tbuckley/cabot-search huggingface dataset:
LGG-03. EFFECT OF AGE AND NEUROFIBROMATOSIS TYPE 1 STATUS ON WHITE MATTER INTEGRITY IN THE OPTIC RADIATIONS IN CHILDREN
Authors: Peter de Blank, Jeffrey Berman, Marisa Prelack, Amy Waldman, Michael Fisher
Journal: Neuro-Oncology (2017)

Reliable measures of vision are essential in children with neurofibromatosis type 1 (NF1) who are predisposed to optic pathway gliomas, cognitive differences and attention deficits that can challenge ophthalmologic assessment. Diffusion tensor imaging (DTI) of the optic radiations is a biomarker of vision in children with optic pathway gliomas.1 However, normal values for DTI measures such as radial diffusivity (RD) have not been defined in young children. We compared clinically acquired DTI in 40 healthy children with NF1 to 55 healthy controls between 0–14 years of age. Subjects were excluded for prematurity or neurologic/ophthalmologic conditions that may affect white matter integrity or vision. 3T Diffusion MR (Siemens Trio, Skyra or Verio; Erlangen, Germany) was acquired with 30 gradient directions, 128 x 128 matrix, b=1000s/mm2, 2mm isotropic voxel, and b=1000 s/mm2. Automated probabilistic tractography was performed between the lateral geniculate nucleus and the occipital pole.2 Regression models of age (linear, exponential, logarithmic, quadratic) on DTI measures were considered. Potential covariates included NF1 status and gender, and interaction terms between age and NF1 status were investigated (p<0.2 threshold of significance). In both NF1 and nonNF1 subjects, age was significantly correlated with DTI measures, and ln(age) was determined to be the best-fit model. While NF1 status was not a significant covariate in the model, NF1*ln(age) met the predetermined threshold for significance (p=0.073). Therefore, NF1 and non-NF1 subjects were modeled separately. Between 0–14 years, a doubling of age predicted a 0.860x10-4mm2/s decrease in RD for children without NF1, but only 0.493x10-4mm2/s decrease for children with NF1. This study demonstrates altered developmental trajectory in the white matter optic radiations of children with NF1 and defines normal DTI values among children, essential to the development of DTI as a biomarker of vision. 1de Blank et al, NeuroOncol 2013. 2de Blank et al, ISMRM 2016, abstract 3058
Building resilient health systems: a proposal for a resilience index
Authors: Margaret E Kruk, Emilia J Ling, Asaf Bitton, Melani Cammett, Karen Cavanaugh, Mickey Chopra, Fadi el-Jardali, Rose Jallah Macauley, Mwihaki Kimura Muraguri, Shiro Konuma, Robert Marten, Frederick Martineau, Michael Myers, Kumanan Rasanathan, Enrique Ruelas, Agnès Soucat, Anung Sugihantono, Heiko Warnken
Journal: BMJ (2017)

Health system resilience begins with
Clinical affect and sensory correlates in adolescent sports concussions
Authors: Dong (Dan) Y Han, Lisa Koehl, Fernanda C Camargo, Mattacola Mattacola
Journal: British Journal of Sports Medicine (2017)

Objective Identifying risk factors is important in adolescent sports concussions. This study aimed to explore the relationship between affective symptoms and physical symptoms in youth concussions. Design Athletes were split into two groups: self-reported emotional symptoms (irritability/aggression, anxiety, depression, apathy, and/or labile mood; EMO, n=22) and a control group without emotional symptoms (CON, n=15). Groups were examined for differences between post-concussive symptoms and peri-concussive factors. Setting Outpatient clinic. Participants 37 concussed adolescents age 12–17 with persisting concussion symptoms were assessed. Concussion diagnoses were indicated by traumatically induced alterations in mental status (with or without LOC), disruption in brain functioning (memory loss/neurological deficits), and other physiologic symptoms post-concussion. Those with baseline psychiatric history and/or special education were excluded. Assessment of risk factors Post-concussive symptom variable relationships were assessed. Outcome measures group differences were analysed using ANOVAs. Results No differences between positive LOC, positive amnesia, or post-concussive criteria existed, indicating likely comparable severity. While there were no group differences for number of concussions, headaches, or nausea, those in EMO were significantly more likely to endorse photo-sensitivity (p=0.003, F=10.155) and phono-sensitivity (p=0.007, F=8.108). Both anxiety and irritability/aggression were significantly (p&lt;0.05) correlated with endorsement of attention difficulties (r=0.332, r=0.474, respectively). Family psychiatric history was not correlated with emotional difficulties post-concussion. Conclusions Results indicate that adolescents who self-report emotional difficulties following sports concussion are more likely to endorse some physical symptoms, particularly photo-sensitivity and phono-sensitivity. Those experiencing anxiety or irritability are also more likely to experience increased attentional difficulties. Competing interests None.
A Network of Activated Cancer Signaling Pathways in a High Risk Subgroup of Acute Myeloid Leukemia Targetable By SRC-Kinase Inhibitors
Authors: Claudia Chiriches, Dilawar Khan, Nathalie Guillen, Michal Rokicki, Carol Guy, Afsar Mian, Oliver G. Ottmann, Martin Ruthardt
Journal: Blood (2016)
TRTH-12. PHASE 1 SAFETY, PHARMACOKINETIC AND IMAGING STUDY OF BLZ-100 TUMOR PAINT IN PEDIATRIC BRAIN TUMOR PATIENTS
Authors: Amy Lee, Bonnie Cole, Sandra Poliachik, Jeff Ojemann, Dennis Miller, Julie Novak, Stacey Hansen, James Olson, Sarah Leary
Journal: Neuro-Oncology (2017)

INTRODUCTION: Maximal safe surgical resection is an essential component of pediatric brain tumor treatment. Intraoperative fluorescence guidance may enable better tumor visualization, leading to improved surgical outcomes. BLZ-100 is a near-infrared imaging agent consisting of a tumor-binding peptide, chlorotoxin, and the fluorescent molecule, indocyanine green. Results from a phase 1 dose escalation clinical study are presented below. METHODS: A 3+3 dose-escalation design was used with five pre-specified dose levels. BLZ-100 was administered as a single IV bolus 6–31 hours prior to surgery. Subjects with confirmed or suspected brain tumor were eligible if planned for maximal safe surgical resection. Other key eligibility requirements included normal cardiac, renal, liver and coagulation function. Dose limiting toxicity (DLT) was defined as any related adverse event of ≥ Grade 3 severity occurring within 7 days of BLZ-100 administration. PK samples were obtained prior to dosing and at 10 minutes, 30 minutes, 1 hour and 2 hours after administration. Tumor fluorescence was evaluated in situ and ex vivo using a Synchronized Infrared Imaging System (SIRIS). Pathologic specimens were evaluated using the Odyssey system. RESULTS: 15 subjects of median age 7 years (range 7 months to 17 years) were treated at 5 dose levels (1.7, 3.5, 6.9, 13.9 and 17.3 mg/m2). Diagnoses included low-grade glioma (n=7), ependymoma (n=4), high-grade glioma (n=2), ATRT and medulloblastoma (n=1 each). No DLT were observed and a single instance of Grade 1 hypoalbuminemia was considered possibly related to BLZ-100. Tumor fluorescence was observed in 13 of 15 tumors including 5 out of 7 low-grade gliomas. Fluorescence intensity increased with increasing BLZ-100 dose. CONCLUSIONS: This is the first trial to evaluate fluorescence-guided neurosurgery in children. BLZ-100 was safe across the dose levels studied, and fluorescence was observed in the majority of tumors evaluated. Dose expansion at 15 mg/m2 is ongoing.
Thomas Cyril Waters
Authors: Steve Waters
Journal: BMJ (2017)

Thomas Cyril Waters (“Tom”) was born into a Welsh mining family at a time when pits were closing and times were hard. His father tried various innovative ways to provide for his new family, settling on a market gardening cooperative. So it was that Tom found himself at Newent Grammar School in Gloucestershire, where the headmaster recognised Tom’s intelligence and convinced his parents that he was capable of going on to university. His mother in particular inspired Tom to believe that he could train to be a doctor. Her illness and death when Tom was 16 strengthened his determination to succeed. Tom knew he would need to obtain a scholarship to …
Clinicopathologic feature and outcome of appendiceal goblet cell carcinoid and neuroendocrine tumor.
Authors: Wungki Park, Geetha D. Vallabhaneni, Ludmila Katherine Martin, Volkan Adsay, Charles A. Staley, Shishir Kumar Maithel, Zhibo Wang, Zhengjia Chen, Bassel F El-Rayes, Tanios S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2012)

e14170 Background: Goblet cell carcinoid (GCC) of the appendix is a rare tumor comprising 5% of primary appendiceal tumors. GCC shares histological features of both neuroendocrine tumor (NET) and adenocarcinoma. Clinically, GCC also has an intermediate behavior between them. The management of GCC is mostly based on small retrospective series. We report the clinicopathological features, treatments, and outcomes of patients with appendiceal GCCs and NETs from a merged database between Emory University and the Ohio State University. Methods: We identified patients with appendiceal GCCs and NETs treated at these institutions over the period of 12 years from 1999 to 2011. Chart reviews for age, gender, date of diagnosis, TNM stage, chemotherapy, intraperitoneal hyperthermic perfusion (IPHP), surgery, and survival were performed. Results: See table. In the GCC patients with stage I, II, and III, 30 received surgery alone and 1 received surgery plus IPHP. 29 out of 31 (94%) patients are alive without disease recurrence. Out of 6 GCC patients with stage IV, 5 received chemotherapy, 1 received chemotherapy plus IPHP, and 2 (33%) are alive. In the NET patients with stage I,II, and III, all 29 were treated with surgery alone. 29 out of 31 patients are alive and there was no disease-related mortality. Out of 2 NET patients with stage IV, one received chemotherapy and both are alive. Conclusions: Our data confirms the excellent prognosis of appendiceal NET regardless of stage. The outcomes of surgery for patients with stage I, II, and III in both GCCs and NETs were excellent. Patients with stage IV GCCs have higher possibility of aggressive clinical courses. Chemotherapy or IPHP should be considered in the management of stage IV GCCs. [Table: see text]
TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling
Authors: Tatyana V. Masyuk, Anatoliy I. Masyuk, Maria Lorenzo Pisarello, Brynn N. Howard, Bing Q. Huang, Pui‐Yuen Lee, Xavier Fung, Eduard Sergienko, Robert J. Ardecky, Thomas D.Y. Chung, Anthony B. Pinkerton, Nicholas F. LaRusso
Journal: Hepatology (2017)

Hepatic cystogenesis in polycystic liver disease is associated with increased levels of cyclic adenosine monophosphate (cAMP) in cholangiocytes lining liver cysts. Takeda G protein receptor 5 (TGR5), a G protein–coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with polycystic liver disease. In vitro , we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to (1) TGR5 agonists (taurolithocholic acid, oleanolic acid [OA], and two synthetic compounds), (2) a novel TGR5 antagonist (m‐tolyl 5‐chloro‐2‐[ethylsulfonyl] pyrimidine‐4‐carboxylate [SBI‐115]), and (3) a combination of SBI‐115 and pasireotide, a somatostatin receptor analogue. In vivo , we examined hepatic cystogenesis in OA‐treated polycystic kidney rats and after genetic elimination of TGR5 in double mutant TGR5−/− ; Pkhd1del2/del2 mice. Compared to control, expression of TGR5 and Gα s (but not Gα i and Gα q ) proteins was increased 2‐fold to 3‐fold in cystic cholangiocytes in vitro and in vivo . In vitro , TGR5 stimulation enhanced cAMP production, cell proliferation, and cyst growth by ∼40%; these effects were abolished after TGR5 reduction by short hairpin RNA. OA increased cystogenesis in polycystic kidney rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5‐deficient TGR5−/−;Pkhd1del2/del2 mice. TGR5 expression and its colocalization with Gα s were increased ∼2‐fold upon OA treatment. Levels of cAMP, cell proliferation, and cyst growth in vitro were decreased by ∼30% in cystic cholangiocytes after treatment with SBI‐115 alone and by ∼50% when SBI‐115 was combined with pasireotide. Conclusion: TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation; our data suggest that a TGR5 antagonist alone or concurrently with somatostatin receptor agonists represents a potential therapeutic approach in polycystic liver disease. (H epatology 2017;66:1197‐1218).
Increase in Diabetes Cases Among Young People
Authors: Jennifer Abbasi
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
MEDU-20. TARGETING OF MYC BY HDAC INHIBITION IN MYC AMPLIFIED GROUP 3 MEDULLOBLASTOMA
Authors: Jonas Ecker, Ina Oehme, Florian Selt, Marcel Kool, Lukas Chavez, Juliane Hohloch, Gintvile Valinciute, Cornelis M. van Tilburg, Martina Schnölzer, Uwe Warnken, Robert Wechsler-Reya, Stefan M. Pfister, Olaf Witt, Till Milde
Journal: Neuro-Oncology (2017)

High-risk medulloblastoma (MB) remains a deadly disease with poor overall survival despite aggressive multi-modal treatment. Survivors suffer from important treatment-associated morbidity. Patients with Group 3 MB tumors with amplification or high expression of the transcription factor MYC have a particularly poor outcome. Previously we have shown that MYC amplified Group 3 MB cell lines are highly susceptible to pan- and class I-selective histone deacetylase (HDAC) inhibitor treatment. We here explore the potentially sensitizing effect of MYC to HDAC inhibition by unraveling the molecular interaction of MYC and HDAC2. In three established MB cell lines, MYC amplified as well as single copy, mRNA and protein expression of MYC and HDAC2 after enzymatic inhibition of class I HDACs and after siRNA-mediated knockdown of HDAC2 was investigated. The direct interaction of HDAC2 and MYC protein was analyzed in co-immunoprecipitation and mass spectrometry studies. Chromatin immunoprecipitation with pulldown of MYC or HDAC2 and subsequent DNA-sequencing (ChIP-Seq) was performed in a MYC amplified cell line. Reduced MYC protein levels were observed after both pharmacological inhibition of class I HDACs (including HDAC2) as well as knockdown of HDAC2, without significant alteration of MYC mRNA levels. Reduced MYC protein levels coincided with increased levels of acetylated MYC protein. MYC and HDAC2 were found to be localized in a protein complex together with other potential drug targets. MYC and HDAC2 co-localize on the DNA with an overlap of DNA binding sites of 80%. Our data suggest that inhibition of class I HDACs destabilizes MYC protein, thus reducing the abundance of one of the cell’s main oncogenic drivers. The direct interaction of MYC/HDAC2 in a multi-protein complex localized on the DNA represents a putative epigenetic target for novel combinatorial treatment approaches. Perturbation of gene expression profiles upon HDACi treatment of MYC amplified MB cell lines are currently under investigation.
Intrinsic Neuronal Stress Response Pathways in Injury and Disease
Authors: Madeline M. Farley, Trent A. Watkins
Journal: Annual Review of Pathology Mechanisms of Disease (2018)

From injury to disease to aging, neurons, like all cells, may face various insults that can impact their function and survival. Although the consequences are substantially dictated by the type, context, and severity of insult, distressed neurons are far from passive. Activation of cellular stress responses aids in the preservation or restoration of nervous system function. However, stress responses themselves can further advance neuropathology and contribute significantly to neuronal dysfunction and neurodegeneration. Here we explore the recent advances in defining the cellular stress responses within neurodegenerative diseases and neuronal injury, and we emphasize axonal injury as a well-characterized model of neuronal insult. We highlight key findings and unanswered questions about neuronal stress response pathways, from the initial detection of cellular insults through the underlying mechanisms of the responses to their ultimate impact on the fates of distressed neurons.
Identification of TRA-1-60-Positive Cells As a Potent Refractory Population in Follicular Lymphomas
Authors: Katsuyoshi Takata, Hidekazu Iioka, Tomoko Miyata-Takata, Yukari Miki, Tadashi Yoshino, Yoshinobu Maeda, Ken Saito, Christian Steidl, Eisaku Kondo
Journal: Blood (2016)
DIPG-42. THE COMBINATION OF THE CDK4/6 INHIBITOR PALBOCICLIB WITH THE RAPALOGUE TEMSIROLIMUS INHIBITS DIPG CELL PROLIFERATION VIA SYNERGISTIC ATTENUATION OF CELL CYCLE REGULATORS
Authors: DJ Asby, AS Bienemann, LJ Wright, C Killick-Cole, WGB Singleton, MJ Wyatt, NU Barua, SS Gill
Journal: Neuro-Oncology (2017)

Current chemotherapy for diffuse intrinsic pontine glioma (DIPG) is ineffective and requires revitalization. DIPG accounts for up to 15% of all childhood central nervous system tumours and has a two-year survival rate of less than 10%. DIPG is highly chemotherapy-resistant and children show little response to conventional high-grade glioma chemotherapies. Palbociclib has the potential to treat DIPG by selectively inhibiting the proliferation of cancer cells via inhibition of cyclin-dependent kinase (CDK) 4 and CDK6, which triggers cell cycle arrest at the G1 checkpoint. However it has been found that CDK inhibitors alone are ineffective as long-term cancer treatments and resistance can be acquired. We aimed to use palbociclib to inhibit DIPG cell proliferation by inducing cell cycle arrest via targeted disruption of cyclin D-CDK4/6 complexes, in combination with the rapamycin analogue temsirolimus, used to attenuate mTOR-driven cyclin protein expression. Cell viability was assessed in two ex vivo DIPG cell lines treated with palbociclib, temsirolimus or both for 24 hours. We demonstrated that palbociclib and temsirolimus both inhibit proliferation in DIPG cells and that their effects were potentiated when used in combination. This was substantiated via flow cytometric and clonogenic analyses, the latter revealing longer-term dose-dependent reductions in colony formation. Quantitative analysis of the dose-effect relationship between the two drugs indicated a synergistic relationship when used in combination. Furthermore, immunoblot analyses showed inhibition of CDK4/6 and mTOR signalling using palbociclib and temsirolimus, respectively, each of which was enhanced in combination. This work illustrates the in vitro effectiveness of these drugs against DIPG when used individually, and the amplified effects when used concurrently. The combination of these two established FDA-approved therapeutics represents a putative fast-track approach to creating a much-needed treatment for DIPG.
TRTH-21. GLIOMA SURVIVAL BENEFITS FROM NEUROSURGICAL DELIVERY OF PLGA/PEG INTERSTITIAL THERAPY
Authors: Stuart Smith, Toby Gould, Betty Tyler, Gareth Veal, Alison Ritchie, Noah Gorelick, John Choi, Nicolas Skuli, Kevin Shakesheff, Henry Brem, Richard Grundy, Ruman Rahman
Journal: Neuro-Oncology (2017)

INTRODUCTION: The blood brain barrier is a critical limiting step to achieving therapeutic CNS drug concentrations. We have developed a poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG)-based Platform Technology to interstitially deliver multiple chemotherapy agents from a single thermo-setting paste, potentially filling the 3-week therapy gap that currently exists between surgery and commencement of radiotherapy in the treatment of high grade gliomas. Here we evaluate mouldable PLGA/PEG paste for combined temozolomide (TMZ) and etoposide (ETOP) delivery in an orthotopic high grade glioma model. METHODS: Drug release and preserved stability of the active TMZ molecule (AIC) was evaluated by fluoroscopic and LC-mass spectrometer based methods. In vitro cytotoxicity of released TMZ/ETOP was evaluated against high grade glioma cell lines and patient-derived primary cultures using metabolic assays. In vivo efficacy and overall survival were evaluated in the syngenic orthotopic 9L glioma rat model of intra cavity chemotherapy. RESULTS: TMZ and ETOP were released from PLGA/PEG alone or in combination over 2 weeks in vitro. Cytotoxicity of released drugs in vitro is comparable to directly applied agents, demonstrating the retained molecular integrity of TMZ/ETOP upon loading and releasing from PLGA/PEG. Both high (20% w/w TMZ / 50% w/w ETOP) and low (10% w/w TMZ / 25% w/w ETOP) doses were well tolerated in vivo, with no observable weight loss nor neurological deficits. Significant survival benefits from PLGA/PEG/TMZ/ETOP therapy were observed compared to surgery alone (49 vs. 14 days; p < 0.001), surgery with blank paste (49 vs. 14 days; p < 0.001) or surgery with daily oral TMZ (49 vs. 33 days; p < 0.004). CONCLUSIONS: This study demonstrates that interstitial delivery of TMZ/ETOP achieves significant glioma survival benefits. As such, PLGA/PEG paste applied to the post-surgical resection cavity offers a realistic opportunity for localised control of residual disease in pediatric and adult high grade gliomas.
Abstract 14237: Effect of CYP2C19 Genotype on Inhibition of Platelet Aggregation in Hemodialysis Patients With Coronary Artery Disease
Authors: Katsuhisa Waseda, Yuki Saka, Hiroaki Takashima, Akiyoshi Kurita, Hirohiko Ando, Shinichiro Sakurai, Akihiro Suzuki, Hiroaki Sawada, Shigeko Sato, Yoshinori Nishikawa, Tetsuya Amano
Journal: Circulation (2016)

Background: Since hemodialysis patients have shown a relatively higher incidence of clinical events associated with thrombus, management of antiplatelet therapy after stenting would be important. T...
Chances and challenges for an active visual search perspective
Authors: Sven Ohl, Martin Rolfs
Journal: Behavioral and Brain Sciences (2017)

Abstract Using fixations as the fundamental unit of visual search is an appealing gear change in a paradigm that has long dominated attention research. To truly inform theories of search, however, additional challenges must be faced, including (1) an empirically motivated definition of fixation in the presence of fixational saccades and (2) the biases and limitations of transsaccadic perception and memory.