tbuckley/cabot-search huggingface dataset:
Abstract 273: Phosphoinositide 3-Kinase γ Regulates Cardio-protective ERK by Kinase Independent Mechanism
Authors: Maradumane L Mohan, George Jolly, Rohit Anand, Sathyamangla V Naga Prasad
Journal: Circulation Research (2015)

Phosphoinositide 3-kinase (PI3K) enzymes are critical in many cellular processes including survival. PI3Kγ, a member of the PI3K family activated by G-protein coupled receptor (GPCR), is known to be a critical player in activation of extracellular regulated kinase (ERK) signal transduction cascade, a cell survival pathway. However, the exact mechanism by which PI3Kγ plays a role in ERK activation is not clearly understood. Our studies show that PI3Kγ plays a crucial role in enhancing the tone of ERK activation as use of PI3K inhibitors reduced GPCR stimulated ERK phosphorylation in HEK293 cells. siRNA knockdown of PI3Kγ resulted in loss of ERK phosphorylation through GPCRs (β-adrenergic) as well as receptor tyrosine kinases. The role of PI3Kγ in ERK activation was further corroborated by loss of insulin stimulated ERK phosphorylation in PI3Kγ-knockout (KO) mouse embryonic fibroblasts (MEFs). Surprisingly, ERK activation in KO MEFs post-insulin stimulation was completely rescued by expression of kinase-dead PI3Kγ mutant in KO MEFs suggesting a kinase-independent role of PI3Kγ in regulating ERK function. Indepth mechanistic studies showed that PI3Kγ mediated activation of ERK by inhibiting ERK dephosphorylation following stimulation, thus stabilizing the ERK phosphorylation. PI3Kγ physically disrupts the interaction between ERK and ERK dephosphorylating phosphatase PP2A as evidenced by increase in phosphatase association with ERK in KO MEFs. Consistent with this observation, ERK activation was completely abolished in KO MEFs following carvedilol suggesting an essential role for PI3Kγ in cardio-protective ERK activation pathway. In this context, it is known that transverse aortic constriction (TAC) in mice leads to increase in ERK activation in the hearts and is also associated with concurrent up-regulation of PI3Kγ suggesting a key role for kinase-independent function of PI3Kγ in activating and maintaining the ERK signaling cascade. These indepth cellular studies and observation from our TAC studies led us to believe that kinase-dependent function of PI3Kγ may contribute to pathology while kinase-independent function may be cardio-protective through inhibition of PP2A by PI3Kγ. This novel signaling mechanism by PI3Kγ will be presented.
West meets East: dynamic ERCP characterization of pancreaticobiliary maljunction without biliary dilation underlying extensive biliary tract cancer
Authors: Vincent Zimmer, Christoph Heinrich
Journal: Endoscopy (2017)

A 62-year-old woman presented with marked cholestasis (bilirubin 9.8 mg/dL), and ultrasound suggested intrahepatic biliary dilation down to the hilum and a solid-filled gallbladder. Claustrophobia precluded magnetic resonance imaging, but computed tomography imaging excluded distant metastases. Endoscopic ultrasound suggested an anomalous pancreaticobiliary junction (APBJ) with extramural pancreaticobiliary confluence, a solid gallbladder mass, and an independent, vague 12 mm hypoechoic hilar lesion, thus suggesting double carcinoma formation in the biliary tract [1] [2].
Therapies That Target PCSK9 Effective at Reducing LDL Cholesterol
Authors: Anita Slomski
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
HGG-05. CAN MULTIMODAL IMMUNOTHERAPY REPLACE RADIOCHEMOTHERAPY IN COMPLETELY RESECTED ADULT GBM?
Authors: Stefaan Van Gool, Dimitri Vanhauwaert, Franceska Dedeurwaerdere, Stefan Pfister, Maria Lulei, Volker Schirrmacher, Wilfried Stuecker
Journal: Neuro-Oncology (2017)

Adults with GBM always relapse, even after complete resection. Therefore radiotherapy with broad margins around the resection cavity is mandatory part of the initial standard of care for these patients, aimed to maximize the local tumor control. Chemotherapy is aimed as function as radiosensitizer and to prolong disease-free survival. Nevertheless, most patients show local and/or even distant tumor re-occurrence more or less shortly after multimodal primary treatment. Hypotheses for this are the infiltrative character of the tumor cells, the residing non-dividing glioma cancer stem cells, chemoresistance, etc. IOZK was confronted with a patient (EORTC RPA class IV) who refused radiochemotherapy and maintenance chemotherapy after complete resection of a left occipital glioblastoma. Pathology showed tissue necrosis, angiogenesis, mitosis and atypical tumor cell nuclei. Molecular classification revealed glioblastoma, IDH wildtye, subtye RTK I. After immunodiagnostic blood sampling, the patient was treated with multimodal immunotherapy consisting of 2 cycles of 6 days Newcastle Disease Virus (NDV) infusions and local modulated electrohyperthermia (mEHT) sessions plus an autologous DC vaccine loaded with serum-derived NDV/mEHT-induced antigenic microparticles + NDV, and additionally four more treatments with NDV infusions + mEHT. Treatment was conducted without any side effect. We observed the induction of tumor antigen-specific IFN-producing T cells measured upon ex vivo stimulation with autologous DCs loaded with a GBM cell line in ELISPOT. At time of writing, 15 months after resection, the patient remains in complete remission with optimal Karnofsky performance index and good quality of life. The % PFS at 12 months in the Stupp 2005 paper is for the total group of patients with radiotherapy alone 9.1% (95%CI 5.8–12.4m). The patient history points to a potential change in paradigm that microscopic infiltrating GBM tumor cells might be brought under permanent control through the combined action of NDV, mEHT and the induction of memory T cells.
포스터전시 : 만성 C형간염 환자에서 C형간염바이러스 유전자형의 분포: 유전자형 3형 중심으로-단일연구기관
Authors: 이창민, 민현주, 장현정, 조현진, 이재민, 임병렬, 하창윤, 김현진, 김태효, 정운태, 이옥재
Journal: Clinical and Molecular Hepatology (2008)
G-quartet oligonucleotides: A new class of Stat3 inhibitors that suppresses growth of prostate and breast tumors through induction of apoptosis
Authors: Lynn G. Feun, Chunjing Wu, Michael Clark, John Bombalaski, Frederick Holtsberg, Medhi Wangpaijit, Carlos Robles, Niramol Savaraj
Journal: Cancer Research (2004)

4565  Malignant melanoma is usually resistant to drug therapy which historically has been non selective and often toxic. We and others have previously shown that unlike other tumor cell lines, melanoma cell lines are auxotrophic for arginine, a non essential amino acid in humans (Cancer Res.62:5443, 2002). Exposure of melanoma cell lines to arginine deiminase (ADI) an enzyme which catalyzes the hydrolysis of arginine to citrulline results in cell death. The IC50 ranged from 0.3-0.01 ug/ml in 17 melanoma cell lines tested whereas in lung cancer cell lines, the IC50 was > 100ug/ml. This differential sensitivity is most likely due to the fact that melanoma cell lines do not express argininosuccinate synthetase (ASS). To maximize the pharmacological effect, ADI was combined with polyethylene glycol (ADI-PEG-20). A phase I-II trial with ADI-PEG-20 in melanoma has shown promising results (Proc.ASCO.2003 Abs #2855 ). We have investigated the mechanism of antitumor activity of ADI-PEG-20. Exposure of A-375 and Sk-Mel-2 to ADI-PEG-20 to 0.1 ug/ml for 72 hr results in apoptosis detected by in situ end labeling assay using the kit from ONCOR. Limited gene array analysis (included 23 genes related to apoptosis, purchased from SuperArray) demonstrated that after exposure to ADI-PEG-20, A-375 expressed DR-5, TRAIL, GADD 45, Caspase 10 and NF-kB. Thus, it is possible that ADI-PEG-20 induces TRAIL production and triggers autocrine induction of apoptosis in addition to amino acid deprivation. We are currently investigating this possibility. Since another important issue is development of resistance to ADI-PEG-20, we have established primary culture obtained from patients who failed ADI-PEG-20 and found that these cells express ASS by RT-PCR, and also showed an ID 50 of >25 ug/ml. Similarly, continuous exposure to low doses of ADI-PEG-20 in melanoma cell line (A-375) also induces ASS expression. Interestingly, exposure of melanoma cells to corticosteroids (hydrocortisone) at 1uM for 48 hr. or 0.5 uM for 7 days, decreases the antitumor activity of ADI-PEG-20. The ID50 increased from 0.07 to 0.36 ug/ml. A small but detectable amount of ASS transcript was seen by RT-PCR. Thus, our data suggest that expression of ASS is most likely one of the mechanisms of treatment failure and that certain drugs such as corticosteroids may decrease the effectiveness of ADI-PEG-20 by inducing ASS expression. Other pharmacological manipulation such as oleic acid is being investigated to decrease ASS expression and thereby augment the antitumor effect of ADI-PEG-20. Thus, ADI-PEG-20 is effective in melanoma cells which lack ASS expression. The use of corticosteroids may decrease the effectiveness of this agent.
IMMU-02. TARGETING CD200 ACTIVATION RECEPTORS TO OVERCOME THE IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT: A NEW DIRECTION FOR CHECKPOINT IMMUNOTHERAPY
Authors: Elisabet Ampudia-Mesias, Christopher Moertel, Michael Olin
Journal: Neuro-Oncology (2017)

Glioblastoma multiforme is an incurable primary brain tumor. The standard of care consists of resection followed by radiation and chemotherapy is associated with a median overall survival of 14.6 months. To address this dismal outcome, aggressive interventions need to be pursued. Recently, the FDA approved immune checkpoint inhibitor therapy for solid tumors that are otherwise refractory to standard therapy heralding a new era for effectively treating cancer. Yet, immune checkpoint inhibitors yield poor responses for patients with glioblastoma, calling into question whether cancer immunotherapy can be applied to glioblastoma. We have recently reported that inhibiting an alternative immune checkpoint, CD200, inhibits tumor-induced immunosuppression without toxic side effects. CD200 protein suppresses immune activation after engaging the CD200 inhibitory receptor, which is restricted to immune cells. Recently, our laboratory reported that CD200 inhibits brain tumor immunity via three separate mechanisms: 1) CD200 is secreted from brain tumors into the cervical lymph nodes where it induces an immunosuppressive environment, 2) CD200 is upregulated in GBM-associated vascular endothelial cells, tolerizing CD200R+ lymphocytes, and 3) CD200 within tumor-derived vaccines suppresses an antitumor response. To combat the suppressive mechanisms of CD200, we are targeting activation receptors to override the suppressive signal of the CD200 checkpoint blockade. Targeting these receptors activate antigen presenting cells enhancing dendritic cell maturation, cytokine production and antigen specific T cell activation, which significantly extend survival in two murine glioma models. In addition, in an ongoing clinical trial using dogs diagnosed with high-grade glioma, patients receiving a canine specific CD200 peptide inhibitor in combination with the autologous tumor lysate vaccine had enhanced survival up to 467 days, relative to 214 days with lysate alone, without any observed toxicity or signs of reoccurrence. Importantly, we developed human CD200 inhibitors demonstrating strong immune responses with the goal of a Phase I trial early 2018.
ONC201, a small molecule Foxo3a activator, activity against patient-derived glioblastoma tumor-initiating cells.
Authors: Dan Zhao, Sudhandra Sundaram, Hiroaki Wakimoto, William T. Curry, Daniel P. Cahill, Tracy Batchelor, Keith Flaherty, Joshua Allen, Andrew S. Chi
Journal: Journal of Clinical Oncology (2014)

e13022 Background: ONC201 is a novel small molecule that inactivates MEK and Akt to induce Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) tumor suppressor expression in a Foxo3a-dependent manner and is able to cross the blood-brain barrier. Previous studies have verified preclinical cytotoxic activity in numerous cancer models including glioma. We sought to determine activity of ONC201 against patient-derived glioma tumor initiating cell (TIC) models in vitro and in orthotopic xenograft. Methods: We tested 5 TIC lines derived using the neurosphere system from untreated (MGG4, MGG8, MGG18) and recurrent (MGG67R and MGG152) glioblastomas. Several lines are known to have variable sensitivity to secreted TRAIL, including one (MGG4) that was reported to be resistant to secreted TRAIL-mediated cell death. We performed cell viability assays using ONC201 and IC50 values were calculated. SCID mouse brains were stereotactically implanted with TICs and mice were treated with ONC201 by oral gavage for in vivo pharmacodynamic and survival experiments. Results: ONC201 potently inhibited in vitro cell proliferation of all 5 lines, with IC50 values of 433 nm (MGG18), 688 nm (MGG152), 1.09 um (MGG8), 1.46 um (MGG4) and 3.97 uM (MGG67R). Pharmacodynamic and survival studies in orthotopic xenograft-bearing mice are ongoing. Conclusions: ONC201 has potent anti-proliferative activity in multiple glioblastoma TIC lines in vitro and may be a promising agent for glioblastoma with the potential to overcome the limitations of recombinant TRAIL and available cancer therapies.
Mechanisms of Persistent Activity in Cortical Circuits: Possible Neural Substrates for Working Memory
Authors: Joel Zylberberg, Ben W. Strowbridge
Journal: Annual Review of Neuroscience (2017)

A commonly observed neural correlate of working memory is firing that persists after the triggering stimulus disappears. Substantial effort has been devoted to understanding the many potential mechanisms that may underlie memory-associated persistent activity. These rely either on the intrinsic properties of individual neurons or on the connectivity within neural circuits to maintain the persistent activity. Nevertheless, it remains unclear which mechanisms are at play in the many brain areas involved in working memory. Herein, we first summarize the palette of different mechanisms that can generate persistent activity. We then discuss recent work that asks which mechanisms underlie persistent activity in different brain areas. Finally, we discuss future studies that might tackle this question further. Our goal is to bridge between the communities of researchers who study either single-neuron biophysical, or neural circuit, mechanisms that can generate the persistent activity that underlies working memory.
Analysing real-world visual search tasks helps explain what the functional visual field is, and what its neural mechanisms are
Authors: John Campion
Journal: Behavioral and Brain Sciences (2017)

Abstract Rejecting information-processing-based theory permits the merging of a top-down analysis of visual search tasks with a bottom-up analysis of brain structure and function. This reveals the true nature of the functional visual field and its precise role in the conduct of visual search tasks. The merits of such analyses over the traditional methods of the authors are described.
The hOCT1 and ABCB1 Polymorphisms Don't Condition the Efficacy and Toxicity of Nilotinib As First-Line Treatment: An Italian Multicentric Experience
Authors: Sara Galimberti, Cristina Bucelli, Elena Arrigoni, Claudia Baratè, Susanna Grassi, Federica Ricci, Francesca Guerrini, Elena Ciabatti, Carmen Fava, Antonio D'Avolio, Giulia Fontanelli, Giovanna Rege Cambrin, Alessandro Isidori, Federica Loscocco, Giovanni Caocci, Marianna Greco, Monica Bocchia, Lara Aprile, Antonella Gozzini, Barbara Scappini, Daniele Cattaneo, Giorgio La Nasa, Alberto Bosi, Mario Petrini, Pietro Leoni, Romano Danesi, Giuseppe Saglio, Giuseppe Visani, Agostino Cortellezzi, Anna Rita Scortechini, Alessandra Iurlo, Antonello Di Paolo
Journal: Blood (2016)
PDTM-29. TRANSCRIPTIONAL DEPENDENCIES IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Surya Nagaraja, Nicholas Vitanza, Pamelyn Woo, Kathryn Taylor, Fang Liu, Lei Zhang, Meng Li, Wei Meng, Anitha Ponnuswami, Wenchao Sun, Jie Ma, Esther Hulleman, Tomek Swigut, Joanna Wysocka, Yujie Tang, Michelle Monje-Deisseroth
Journal: Neuro-Oncology (2017)

Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade. Identification of super-enhancers in DIPG provides insights toward the cell of origin, highlighting oligodendroglial lineage genes, and reveals unexpected mechanisms mediating tumor viability and invasion, including potassium channel function and EPH receptor signaling. The findings presented demonstrate transcriptional vulnerabilities and elucidate previously unknown mechanisms of DIPG pathobiology.
DIPG-43. PROLONGED CONVECTION-ENHANCED DELIVERY IN THE PONS WITH SN-38 LOADED NANOPARTICLES AND IRINOTECAN
Authors: A Charlotte Sewing, Nagore G Olaciregui, Carles Monterrubio, Gertjan Kaspers, Jaume Mora, Esther Hulleman, Angel M Carcaboso
Journal: Neuro-Oncology (2017)

INTRODUCTION: Inadequate drug delivery due to an intact blood-brain barrier (BBB) could explain part of the resistance to chemotherapeutic agents in diffuse intrinsic pontine glioma (DIPG). Convection-enhanced delivery (CED) is an alternative mode of local delivery and irinotecan, and its active compound SN‐38, are potentially effective agents. In this study we aim to perform prolonged CED in the pontine area of rats using irinotecan and newly designed SN‐38 loaded polymer nanoparticles (NPs). METHODS: Efficacy of irinotecan and SN‐38 against patient-derived HSJD-DIPG-007 cells was determined in vitro. Stability and release of SN‐38 from the NPs was tested with a dialysis chamber. Prolonged CED (200 μL in 24 hours using an Alzet Osmotic pump) was performed in naïve rats, and maximum tolerated dose (MTD) was determined by neurological follow-up using Rota-rod testing. Orthotopic HSJD-DIPG-007 xenografts were treated with the MTD of SN-38NPs, irinotecan, or vehicle (NaCl 0.9%). RESULTS: IC50 of SN‐38 against HSJD‐DIPG-007 cells was in the nanomolar range. IC50 of irinotecan was 1000 fold higher. Rota-rod scores in rats with HSJD-DIPG-007 tumors declined significantly before weight loss could be objectified. Stability of SN‐38 and release from NPs was adequate for the aimed experiment. Prolonged CED with SN-38 and irinotecan in the pontine area was tolerated at 1.2 μg (~8 μg/kg) and 0.08 mg (~5 mg/kg), respectively. These dosages did not show efficacy against HSJD-DIPG-007 tumors. DISCUSSION: This study shows that prolonged CED in the rat pons using potent chemotherapeutic agents is feasible and safe; it validates stability of newly‐designed NPs containing SN38 in the used vehicle, and it shows Rota-rod testing to be an effective tool for studying transitory functional changes related to toxicity in the pons and cerebellum of rats. The lack of efficacy in treating HSJD-DIPG-007 tumors identifies important new starting points for further research.
How to distinguish gesture from sign: New technology is not the answer
Authors: Karen Emmorey
Journal: Behavioral and Brain Sciences (2017)

Abstract Linguistic and psycholinguistic tests will be more useful than motion capture technology in calibrating the borders between sign and gesture. The analogy between motion capture (mocap) technology and the spectrograph is flawed because only vocal articulators are hidden. Although information about gradience and variability will be obtained, the technology provides less information about linguistic constraints and categories. Better models are needed to account for differences between co-speech and co-sign gesture (e.g., different degrees of optionality, existence of beat gestures).
Epidemiology of head and neck injuries in elite football – a prospective survey of fifa tournaments between 1998 and 2015
Authors: Annika Prien, Jiri Dvorak, Astrid Junge
Journal: British Journal of Sports Medicine (2017)

Objective Recently the potential long-term effect of sports-related head injuries has been discussed. To develop effective injury prevention strategies, epidemiological information is required. The aim of this study was to analyse the incidence and characteristics of head and neck match injuries. Design Prospective cohort study. Setting FIFA tournaments and Olympic Games. Participants All football teams participating in FIFA tournaments and Olympic Games between 1998 and 2015 were included in the study. The team physicians reported injuries from 2106 matches from 65 outdoor tournaments (20 women’s and 45 men’s). The average response rate was 96%. Outcome measures Incidence rates per match and a variety of injury characteristics (type, severity, cause, gender) of head/neck injuries compared to other football injuries were analysed. Main results 4756 injuries (2.4 injuries/match) were reported. Most injuries affected the lower extremity (70%), followed by the head/neck (15%), trunk (8%) and upper extremity (7%). Head injuries (n=674; 14.4%) were more frequent than neck injuries (n= 34;0.7%), and the incidence was higher in female (18%) than in male (14%) players. Most head/neck injuries were contusions (n=362; 50.3%) and non-time-loss injuries (n= 164;22.8%). Of the 108 (15%) reported concussions, 62% resulted in time-loss. Only one head injury (fracture) had an estimated time-loss of more than four weeks. Conclusion While neck injuries are rare, head injuries are more frequent, and particularly concussions often result in time-loss. No career-ending injuries of the head or neck were reported. Potential long-term effects of head/neck injuries warrant further evaluation in clinical studies. Competing interests None.