tbuckley/cabot-search huggingface dataset:
PDTM-18. ACTIVATION OF TUMOR-REACTIVE T CELLS AGAINST BRAIN STEM GLIOMA USING HEMATOPOIETIC STEM CELLS
Authors: Catherine Flores, Delaney Woodworth, Cameron Moorley, Ginger Moore, Duane Mitchell
Journal: Neuro-Oncology (2018)

Adoptive cellular therapy is demonstrably efficacious in two preclinical models of brain stem glioma (BSG), OB1 (wildtype H3.3), and K2 (H3.3K27M mutation). The survival benefit of adoptive cellular therapy is significantly enhanced by concomitant transfer of bone marrow derived hematopoietic stem cells (HSC) with tumor-reactive T cells. We demonstrate in orthotopic models that HSC-derived cells differentiate into dendritic cells within the tumor microenvironment and cross-prime adoptively transferred T lymphocytes in BSG. Using a novel method of 3D printing to fabricate microtumors using OB1 and K2 cells, we interrogate the BSG tumor microenvironment and demonstrate direct activation of tumor-reactive T cells in situ by HSC-derived dendritic cells. We employ orthotopic K2 and OB1 BSGs as well as an in vitro system using an innovative technique where 3Dtumoroids are fabricated using K2 and OB1 cells into engineered medium that allows in situ imaging over >30 days. Tumor-reactive T cells and HSCs are also applied to the system. T cells were generated using mice with fluorescent reporters. High resolution imaging is used for visualization of cell-to-cell interactions. Flowcytometry and immunofluorescence is used to confirm T cell and HSC immunophenotypes and activation status. RESULTS & In orthotopic models of K2 and OB1, we found that HSCs are required for T cell infiltration to BSGs. T cell infiltration into BSG is an impactful observation in this tumor type. 3D models of BSG, tumor-reactive T cell infiltration was significantly increased in the presence of HSCs. Using T cells generated from GREAT mice which have YFP reporter on the IFNγ promoter, we visualized direct activation of tumor-reactive T cells in situ. These studies are unique in that the in situ interrogation of BSG is not possible due to location. Here were are able to bypass this limitation with this technology to make key immunological observations.
PATH-34. VENTRICULAR-SUBVENTRICULAR ZONE CONTACT BY GLIOBLASTOMA IS NOT ASSOCIATED WITH MOLECULAR SIGNATURES IN BULK TUMOR DATA
Authors: Akshitkumar Mistry, David Wooten, Bret Mobley, Vito Quaranta, Rebecca Ihrie
Journal: Neuro-Oncology (2018)

Whether patients with glioblastoma that contacts the stem cell niche of the ventricular-subventricular zone (V-SVZ+GBM) have a distinct survival profile from V-SVZ-GBM patients independent of other known predictors or molecular profiles is unclear. Using multivariate Cox analysis to adjust survival for widely-accepted predictors, hazard ratios (HRs) for overall (OS) and progression free (PFS) survival between V-SVZ+GBM and V-SVZ-GBM patients were calculated in 170 single-institution patients and 254 patients included in both The Cancer Genome (TCGA) and Imaging (TCIA) atlases. A multivariable analysis adjusted for age, Karnofsky performance score, IDH1 mutation, MGMT promoter methylation status, chemotherapy, radiation therapy, and extent of surgical resection revealed that V-SVZ contact was independently associated with decreased survival in both datasets (institutional patients: OS HR 1.55 [95% CI 1.03–2.33], P=0.037; PFS HR 1.57 [1.08–2.28], P=0.018; TCIA/TCGA patients: OS HR 1.69 [1.28–2.24], P<0.001; PFS HR 1.24 [0.91–1.7], P=0.18). Thorough TCGA molecular data analyses were conducted using differential molecular feature extraction, gene expression network construction, clustering methods, and dimensionality reduction. All analyses revealed that V-SVZ contact by GBM was independent of mutational, DNA methylation, gene expression, and protein expression signatures in the bulk tumor. Therefore, while survival of GBM patients is independently stratified by V-SVZ contact, with V-SVZ+GBM patients displaying a poor prognosis, the V-SVZ+GBMs do not possess a distinct molecular signature at the bulk sample level. Focused examination of the interplay between V-SVZ cytoarchitectural features, microenvironmental factors, and cancer cells within glioblastomas using subpopulation- or single-cell-based approaches is warranted.
CSIG-35. MST4 PHOSPHORYLATION OF ATG4B REGULATES AUTOPHAGIC ACTIVITY, TUMORIGENICITY, AND RADIORESISTANCE IN GLIOBLASTOMA
Authors: Tianzhi Huang, Chung Kwon Kim, Angel Alvarez, Rajendra Pangeni, Xuechao Wan, Song Xiao, Taiping Shi, Yongyong Yang, Namratha Sastry, Craig Horbinski, Songjian Lu, Roger Stupp, John Kessler, Ryo Nishikawa, Ichiro Nakano, Erik Sulman, Xinghua Lu, C David James, Xiao-Ming Yin, Bo Hu, Shi-Yuan Cheng
Journal: Neuro-Oncology (2018)

Autophagy is a conserved catabolic process that maintains homeostasis by regulating the energy balance of the cell. Cancer cells use autophagy to remove damaged organelles and aggregated proteins, and to recycle nutrients in high demand to support tumor growth. Radiation therapy (RT) and temozolomide (TMZ), are front-line treatments for glioblastoma (GBM), the common and most malignant brain tumors in humans. However, RT and TMZ are known activating the autophagic response in tumor cells, which protects GBM cells from therapy-induced cell death. Thus, improved understanding of mechanisms regulating autophagy could reveal targets for selective and specific inhibition, which would enhance the anti-tumor activity of RT and TMZ while reducing toxic effects of treatment. In this study, we determined the roles of MST4, a less known protein serine/threonine kinase in its cellular functions in regulation of GBM tumorigenicity and therapy responses through activating autophagic activities. By using proteomic, biochemical and genetic approaches, we identified ATG4B as a novel substrate of MST4. ATG4B is a key regulator that facilitates autophagic process through reversible modification of ATG8/LC3. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B enzymatic activity towards LC3, increasing autophagic flux. Inhibition of MST4 or ATG4B activities suppresses autophagic activities and tumorigenicity of patient-derived glioma stem cells (GSCs) in vitro and in the brain of mice. Furthermore, RT induces MST4 expression, ATG4B phosphorylation and autophagic activity. Inhibiting ATG4B by using a novel inhibitor NSC185058 in combination with RT in treating mice with intracranial GBM tumor xenografts markedly slows tumor growth and provides significant survival benefit to animal subjects. This study not only describes a novel regulatory mechanism by which the MST4-ATG4B axis accelerates autophagic process, regulates GBM tumorigenicity, and responses to RT, but also explores imminent clinical utility of combination of ATG4B inhibition with RT to suppress orthotopic GBM tumor xenografts.
Immunotherapy Combinations in Multiple Myeloma — Known Unknowns
Authors: Nicole J. Gormley, Richard Pazdur
Journal: New England Journal of Medicine (2018)

The FDA required labeling changes for the programmed cell death 1 inhibitor pembrolizumab and thalidomide-analogue immunomodulatory agents to include information on increased mortality in multiple myeloma. Yet PD-1 therapy’s role in the disease is not a closed book.
COMP-17. BINDING FREE ENERGY ANALYSIS OF PROGRAMMED CELL DEATH PROTEIN PD1 TO ITS LIGAND PD-L1
Authors: Peter Pan, Alireza Tafazzol, Xianwei Zhang, Yong Duan
Journal: Neuro-Oncology (2018)

Therapies targeting immune checkpoints such as the programmed cell death protein receptor PD1 pathway represent a step forward for treatment of multiple solid cancers such as non-small cell lung cancer, metastatic melanoma, and renal cell carcinoma. Despite promising pre-clinical data, anti-PD1 monoclonal antibody nivolumab failed to reach its primary efficacy endpoint in a recent phase III randomized clinical trial, CheckMate-143. One possible barrier in glioblastoma is poor diffusion of large monoclonal antibodies across the blood-brain barrier. Identification of the amino acid residue hot spots in PD1 to PDL1 binding could help guide future efforts towards a small molecular inhibitor. We investigate the binding free energies involved in PD1-PDL1 complex formation with a molecular dynamics approach, and identify the specific amino acid sites important for PD1-PDL1 complex formation. Binding free energies were calculated by Molecular mechanics / generalized Born hydrophobic solvent accessible surface area (MM-GBSA) calculations. The residues on PD-L1 with the largest binding free energy delta between bound and unbound states include Arg 125, Tyr 123, and Arg 113 with -7.3 kcal/mol, -6.5 kcal/mol, and -4.3 kcal/mol respectively (with smaller contributions from Tyr 56, Met 115, Asp 122, Ala 121, Phe 19, and Ile 54), while those for PD1 are Glu 136, Gln 75, and Ile 134 with -5.9 kcal/mol, -5.3 kcal/mol, and -5.0 kcal/mol respectively (with smaller contributions from Ile 126, Tyr 68, Thr 76, Leu 128, Ala 132, and Asn 74). These residues define the core of the binding interface between PD1 and PD-L1.
CMET-22. INTRATHECAL (IT) TRAZTUZUMAB (T) FOR THE TREATMENT OF LEPTOMENINGEAL METASTASES (LM) IN PATIENTS (PTS) WITH HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2-POSITIVE (HER2+) CANCER: A MULTICENTER PHASE 1/2 STUDY
Authors: Priya Kumthekar, William Gradishar, Nancy Lin, Elena Pentsova, Morris Groves, Suriya Jeyapalan, Michelle Melisko, Sean Grimm, Andrew B. Lassman, Jeffrey Raizer
Journal: Neuro-Oncology (2018)

Pts with HER2+ breast cancer have frequent LM. No current FDA approvals exist. A multicenter phase I/II trial assessing safety and efficacy of IT T in LM pts was conducted. The primary endpoint in phase 2 was response rate (RR). Complete response (CR) required cytologic CR (CCR) + radiographic CR (RCR) + stable clinical function. Partial response (PR) required either CCR with stable/improved imaging and clinical function or RCR + stable cytology + stable/improving clinical functioning. Pts received IT T via an intraventricular Ommaya reservoir. Phase I dosing started at 10 mg, then increasing by 20 mg up to 80mg. Each cycle (C) was 4 weeks with 2x/week treatment in C1, weekly in C2, and every two weeks after C2. Pts were allowed to continue on hormonal agents if systemic disease was controlled at LM development. Concurrent radiation therapy was not allowed, with the exception of localized treatment for pain control. 34 pts were enrolled with 26 in phase 2. The median age was 51 (25–69). IT T was well tolerated with no DLTs seen throughout; determined MTD was 80 mg for phase 2. All pts treated in phase 2 had Her2+ breast cancer, 2 pts in the phase 1 had non-breast histologies. Median cycles completed was 2 (1–22). Median follow up was 9.1 months (0.4–28.9). In phase 2, 5 pts (19.2%) had PR, 13 (50%) had stable disease (SD) and 8 (30.8%) had progressive disease. For phase 2 pts, median PFS pts was 2.4 months (CI 1.0–5.5) and median OS was 12.1 months (CI 4.3–19.6). IT T was tolerated up to a dose of 80mg. Primary endpoint (25% RR) was not met, however 69% of pts showed clinical benefit (SD or better); median OS exceeded historical controls. Future studies are warranted to evaluate IT T in HER2+ LM.
IMMU-24. THE IMPACT OF BRAIN TUMORS ON HEMATOPOIETIC STEM CELL-DERIVED T CELLS
Authors: Bayli DiVita Dean, Brandon Fernandez, Delaney Woodworth, Tyler Wildes, Duane Mitchell, Catherine Flores
Journal: Neuro-Oncology (2018)

The T cell repertoire of brain tumor bearing hosts has been previously described to be skewed to have increased regulatory phenotype relative to healthy hosts (Woroniecka et al 2018). We have found that hematopoietic stem cells (HSCs) isolated from tumor bearing mice are inefficient at engraftment and reconstitution of the hematopoietic compartment, giving rise to less live cells than HSCs derived from healthy controls. We found that CD4+ splenocytes and CD8+ bone marrow-derived cells and splenocytes that arise from HSCs of tumor bearing hosts are polarized towards a terminal memory phenotype relative to HSCs derived from healthy hosts. We believe that this dysregulation in T cell reconstitution is a major player in mounting immune responses against CNS malignancies. Lineage negative HSCs were isolated from GFP transgenic healthy donors or DsRed transgenic tumor-bearing mice and adoptively transferred into C57BL/6 recipient cohort of lethally irradiated mice. HSCs are derived from DsRed or GFP transgenic mice to allow for tracking of HSC-derived populations. One month after transfer, mice are sacrificed and spleen, bone marrow, and blood are harvested and stained for flow cytometry. RESULTS & T cells derived from TB HSCs have a distinct phenotype compared to T cells from healthy HSCs, demonstrating intracranial brain tumors likely have an impact on HSC differentiation outcomes.
Medications With Depression as an Adverse Effect
Authors: Patrick B. M. Burch
Journal: JAMA (2018)

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
CREBBP gene mutations are frequently detected in in situ follicular neoplasia
Authors: Janine Schmidt, Joan Enric Ramis-Zaldivar, Irina Bonzheim, Julia Steinhilber, Inga Müller, Andrea Haake, Shan Chi Yu, Mark Raffeld, Falko Fend, Itziar Salaverria, Reiner Siebert, Elaine S. Jaffe, Leticia Quintanilla-Martinez
Journal: Blood (2018)
INNV-44. GRAM POSITIVE COLONIZATION OF THE OMMAYA RESERVOIR; TREATMENT RECOMMENDATIONS WITH CLINICAL EXAMPLES.
Authors: Christa Seligman, Eva Lu Lee, Sudhakar Tummala, Carlos Kamiya-Matsuoka
Journal: Neuro-Oncology (2018)

Infectious complications of Ommaya reservoirs occur in 3–15% of patients and can lead to removal of the device and other complications. Removal of the device is suboptimal as intrathecal chemotherapy is then delayed or discontinued. Gram positive skin flora, staphylococci and Propionibacterium acnes, are the most common colonizers of the reservoir. Understanding how to treat these bacteria can prevent poor outcomes. Both staphylococci and P. acnes are biofilm-forming bacteria. In implants colonized with P. acnes, a modeling study showed single agent rifampin to have a 36% cure rate. Despite good biofilm penetration, Rifampin’s bactericidal activity is not as effective as when combined with other agents. When combined with daptomycin, the cure rate increased to 63%. We evaluate two cases of P. acnes colonization in the Ommaya reservoir that illustrate effective treatment. Case-1: Ommaya placed in September, 2016 for intrathecal treatment of malignant meningitis with regularly occurring taps. In February 2018, CSF cultures revealed colonization with P. acnes. Patient was asymptomatic with CSF WBC of 0. Patient was treated with IV daptomycin 6mg/kg via PICC line daily for 14 days plus oral rifampin 300mg daily for 14 days. CSF cultures were negative after 7 days of antibiotics. Case-2: Ommaya placed in December, 2017 for intrathecal treatment of malignant meningitis. In February 2018, CSF cultures were positive for P. acnes with elevated CSF WBC and headaches. Patient refused IV antibiotic therapy and was treated only with oral rifampin 300mg daily for 14 days. CSF cultures were negative after 11 days of antibiotics. CSF WBC returned to normal limits; with resolution of headache. We recommend monitoring for colonization of insidious skin flora in patients on long term intrathecal chemotherapy using CSF cultures with every tap. Gram positive colonization can be detected early and treated effectively.
CT scan shortage endangers angina patients, say radiologists
Authors: Jacqui Wise
Journal: BMJ (2018)

At least 56 000 patients with angina in the UK who should have had a computed tomography coronary angiography (CTCA) scan last year missed out because of a shortage of scanners and radiologists, say the Royal College of Radiologists and the British Society of Cardiovascular Imaging.

They warn that underlying heart conditions may be missed if patients presenting with chest pain have their heart function assessed by exercise tests rather than CTCA scans. The National Institute for Health and Care Excellence (NICE) updated its guideline in 2016 to recommend that all patients with chest pain should be investigated using CTCA.1

A Scottish study published this year in the New England Journal of Medicine found that investigating patients with stable chest …
The Global Landscape of Tuberculosis Therapeutics
Authors: Jeffrey A. Tornheim, Kelly E. Dooley
Journal: Annual Review of Medicine (2018)

Tuberculosis (TB) is one of the oldest infections afflicting humans yet remains the number one infectious disease killer worldwide. Despite decades of experience treating this disease, TB regimens require months of multidrug therapy, even for latent infections. There have been important recent advances in treatment options across the spectrum of TB, from latent infection to extensively drug-resistant (XDR) TB disease. In addition, new, potent drugs are emerging out of the development pipeline and are being tested in novel regimens in multiple currently enrolling trials. Shorter, safer regimens for many forms of TB are now available or are in our near-term vision. We review recent advances in TB therapeutics and provide an overview of the upcoming clinical trials landscape that will help define the future of worldwide TB treatment.
Sodium Restriction in Heart Failure: Too Much Uncertainty—Do the Trials
Authors: Clyde W. Yancy
Journal: JAMA Internal Medicine (2018)

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 Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast 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 Internal Medicine journal
The response of cell growth and antioxidant enzymes in hydrogen peroxide mediated DNA damage in human cells
Authors: Chun-Wen Cheng, Tzung-De Lin, Bing-Huei Liu, Tin-Yu Chin, Chin-Yi Lin, Chen-Yang Shen
Journal: Cancer Research (2006)

811  In humans, to maintain genomic integrity against oxidative stress, aerobic cells have evolved a wide array of various mechanisms by which were manifested the induction of antioxidant enzymes and signaling to arrest cell cycle through activation of tumor suppressor genes in sensing DNA damage that were assaulted by reactive oxygen species (ROS). In this study, human kidney HEK293 and breast MCF-7 cell lines, were examined to differentiate the influence of cell growth, cell cycle checkpoints and antioxidant detoxifying enzymes on the response of the cultured cells to oxidative stress. Finding of fluorescent intensity representing DNA strand break was strengthened in COMET assay of H2O2 concentration-dependent relationship than that detected in untreated cells. And, the extent of DNA damage found in HEK293 cells was more significantly sensitive than MCF-7 cells when treated with 200 μM H2O2, 5 min (moment tail length, 39.9±0.8 vs. 35.8±1.9μm, p
Abstract 19974: Semi-automated Quantification of Left Atrial Size Using 3 Beat Averaging Real Time 3D Echocardiography in Patients with Atrial Fibrillation; A Validation Study
Authors: Ran Heo, Geu-Ru Hong, Young-Jin Kim, Jang-Won Son, Peter Chipeta, In-Jeong Cho, Chi Young Shim, Hyuk-Jae Chang, Jong-Won Ha, Namsik Chung
Journal: Circulation (2014)

Introduction: Left atrial (LA) volume has an important prognostic value in patients with atrial fibrillation (AF). However, current recommendation for that is not easily assessable as multi-beat LA...
NCMP-32. OUTCOMES AND PREDICTIVE FACTORS OF RECRANIOTOMY FOR SEVERE COMPLICATIONS FOLLOWING SELECTIVE CRANIOTOMY FOR INTRACRANIAL TUMORS
Authors: Yong Liu, Yan Qu, Qiang Meng, Yang Sun, Bei Liu, Xue Jiang, Hua Zhang, Guodong Gao, Liang Wang
Journal: Neuro-Oncology (2018)

The outcomes of recraniotomies for severe complications following selective craniotomies for intracranial tumors were rarely reported by far. Hence, the objective of this study was to analyze the outcomes and predictive factors of unscheduled recraniotomies. Patients undergoing recraniotomies for complications after selective craniotomies for intracranial tumors from Jan 2014 to Dec 2017 were collected. Primary outcome was KPS (Karnofsky Performance Status) score at discharge. Patients were divided into three groups according to this KPS score: good KPS group with KPS≥70, poor KPS group with KPS≤10, and others were moderate KPS group. Predictive factors included demographics, imaging findings and characteristics of two craniotomies. There were 109 patients included with 39 patients in good KPS group, 39 in moderate KPS group, and 31 in poor KPS group. The rate of poor KPS outcome was 28.4%. Univariate and multivariate regression analysis showed tumor diameter (odds ratio 0.589, P=0.016), reoperative blood loss (odds ratio 0.001, P=0.021), and time interval between two craniotomies (odds ratio 13.680, P=0.000) were positively associated with poor KPS. In contrast, GCS score before recraniotomies (odds ratio -0.713, P=0.004) were positively associated with good KPS. CONCLUSIONS: The major outcome of recraniotomies was good and moderate KPS at discharge. Tumor diameter, reoperative blood loss, and time interval between two craniotomies were positive predictive factors for poor KPS outcome. GCS score before recraniotomies was positive factors for good KPS outcome.