSE AND MANAGEMENT OF SMALL ASYMPTOMATIC LESION SUSPECTED OF LOW-GRADE GLIOMA IN CHILDREN
Authors: Ai Muroi, Takao Tsurubuchi, Hidehiro Kohzuki, Ryoko Suzuki, Hiroko Fukushima, Yuni Yamaki, Eiichi Ishikawa, Akira Matsumura
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE The natural course of incidentally discovered small intracranial lesions has not been well discussed. Surgical intervention, including resection and biopsy, could be achieved if the lesion is growing. We present 13 cases with incidentally found, small non-enhancing lesions without related symptoms. METHODS We retrospectively reviewed a series of 13 children with T1 hypointense and T2 hyperintense intracranial lesions less than 20 mm in diameter without enhancement. We excluded the patients with NF-1 or Tuberous sclerosis. RESULTS Most patients underwent MRI for headache unrelated to the lesions. All cases were located supratentorially. The median age of the patients at the initial examination was 8.9 years (range, 2.2–14.6). Of these children, 2 patients (15.3%) underwent surgery because of progression on follow-up MR images. The pathological diagnosis was compatible with diffuse astrocytoma. Patients were followed for a median of 55 months (range, 11–87) and the overall survival rate was 100%. No patient experienced increase in size after 3 years of follow-up. CONCLUSIONS In most patients with small intracranial lesions, the lesions remained stable and conservative management was appropriate. However, in a few cases, the lesions changed in size or quality and surgical intervention was necessary. Long-term follow-up at least 3 years is mandatory.
FRI0120 Valvular abnormalities in sle is strongly related to arterial disease
Authors: EK Svenungsson, K Jensen-Urstad, U De Faire, J Frostegård
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> In patients with SLE of long duration cardiovascular disease is the most important cause of increased mortality. Valvular lesions are common in SLE patients but it has not been studied how these abnormalities relate to arterial disease in general in SLE. <h3>Objectives</h3> To study cardiac heart and valve function in SLE patients with and without arterial disease and to compare these groups to each other and to population controls. <h3>Methods</h3> Twenty-six women and two men (mean age 53 ± 8 years) with SLE and arterial disease (objectively verified history of myocardial infarction, angina, cerebral infarction or intermittent claudication) (SLE cases) were compared to SLE patients with no signs of arterial disease (SLE controls) and to population controls. The three groups were matched for age and gender. Echocardiography was performed on all together with a thorough clinical and laboratory evaluation. <h3>Results</h3> 15/28 SLE cases had cardiac valvular abnormalities. Three of these had undergone valve replacement, one had a significant aortic insufficiency, and the other eleven had thickening of valvular leaflets of no measurable haemodynamic importance. Only 1/28 SLE controls and 2/28 population controls had similar valvular thickening. Among SLE cases those with valvular abnormalities had significantly higher levels of plasma homocysteine (p &lt; 0.0001), orosomucoid (p = 0.05), plasma triglycerides (p = 0.02) and the cholesterol fraction of very low-density lipoproteins (VLDL) (p = 0.01). There was no association with antiphospholipid antibodies (antibodies to cardiolipin IgG, cardiolipin IgM, b2 glykoprotien-1 or lupus anticoagulant). <h3>Conclusion</h3> SLE patients with arterial disease have a high prevalence of valvular abnormalities 54%. The most common abnormality is diffuse valvular thickening. In SLE patients without clinical signs of arterial disease valve abnormalities are as uncommon as in age matched population controls. Hyperhomocysteinemia and dyslipidemia, both of which have been linked to endothelial dysfunction, correlated strongly with valvular abnormalities. It is thus possible that valvular thickening in SLE patients may be a manifestation of endothelial damage, which needs further attention and prospective clinical evaluation.
Role of microRNAs in inflammatory upper airway diseases
Authors: Valeria Tubita, Borja Callejas‐Díaz, Jordi Roca‐Ferrer, Concepció Marin, Zheng Liu, De Yun Wang, Joaquim Mullol
Journal: Allergy (2020)

MicroRNAs (miRNAs) are a conserved family of small endogenous noncoding RNA molecules that modulate post-transcriptional gene expression in physiological and pathological processes. miRNAs can silence target mRNAs through degradation or inhibition of translation, showing their pivotal role in the pathogenesis of many human diseases. miRNAs play a role in regulating immune functions and inflammation and are implicated in controlling the development and activation of T and B cells. Inflammatory chronic upper airway diseases, such as rhinitis and rhinosinusitis, are spread all over the world and characterized by an exaggerated inflammation involving a complex interaction between immune and resident cells. Until now and despite allergy, little is known about their etiology and the processes implicated in the immune response and tuning inflammation of these diseases. This review highlights the knowledge of the current literature about miRNAs in inflammatory chronic upper airways diseases and how this may be exploited in the development of new clinical and therapeutic strategies.
The 2020 annual report of DataDerm: The database of the American Academy of Dermatology
Authors: Marta J. Van Beek, Robert A. Swerlick, Barbara Mathes, George J. Hruza, Jack Resneck, Hon S. Pak, Toni Kaye, Arik Aninos, Bianca Agregado, Matthew Fitzgerald, Jeffrey P. Jacobs
Journal: Journal of the American Academy of Dermatology (2020)
Targeting the De Novo Purine Synthesis Pathway Through Adenylosuccinate Lyase Depletion Impairs Liver Cancer Growth by Perturbing Mitochondrial Function
Authors: Tingting Jiang, Francisco J. Sánchez‐Rivera, Yadira M. Soto‐Feliciano, Qiyuan Yang, Chun‐Qing Song, Arjun Bhuatkar, Cole M Haynes, Michael T. Hemann, Wen Xue
Journal: Hepatology (2020)

Hepatocellular carcinoma (HCC) is among the most common cancer types worldwide, yet patients with HCC have limited treatment options. There is an urgent need to identify drug targets that specifically inhibit the growth of HCC cells.
Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance
Authors: Meng Zhao, Yizhuo Wang, Ling Li, Shuyun Liu, Chengshi Wang, Yujia Yuan, Guang Yang, Younan Chen, Jingqiu Cheng, Yanrong Lu, Jingping Liu
Journal: Theranostics (2020)

Aims: Ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-AKI) is characterized by elevated levels of reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation, but the potential link among these features remains unclear. In this study, we aimed to investigate the specific role of mitochondrial ROS (mtROS) in initiating mitochondrial DNA (mtDNA) damage and inflammation during IRI-AKI. Methods: The changes in renal function, mitochondrial function, and inflammation in IRI-AKI mice with or without mtROS inhibition were analyzed in vivo. The impact of mtROS on TFAM (mitochondrial transcription factor A), Lon protease, mtDNA, mitochondrial respiration, and cytokine release was analyzed in renal tubular cells in vitro. The effects of TFAM knockdown on mtDNA, mitochondrial function, and cytokine release were also analyzed in vitro. Finally, changes in TFAM and mtDNA nucleoids were measured in kidney samples from IRI-AKI mice and patients. Results: Decreasing mtROS levels attenuated renal dysfunction, mitochondrial damage, and inflammation in IRI-AKI mice. Decreasing mtROS levels also reversed the decrease in TFAM levels and mtDNA copy number that occurs in HK2 cells under oxidative stress. mtROS reduced the abundance of mitochondrial TFAM in HK2 cells by suppressing its transcription and promoting Lon-mediated TFAM degradation. Silencing of TFAM abolished the Mito-Tempo (MT)-induced rescue of mitochondrial function and cytokine release in HK2 cells under oxidative stress. Loss of TFAM and mtDNA damage were found in kidneys from IRI-AKI mice and AKI patients. Conclusion: mtROS can promote renal injury by suppressing TFAM-mediated mtDNA maintenance, resulting in decreased mitochondrial energy metabolism and increased cytokine release. TFAM defects may be a promising target for renal repair after IRI-AKI.