tbuckley/cabot-search huggingface dataset:
TMOD-33. ESTABLISHMENT AND PRELIMINARY EVALUATION OF BEVACIZUMAB-RESISTANT GLIOMA XENOGRAFT MODELS
Authors: Stephen Keir, Matthew Waitkus, Martin Roskoski, Henry Friedman, Darell Bigner, Hai Yan, David Ashley
Journal: Neuro-Oncology (2018)

High-grade gliomas characteristically exhibit aberrant neovascularization which is thought to play an important role in GBM progression. One of the main drivers of angiogenesis in GBM is vascular endothelial growth factor A (VEGF-A), which binds to VEGF receptors on endothelial cells and stimulates neovascularization and vascular permeability. For these reasons, VEGF-A mediated signaling is an attractive target for developing anti-angiogenic therapies for GBM. Clinical trials in GBM patients have shown that treatment with bevacizumab, a humanized anti-VEGF-A antibody, is associated with improvements in radiographic response, progression-free survival and quality of life. Despite these benefits, patients inevitably develop resistance and frequently fail to demonstrate significantly better overall survival. A critical issue in GBM research is to develop a better understanding of mechanisms of resistance to VEGF-targeted therapies and their clinical importance in GBM relapse. To address this question, we established two patient derived xenograft (PDX) lines from which bevacizumab-resistant sub-lines were generated by prolonged treatment over serial passages. Parental lines were generated from tumor tissue acquired at the time of tumor resection originating from newly diagnosed, untreated patients and subcutaneously engrafted in athymic mice. Tumors from initial subcutaneous parental PDXs were then serially treated with bevacizumab (5mg/kg, IP twice weekly, 5 weeks) and passed until resistance was obtained. Sensitivity to bevacizumab was reduced by 54–87% and 52–90% in subcutaneous and intracranial models respectively. Treatment with a panel of standard of care therapies are currently underway to identify differences in response rates between parental and bevacizumab-resistant PDX models. Furthermore, studies are ongoing to characterize differences in mutational profiles, gene expression signatures, and cytokine production between bevacizumab sensitive and resistant PDX lines. Results from these studies will be used to investigate novel therapeutic combinations aimed at overcoming resistance to chemotherapies and anti-angiogenic agents in GBM.
TMIC-38. ENHANCED EFFICACY OF TUMOR TREATING FIELDS AND AURORA B KINASE INHIBITOR COMBINATION IN GLIOMA CELL LINES
Authors: Dietmar Krex, Paula Bartmann, Achim Temme, Rosa S Schneiderman, Tali Voloshin, Moshe Giladi, Adrian Kinzel, Eilon Kirson, Yoram Plati
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) are anti-mitotic, low intensity, intermediate frequency, alternating electric fields approved for glioblastoma. The efficiency of TTFields may be enhanced by drugs that extend metaphase-anaphase transition and telophase such as Aurora B kinase. We studied if TTFields’ effect on tumor cells is enhanced by additional inhibition of cytokinesis through Aurora B kinase. TTFields and Aurora B kinase inhibitors (AZD1152) combination was tested in glioma cell lines: in U87-MG, U87-MGshP53 and U-251, and U87-MG, first and then in two primary glioblastoma cell lines (HT16360, HT18503). TTFields (1.6 V/cm RMS, 200 kHz) were applied for 72 hours using the inovitro system. AZD1152 was added up to 100 nmol/L. Cell counts, cell cycle and clonogenic potential were determined. Multinuclear cells formation was determined using crystal violet staining. TTFields and AZD1152 combination led to a significant reduction in the number of U251, U-87 MG and U-87 MGshP53 cells (2-way ANOVA, pshP53 and U-251 cells (2-way ANOVA, pshP53 cells stained with crystal violet after treatment revealed high prevalence of multi nuclear cells in cells exposed to TTFields and AZD1152 (25nM) versus AZD1152 (25nM) alone. Cells treated with TTFields and higher doses of AZD1152 (50-100nM) demonstrated increased rates of pyknosis. Data could be confirmed in primary tumor-cell lines. These results demonstrate that combining TTFields and AZD1152 can be an effective treatment in glioma. There is a strong rational to continue exploring the potential of combining TTFields and AZD1152 in the clinical settings.
PLK1: a promising and previously unexplored target in double-hit lymphoma
Authors: Quais N. Hassan, Lapo Alinari, John C. Byrd
Journal: Journal of Clinical Investigation (2018)

Inhibitors that target specific kinases or oncoproteins have become popular additions to or replacements for cytotoxic chemotherapies to treat many different types of cancer. However, many tumors lack a discernable target kinase and an amplified oncoprotein and/or rely on several cooperating mechanisms for progression. Thus, combinations of targeted therapies are essential for treating many cancers to avoid the rapid emergence of resistance. In this issue of the JCI, Ren et al. use an elegant kinase activity–profiling method and identify activity of the oncogene polo-like kinase-1 (PLK1) as an important driver of double-hit lymphoma (DHL), an aggressive subgroup of B cell lymphoma characterized by chromosomal translocations involving c-MYC and BCL2 or BCL6. Moreover, PLK1 activity was associated with MYC expression and poor prognosis in DHL patients. PLK1 inhibition with volasertib, alone and in combination with the BCL-2 inhibitor venetoclax, was efficacious in multiple DHL models, including mice harboring DHL patient–derived xenografts. Together, these data support PLK1 as a promising prognostic marker and therapeutic target for DHL.
Abstract 14327: Kir2.1 Channels Settle Two Levels of Resting Membrane Potential With Inward Rectification
Authors: Dongchuan Zuo, Kuihao Chen, Zheng Liu, Haijun Chen
Journal: Circulation (2017)

Introduction: Inward rectifier Kir2.1 channels primarily maintain resting membrane potential. Human cardiomyocytes and cardiac Purkinje fibers exhibit a similar phenomenon of the two levels of resting membrane potential in pathological hypokalemia, which is associated with cardiac arrhythmia. We recently demonstrated that Kir2.1 and K2P1 currents partially account for the phenomenon in human cardiomyocytes. However, the mechanism of how Kir2.1 channels similarly settle the two levels of resting membrane potential in various types of cardiac cells that may express different inward cation currents is not well understood. Hypothesis: we hypothesize that Kir2.1 channels settle two levels of resting membrane potential through a common mechanism by non-linear balances of various opposing cation currents. Methods: We employed conventional electrophysiological techniques to record membrane potentials and whole-cell currents in either CHO cells or human iPSC-derived cardiomyocytes that engineered to express indica...
Clinical Decision Support in the Era of Artificial Intelligence
Authors: Edward H. Shortliffe, Martin J. Sepúlveda
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
RARE-40. PERSONALIZED MEDICINE DIAGNOSIS AND RESPONSE TO TREATMENT WITH BRAF MEK INHIBITION IN A PLEOMORPHIC XANTHOASTROCYTOMA PATIENT
Authors: Yolanda Pina, Robert Macaulay, Christine Walko, Brittany Evernden, Peter Forsyth
Journal: Neuro-Oncology (2018)

To highlight personalized medicine in a patient with a brafmt Pleomorphic Xanthoastrocytoma (PXA) treated with Braf-MEKi. PXA is a rare low-grade astrocytoma. Rarely (as in this patient) may be malignant, accounting for less than 1% of all CNS neoplasms. BRAF-V600E mutation is usually found in PXA. Clinical trials showed BRAF tyrosine-kinase inhibitors as viable options to treat metastatic brain melanoma tumors. Recent studies showed similar therapy efficacy in primary brain tumors with BRAF mutations. Other studies suggest that brain tumors with BRAF-V600E mutation that fail BRAF inhibitors can benefit from chloroquine, an autophagy inhibitor, by overcoming the resistance of the kinase inhibitors. CASE REPORT: A 20 year-old man presented with a headache. MRI showed a large lesion, which appeared unusual for a classical Glioblastoma Multiforme (GBM). He was diagnosed with “GBM” and treated with radiation/temozolomide. Follow-up imaging showed recurrence. Histology at Moffitt showed an atypical malignant glioma that resembled PXA. Molecular testing demonstrated a BRAF-V600E mutation. Based on this, targeted therapy to inhibit Braf/Mek with Dabrafenib/Trametinib was initiated. Subsequent MRI showed decrease lesion size. After eight-months, he was given a chemotherapy holiday; however, repeat imaging showed disease progression and treatment was re-started. His disease progressed months later, and chloroquine was added to chemotherapy. Follow-up imaging showed tumor remained stable, suggesting addition of chloroquine to Dabrafenib/Trametinib halted tumor progression. Patient remains under surveillance. A molecular diagnosis of PXA was made guiding targeted therapy. Molecular testing provides new avenues of diagnosis and treatment for NeuroOncology patients. Molecular interrogation should be routine for all NeuroOncology patients who are young or with unusual tumors. Addition of chloroquine overcame resistance to BRAF inhibition in this patient with a brain tumor with BRAF-V600E mutation.
Schizophrenia Polygenic Risk Score as a Predictor of Antipsychotic Efficacy in First-Episode Psychosis
Authors: Jian-Ping Zhang, Delbert Robinson, Jin Yu, Juan Gallego, W. Wolfgang Fleischhacker, Rene S. Kahn, Benedicto Crespo-Facorro, Javier Vazquez-Bourgon, John M. Kane, Anil K. Malhotra, Todd Lencz
Journal: American Journal of Psychiatry (2018)

Objective: Pharmacogenomic studies of antipsychotics have typically examined effects of individual polymorphisms. By contrast, polygenic risk scores (PRSs) derived from genome-wide association studies (GWAS) can quantify the influence of thousands of common alleles of small effect in a single measure. The authors examined whether PRSs for schizophrenia were predictive of antipsychotic efficacy in four independent cohorts of patients with first-episode psychosis (total N=510). Method: All study subjects received initial treatment with antipsychotic medication for first-episode psychosis, and all were genotyped on standard single-nucleotide polymorphism (SNP) arrays imputed to the 1000 Genomes Project reference panel. PRS was computed based on the results of the large-scale schizophrenia GWAS reported by the Psychiatric Genomics Consortium. Symptoms were measured by using total symptom rating scales at baseline and at week 12 or at the last follow-up visit before dropout. Results: In the discovery cohort, higher PRS significantly predicted higher symptom scores at the 12-week follow-up (controlling for baseline symptoms, sex, age, and ethnicity). The PRS threshold set at a p value <0.01 gave the strongest result in the discovery cohort and was used to replicate the findings in the other three cohorts. Higher PRS significantly predicted greater posttreatment symptoms in the combined replication analysis and was individually significant in two of the three replication cohorts. Across the four cohorts, PRS was significantly predictive of adjusted 12-week symptom scores (pooled partial r=0.18; 3.24% of variance explained). Patients with low PRS were more likely to be treatment responders than patients with high PRS (odds ratio=1.91 in the two Caucasian samples). Conclusions: Patients with higher PRS for schizophrenia tended to have less improvement with antipsychotic drug treatment. PRS burden may have potential utility as a prognostic biomarker.
IMMU-69. PROGNOSTIC IMPLICATION OF B-CELL INFILTRATE IN PATIENTS WITH GLIOBLASTOMA (GBM)
Authors: Ileana Mauldin, Jasmin Jo, Loren Erickson, Nolan Wages, Craig Slingluff, M Beatriz Lopes, Camilo E Fadul
Journal: Neuro-Oncology (2018)

One of the purported reasons of ineffectiveness of immunotherapy for GBM is the meager immune response in the tumor microenvironment. We have observed that GBM can harbor dense B-cell infiltrate, but their prevalence and function is unknown. Pre-clinical studies have shown that B-cells can act as antigen-presenting cells which can stimulate T-cell proliferation; however, B-cells can also downregulate effector T-cells by secreting immunosuppressive cytokines including IL-10. Our study aims to determine the roles of B-cells in GBM and their association with patient outcomes. Multiplexed immunohistochemistry, imaging and quantitation was performed on primary GBM samples obtained between 1/2008-8/2015. Intratumoral CD20+B-cells and CD8+T-cells infiltrate were enumerated from 3 serial GBM sections. Relevant prognostic clinical and molecular variables were reviewed. We also analyzed the association of MS4A1 gene encoding B-cell antigen CD20 with survival from the TCGA. We observed an average infiltrate of 5.5 CD20+ cells/mm2and 36.7 CD8+cells/mm2tumor. B-cells were stratified into CD20low(12 patients) and CD20highgroups (36 patients) with 0.24 B-cells/mm2 cut off. Kaplan-Meier analyses indicated that the CD20lowgroup had better overall survival (OS) than the CD20highcohort (31.7 versus 18.7 months; p=0.02), while a trend toward improved survival was observed with high CD8+T-cell infiltration (p=0.06). Cox proportional hazard demonstrated an association between decreased OS and CD20highcohort (HR=2.8, p=0.03), but no significance seen between CD8+infiltration and OS (p=0.16). A positive correlation was detected between CD8+and CD20+density (p Our results suggest that B-cell infiltrate carries an inverse correlation with survival. We hypothesize that CD20+B-cells may be regulatory B-cells, limiting immune activation in GBM. Further studies are underway to understand the role of B-cells in the GBM microenvironment.
ACTR-50. EFFECT OF CONCURRENT AND ADJUVANT TEMOZOLOMIDE ON SURVIVAL IN PATIENTS WITH NEWLY DIAGNOSED GRADE III GLIOMAS WITHOUT 1p/19q CO-DELETION: A RANDOMIZED, OPEN-LABEL, PHASE 2 STUDY (INTERIM RESULTS FROM THE KNOG-1101 STUDY)
Authors: Chae-Yong Kim, Kihwan Hwang, Tae Min Kim, Chul-Kee Park, Jong Hee Chang, Tae-Young Jung, Dong-Eun Lee, Jungnam Joo, Ghee Young Choe, Yu Jung Kim, Byung Se Choi, Jeong Hoon Kim
Journal: Neuro-Oncology (2018)

OBJECTIVE: We investigated the efficacy between radiotherapy alone versus concurrent chemoradiotherapy with temozolomide followed by adjuvant temozolomide in Korean adult patients with newly diagnosed non-co-deleted grade III gliomas. This was a randomized, open-label, phase 2 study, and the first multicenter, prospective clinical trial for Korean patients with glioma. Eligible patients were aged 18 years or older and had newly diagnosed grade III gliomas with ECOG performance status of 0–2. No co-deletion of chromosome 1p/19q and further genetic biomarker was identified for available subjects. Patients were enrolled at 11 centers, and randomized 1:1 to receive radiotherapy alone (daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) [Control group (n=44)], or to receive radiotherapy with daily temozolomide (75 mg/m2/day, 7 days/week from the first to the last day of radiotherapy) followed by six cycles of adjuvant temozolomide (150 to 200 mg/m2/day for 5 days during each 28-day cycle) [Treatment group (n=40)]. The primary endpoint was 2-year progression-free survival (PFS). At the time of the preliminary analysis, PFS at 2 years was 42.2% with treatment group and 37.2% with control group. On univariable analysis, extent of tumor resection, age, and IDH-1 mutant were significantly associated with PFS. On multivariable analysis, IDH-1 mutant was the only significant prognostic factor for PFS (HR0.27; 95% CI, 0.12–0.59; p=0.001). IDH-1 mutant was also the only independent prognostic factors for overall survival (HR0.10; 95% CI, 0.02–0.41; p=0.002). Adverse events over grade 3 were seen in 16 (40.0%) patients with Treatment group, but were mild and reversible. Radiotherapy with concurrent and adjuvant temozolomide in patients with newly diagnosed non-co-deleted anaplastic gliomas in Korean adults trended toward improved 2-year PFS. The survival benefit of this regimen would need further analysis for long-term follow-up.
Rapid Self-Assembly of Bioengineered Cardiovascular Bypass Grafts From Scaffold-Stabilized, Tubular Bilevel Cell Sheets
Authors: Daniel von Bornstädt, Hanjay Wang, Michael J. Paulsen, Andrew B. Goldstone, Anahita Eskandari, Akshara Thakore, Lyndsay Stapleton, Amanda N. Steele, Vi N. Truong, Kevin Jaatinen, Camille Hironaka, Y. Joseph Woo
Journal: Circulation (2018)

Background: Cardiovascular bypass grafting is an essential treatment for complex cases of atherosclerotic disease. Because the availability of autologous arterial and venous conduits is patient-limited, self-assembled cell-only grafts have been developed to serve as functional conduits with off-the-shelf availability. The unacceptably long production time required to generate these conduits, however, currently limits their clinical utility. Here, we introduce a novel technique to significantly accelerate the production process of self-assembled engineered vascular conduits. Methods: Human aortic smooth muscle cells and skin fibroblasts were used to construct bilevel cell sheets. Cell sheets were wrapped around a 22.5-gauge Angiocath needle to form tubular vessel constructs. A thin, flexible membrane of clinically approved biodegradable tissue glue (Dermabond Advanced) served as a temporary, external scaffold, allowing immediate perfusion and endothelialization of the vessel construct in a bioreactor. Subsequently, the matured vascular conduits were used as femoral artery interposition grafts in rats (n=20). Burst pressure, vasoreactivity, flow dynamics, perfusion, graft patency, and histological structure were assessed. Results: Compared with engineered vascular conduits formed without external stabilization, glue membrane–stabilized conduits reached maturity in the bioreactor in one-fifth the time. After only 2 weeks of perfusion, the matured conduits exhibited flow dynamics similar to that of control arteries, as well as physiological responses to vasoconstricting and vasodilating drugs. The matured conduits had burst pressures exceeding 500 mm Hg and had sufficient mechanical stability for surgical anastomoses. The patency rate of implanted conduits at 8 weeks was 100%, with flow rate and hind-limb perfusion similar to those of sham controls. Grafts explanted after 8 weeks showed a histological structure resembling that of typical arteries, including intima, media, adventitia, and internal and external elastic membrane layers. Conclusions: Our technique reduces the production time of self-assembled, cell sheet–derived engineered vascular conduits to 2 weeks, thereby permitting their use as bypass grafts within the clinical time window for elective cardiovascular surgery. Furthermore, our method uses only clinically approved materials and can be adapted to various cell sources, simplifying the path toward future clinical translation.
TMOD-19. MUTANT IDH1 PROMOTES GLIOMA FORMATION IN VIVO
Authors: Diana Yu, Ryan Boekholder, Matthew VanBrocklin, Joshua Sonnen, Howard Colman, Sheri Holmen
Journal: Neuro-Oncology (2018)

Gliomas are the most common primary central nervous system tumor but the molecular mechanisms responsible for their development and progression are not completely understood. Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated gene in grade II-III glioma and secondary glioblastoma (GBM) but functional validation of this alteration has been hampered by difficulties generating autochthonous mouse models harboring mutant IDH. In this study, we used the RCAS/TVA glioma mouse model to assess the role of IDH1R132H in glioma development in the context of clinically-relevant cooperating genetic alterations in vitro and in vivo. Immortal Cdkn2a, Pten, and Atrx-deficient astrocytes expressing IDH1R132H exhibited elevated (R)-2-hydroxyglutarate (2-HG) levels, reduced NADPH, increased proliferation, and anchorage-independent growth. Cell proliferation and soft agar growth was significantly enhanced by co-expression of PDGFA. Substitution of IDH1R132H with a cell membrane-permeable [tri-fluoromethyl benzyl (TFMB)-esterified] version of (R)-2HG mimicked the phenotype observed in cells expressing IDH1R132H. Interestingly, addition of TFMB-(R)-2HG further enhanced colony formation in cells expressing IDH1R132H while treatment with the mutant IDH1 inhibitor AG-120 reduced anchorage independent growth. These data suggest that the effects of IDH1R132H are mediated by 2-HG and not loss of native IDH1 activity. Although not sufficient on its own, IDH1R132H cooperated with PDGFA and loss of Cdkn2a, Atrx, and Pten to promote glioma development in vivo. These tumors resembled proneural human mutant IDH1 GBM genetically, histologically, and functionally. Our findings support the hypothesis that IDH1R132H promotes glioma development through production of 2-HG. This model validates a role for IDH1R132H in glioma development, permits mechanistic studies that further our understanding of oncogenesis in this context, and enables rapid testing of rationale therapeutic strategies designed to combat this deadly disease.
Endoscopic exchange of a lumen-apposing metal stent after endoscopic ultrasound-guided gastroenterostomy in severe acute pancreatitis
Authors: Wei Wang, Ke Qi, Zhendong Jin, Zhaoshen Li
Journal: Endoscopy (2018)

Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) has been an effective and safe alternative to surgery for the palliation of symptoms of gastric outlet obstruction (GOO) due to benign or malignant conditions [1] [2] [3]. The lumen-apposing metal stent (LAMS) is a necessary device for EUS-GE because of its anti-migration role and long-term patency [4]. However, there is no clear in vivo evidence of the duration of LAMS efficacy. There is still no evidence on when the LAMS should be exchanged especially when used in benign GOO. We report a case of endoscopic exchange of LAMS after EUS-GE in severe acute pancreatitis.