tbuckley/cabot-search huggingface dataset:
EXTH-68. INTRANASAL DELIVERY OF DRUG-LOADED LIPOSOMES SENSITIZES TUMORS TO IRRADIATION IN SYNGENEIC MODEL OF GLIOMA.
Authors: Peng Zhang, Markella Zannikou, Maciej S Lesniak, Irina Balyasnikova
Journal: Neuro-Oncology (2019)

Abstract Tumor-associated myeloid cells (TAMCs) are appealing therapeutic target in glioblastoma (GBM) due to their immunosuppressive function and robust presence in the tumor tissue. We designed a lipid nanoparticle (LNP) modified with anti-PD-L1 antibody (αPD-L1) for targeted delivery to PD-L1 expressing cells within the tumor. We demonstrate that αPD-L1-LNP are effectively and specifically taken up by TAMCs. The encapsulation of dinaciclib, an inhibitor of a cyclin-dependent kinase, into αPD-L1-LNP, leads to a robust depletion of TAMCs upon local delivery. We next investigated the therapeutic relevance of non-invasive intranasal delivery of αPD-L1-LNP drug nano formulation in a GL261 syngeneic model of glioma. We show that intranasal administration of αPD-L1-LNP/dinaciclib alone did not significantly affect the survival of tumor-bearing mice, whereas a regimen combing with fractionated irradiation led to a significantly improved animal survival of mice bearing GL261 glioma over monotherapies. Histological analysis of tissue demonstrated about a four-fold increase in the uptake of nanoparticles within the tumor bed but not in the normal brain in mice treated with fractionated irradiation over the control mice. These results warrant further development and validation of intranasal delivery of therapeutic nanoformulations targeting TAMCs in preclinical animal models to improve the outcome in GBM patients.
Pegaspargase Can Safely be Administered in Adults Age 40 and Older with Acute Lymphoblastic Leukemia
Authors: Ryan J. Daley, Sridevi Rajeeve, Charlene C. Kabel, Jeremy J. Pappacena, Sarah E. Stump, Jessica A. Lavery, Martin S. Tallman, Mark B. Geyer, Jae H. Park
Journal: Blood (2019)
Circulating Plasminogen Activator Inhibitor-1 (PAI-1) Is Reduced By In Vivo Thrombin Generation and Subsequent Formation of Activated Protein C (APC)
Authors: Sara Reda, Franziska Isabelle Winterhagen, Christina Berens, Jens Müller, Johannes Oldenburg, Bernd Pötzsch, Heiko Rühl
Journal: Blood (2019)
Heterogeneity Between Genetic Variants as a Proxy for Pleiotropy in Mendelian Randomization—Reply
Authors: Milad Nazarzadeh, Kazem Rahimi
Journal: JAMA Cardiology (2019)

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 Cardiology 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 Cardiology journal
AL Amyloidosis: The Effects of Maintenance Therapy on Autologous Stem Cell Transplantation Outcomes
Authors: Michael Ozga, Qiuhong Zhao, Don M. Benson, Patrick Elder, Nita Williams, Naresh Bumma, Ashley E. Rosko, Maria Chaudhry, Abdullah Mohammad Khan, Srinivas Devarakonda, Rami Kahwash, Ajay Vallakati, Courtney Campbell, Samir Parikh, Salem Almaani, Jason Prosek, Elyse Redder, Yvonne A. Efebera, Nidhi Sharma
Journal: Blood (2019)
Next-Generation Optical Mapping Reveals Numerous Previously Unrecognizable Structural Variants in Chronic Lymphocytic Leukemia
Authors: Regina Fillerova, Anna Petrackova, Tomas Papajik, Peter Turcsanyi, Marek Behalek, Petr Gajdos, Pavlina Ryznerova, Lenka Kruzova, Helena Urbankova, Jiri Minarik, Eva Kriegova
Journal: Blood (2019)
Heparanase and Chemotherapy Synergize to Drive Macrophage Activation and Enhance Tumor Growth
Authors: Udayan Bhattacharya, Lilach Gutter-Kapon, Tal Kan, Ilanit Boyango, Uri Barash, Shi-Ming Yang, JingJing Liu, Miriam Gross-Cohen, Ralph D. Sanderson, Yuval Shaked, Neta Ilan, Israel Vlodavsky
Journal: Cancer Research (2019)

The emerging role of heparanase in tumor initiation, growth, metastasis, and chemoresistance is well recognized, encouraging the development of heparanase inhibitors as anticancer drugs. Unlike the function of heparanase in cancer cells, little attention has been given to heparanase contributed by cells composing the tumor microenvironment. Here, we focused on the cross-talk between macrophages, chemotherapy, and heparanase and the combined effect on tumor progression. Macrophages were markedly activated by chemotherapeutics paclitaxel and cisplatin, evidenced by increased expression of proinflammatory cytokines, supporting recent studies indicating that chemotherapy may promote rather than suppress tumor regrowth and spread. Strikingly, cytokine induction by chemotherapy was not observed in macrophages isolated from heparanase-knockout mice, suggesting macrophage activation by chemotherapy is heparanase dependent. paclitaxel-treated macrophages enhanced the growth of Lewis lung carcinoma tumors that was attenuated by a CXCR2 inhibitor. Mechanistically, paclitaxel and cisplatin activated methylation of histone H3 on lysine 4 (H3K4) in wild-type but not in heparanase-knockout macrophages. Furthermore, the H3K4 presenter WDR5 functioned as a molecular determinant that mediated cytokine induction by paclitaxel. This epigenetic, heparanase-dependent host-response mechanism adds a new perspective to the tumor-promoting functions of chemotherapy, and offers new treatment modalities to optimize chemotherapeutics. SIGNIFICANCE: Chemotherapy-treated macrophages are activated to produce proinflammatory cytokines, which are blunted in the absence of heparanase.
ATIM-47. NIVOLUMAB VS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA: EXPLORATORY ANALYSIS OF MGMT METHYLATION STATUS AND BASELINE CORTICOSTEROID USE
Authors: Michael Weller, David Reardon, Alba Brandes, John Sampson, Paul Mulholland, Antje Wick, Joachim Baehring, Manmeet Ahluwalia, Patrick Roth, Oliver Bähr, Surasak Phuphanich, Juan Sepulveda, Paul de Souza, Solmaz Sahebjam, Von Potter, Kay Tatsuoka, Corina Taitt, Ricardo Zwirtes, Antonio Omuro, Michael Lim
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Current therapies for recurrent glioblastoma provide limited survival benefit. In the open-label, phase 3 CheckMate 143 study (NCT02017717), although the primary endpoint was not met, the median overall survival (mOS) was comparable between nivolumab (anti–PD-1) and bevacizumab in the overall population of patients with glioblastoma at first recurrence after temozolomide chemoradiotherapy (Reardon et al, WFNOS 2017). Exploratory subgroup analyses were conducted to evaluate the association of O-6-methylguanine DNA methyltransferase (MGMT) promoter methylation status and corticosteroid use at baseline with mOS. METHODS Prespecified patient subgroups included MGMT promoter status (methylated vs unmethylated) and baseline corticosteroid use (yes [within 5 days of first dose] vs no). FINDINGS: Methylation status was available for 102/184 (55%) nivolumab-treated and 109/185 (59%) bevacizumab-treated patients. Using a multivariable Cox proportional hazards model analysis, no baseline corticosteroid use (HR, 0.59 [95% CI, 0.36–0.95]) and methylated MGMT status (HR, 0.47 [95% CI, 0.29–0.78]) were each associated with longer mOS among nivolumab-treated patients. Among patients with methylated MGMT and no baseline corticosteroid use, mOS was 17.0 months with nivolumab (n=31) and 10.1 months with bevacizumab (n=22; HR, 0.58 [95% CI, 0.30–1.11]). In patients with methylated tumors and baseline corticosteroids, mOS was 7.7 months with nivolumab (n=12) and 13.5 months with bevacizumab (n=17). Among patients with unmethylated tumors and no baseline corticosteroids, mOS was 8.3 months with nivolumab (n=30) and 10.3 months with bevacizumab (n=29). In patients with unmethylated tumors and baseline corticosteroids, mOS was 5.6 months with nivolumab (n=28) and 8.3 months with bevacizumab (n=28). CONCLUSION A trend toward longer mOS with nivolumab was observed in a subgroup of patients with methylated MGMT and no baseline corticosteroid use. These findings suggest that MGMT methylation status and corticosteroid use at baseline could be used to identify patients who may benefit from nivolumab and thus warrant further study.
Ifitm3 Is Essential for PI(3,4,5)P3-Dependent B-Cell Activation and Leukemogenesis
Authors: Jaewoong Lee, Gang Xiao, Kadriye Nehir Nehir Cosgun, Huimin Geng, Ning Ma, Lai N Chan, Kohei Kume, Matthew Nix, Zhengshan Chen, Chun-Wei David Chen, Jianjun Chen, Vishal Khairnar, Arun P. Wiita, Andrei Thomas-Tikhonenko, Michael Farzan, Michael S. Diamond, Jae U Jung, Nagarajan Vaidehi, Markus Müschen
Journal: Blood (2019)
Prevalence of Pemphigoid as a Potentially Unrecognized Cause of Pruritus in Nursing Home Residents
Authors: Joost M. Meijer, Aniek Lamberts, Hendrika J. Luijendijk, Gilles F. H. Diercks, Hendri H. Pas, Sytse U. Zuidema, Marcel F. Jonkman
Journal: JAMA Dermatology (2019)

Prevalence of Pemphigoid as a Potentially Unrecognized Cause of Pruritus in Nursing Home ResidentsBullous pemphigoid may commonly present as pruritus in elderly patients. 1Approximately 1 in 5 patients with pemphigoid has nonbullous skin manifestations that resemble other pruritic skin diseases, termed nonbullous pemphigoid. 1,2 According to recently established minimal diagnostic criteria, the diagnosis of bullous and nonbullous pemphigoid can be based on either a skin biopsy or a serum sample. 2 The prevalence of bullous pemphigoid strongly increases with age, and the disease is associated with neurodegenerative diseases such as dementia and Parkinson disease. 3,4 Our aim was to assess the prevalence of pemphigoid in a high-risk population of nursing home residents, with nonbullous pemphigoid as a potentially unrecognized cause of pruritus.
Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction
Authors: Jean-Claude Tardif, Simon Kouz, David D Waters, Olivier F Bertrand, Rafael Diaz, Aldo P Maggioni, Fausto J Pinto, Reda Ibrahim, Habib Gamra, Ghassan S Kiwan, Colin Berry, José López-Sendón, Petr Ostadal, Wolfgang Koenig, Denis Angoulvant, Jean C Grégoire, Marc-André Lavoie, Marie-Pierre Dubé, David Rhainds, Mylène Provencher, Lucie Blondeau, Andreas Orfanos, Philippe L L'Allier, Marie-Claude Guertin, François Roubille
Journal: New England Journal of Medicine (2019)

Experimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis.
GENE-25. GWAS BY MOLECULAR SUBTYPE IDENTIFIED NOVEL RISK LOCI FOR ADULT DIFFUSE GLIOMA
Authors: Jeanette Eckel-Passow, Paul Decker, Matthew Kosel, Thomas Kollmeyer, Annette Molinaro, Terri Rice, Kristen Drucker, Helen Hansen, Lucie McCoy, Paige Bracci, Joseph Wiemels, John Wiencke, Daniel Lachance, Margaret Wrensch, Robert Jenkins
Journal: Neuro-Oncology (2019)

Abstract Genome-wide association studies (GWAS) have revealed that 25 regions in 24 genes are associated with adult diffuse glioma development. These regions were identified by performing GWAS of glioma overall and GWAS by pathology (GBM and nonGBM). Subsequently, these regions have been evaluated for associations with specific molecular subtypes. The 2016 WHO Classification of Tumors of the Central Nervous System utilizes two somatic alterations to molecularly-classify adult diffuse glioma: IDH mutation and 1p/19q codeletion. TERT promoter mutation has also been shown to be associated with age at diagnosis and patient outcome. We hypothesized that germline variants may increase susceptibility to, or interact with, these somatic alterations to accelerate the development of specific molecular subtypes of glioma. To test our hypothesis, we performed a GWAS by glioma molecular subtype – as defined by presence or absence of IDH and TERT somatic mutation and 1p/19q codeletion – utilizing a two-stage design and subsequent meta analysis that included 3001 total glioma cases and 2697 total controls. Data were imputed using the Michigan Server and logistic regression was used, adjusting for age and sex. The Cancer Genome Atlas (TCGA) data were used to perform an expression quantitative trait loci (eQTL) analysis on candidate germline variants. Variants in 2q37 and 7p22 were associated with IDH-mutated glioma (meta analysis p&lt; 5x10-8). The eQTL analyses demonstrated significant associations between 2q37 variants and expression of nearby genes as well as associations between 7p22 variants and nearby genes (p&lt; 0.0001). In conclusion, we identified and validated novel germline variants in two genes that are associated with etiology of IDH-mutated adult diffuse glioma.
Vitamin B<sub>12</sub> Therapy in Older Adults and Misconception of Its Inappropriateness—Reply
Authors: William K. Silverstein, Yulia Lin, Matthew C. Cheung
Journal: JAMA Internal Medicine (2019)

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
PDTM-17. MiR-126, miR-369-5p AND miR-487b DRIVE PEDIATRIC GLIOBLASTOMA INVASION VIA KCNA1
Authors: Yulun Huang, Lin Qi, Mari Kogiso, Yuchen Du, Frank Braun, Huiyuan Zhang, Lei Huang, Wan-yee Teo, Holly Lindsay, Sibo zhao, Patricia Baxter, Jack Su, Adesina Adekunle, Jianhua yang, Sebastian Brabetz, Marcel Kool, Stefan Pfister, Murali Chintagumpala, Williams Parsons, Laszlo Perlaky, Zhong Wang, You-Xin Zhou, Chris Man, Xiao-Nan Li
Journal: Neuro-Oncology (2019)

Abstract Diffuse invasion is one of the key features that make GBM particularly difficult to treat. We hypothesize that direct comparison of matched invasive (GBMINV) and tumor core GBM cells (GBMTC) would facilitate the discovery of drivers of pediatric GBM (pGBM) invasion. However, GBMINV cells are extremely difficult to obtain from normal brain tissues because aggressive surgical resection of normal tissue carries the risk of serious neurological deficits. Most past and current studies on GBM invasion were and are forced to utilize the resected primary tumor masses. To overcome this barrier, we utilized a panel of 6 pediatric patient tumor-derived orthotopic xenograft (PDOX) mouse models to isolate matching pairs of GBMTC cells and GBMINV cells and confirmed a significantly elevated invasive capacity in GBMINV cells both in vitro and in vivo. Global profiling of 768 human microRNA using a real-time PCR-based Taqman system identified 23 microRNAs were upregulated in the GBMINV cells in at least 4 of the 6 pGBM models as compared with the matching GBMTC cells. We subsequently showed that silencing the top three miRNAINV, miR-126, miR-369-5p, and miR-487b, suppressed tumor cell migration in vitro (both as neurospheres and monolayer cultures) without affecting cell proliferation, and blocked pGBM invasion in mouse brains. Integrated analysis of the mRNA profiling of the same set of GBMTC and GBMINV cells revealed the affected signaling pathways and identified KCNA1 as the sole common computational target gene of the three miRNAINV. Treatment of three pairs of GBMTC and GBMINV cells with two KCNA1 inhibitors, ADWX1 and Agitoxin 2, caused significant suppression of pGBM cell migration in vitro. In conclusion, this study revealed an intrinsically elevated invasive phenotype in GBMINV cells, identified miR-126, -369-5p, and -487b as novel drivers of pGBM invasion, and characterized KCNA1 as a potential therapeutic target for arresting pGBM invasion.
A Phase I Study of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody–Drug Conjugate, in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma
Authors: Brad S. Kahl, Mehdi Hamadani, John Radford, Carmelo Carlo-Stella, Paolo Caimi, Erin Reid, Jay M. Feingold, Kirit M. Ardeshna, Melhem Solh, Leonard T. Heffner, David Ungar, Shui He, Joseph Boni, Karin Havenith, Owen A. O'Connor
Journal: Clinical Cancer Research (2019)

ADCT-402 (loncastuximab tesirine) is an antibody-drug conjugate comprising a CD19-targeting antibody and pyrrolobenzodiazepine dimers. A first-in-human study evaluated the safety and preliminary clinical activity of loncastuximab tesirine in patients with B-cell non-Hodgkin lymphoma (NHL).A multicenter, phase I, dose-escalation and dose-expansion study enrolled patients ages ≥18 years with relapsed/refractory (R/R) B-cell NHL. Patients received loncastuximab tesirine every 3 weeks at doses assigned by a 3+3 dose-escalation design. Dose escalation was used to assess the safety and tolerability of loncastuximab tesirine to determine the dose for expansion. Secondary objectives evaluated clinical activity, characterized the pharmacokinetic profile, and evaluated antidrug antibodies.During dose escalation, 88 patients with R/R B-cell NHL were treated with loncastuximab tesirine at doses 15 to 200 μg/kg. Treatment-emergent adverse events (TEAEs) were experienced by 87/88 (98.9%) patients. Most common TEAEs (≥20% of patients) were hematologic abnormalities, fatigue, edema, liver test abnormalities, nausea, rash, and dyspnea. Grade ≥3 TEAEs (≥5% of patients) included hematologic abnormalities, liver test abnormalities, fatigue, and dyspnea. Overall response rate at doses ≥120 μg/kg was 59.4% (41 of 69 patients; 40.6% complete response; 18.8% partial response). Median duration of response, progression-free survival, and overall survival (all doses) were 4.8, 5.5, and 11.6 months, respectively. Drug exposure increased with increasing dose, showing moderate accumulation with multiple doses ≥150 μg/kg. There was no evidence of immunogenicity.Loncastuximab tesirine had promising activity with acceptable safety in this dose-escalation study. A phase II study with initial dosing at 150 μg/kg has been initiated based on these results.
Single Nucleotide Polymorphism Array-Based Signature of Genetic Ploidy Groups in Acute Lymphoblastic Leukemia
Authors: Thomas Creasey, Amir Enshaei, Kathryn Watts, Gavin Cuthbert, Claire Schwab, Christine J. Harrison, Ajay Vora, Adele K. Fielding, Anthony V. Moorman
Journal: Blood (2019)
From cytogenetics to cytogenomics: whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability
Authors: Anna Lindstrand, Jesper Eisfeldt, Maria Pettersson, Claudia M. B. Carvalho, Malin Kvarnung, Giedre Grigelioniene, Britt-Marie Anderlid, Olof Bjerin, Peter Gustavsson, Anna Hammarsjö, Patrik Georgii-Hemming, Erik Iwarsson, Maria Johansson-Soller, Kristina Lagerstedt-Robinson, Agne Lieden, Måns Magnusson, Marcel Martin, Helena Malmgren, Magnus Nordenskjöld, Ameli Norling, Ellika Sahlin, Henrik Stranneheim, Emma Tham, Josephine Wincent, Sofia Ygberg, Anna Wedell, Valtteri Wirta, Ann Nordgren, Johanna Lundin, Daniel Nilsson
Journal: Genome Medicine (2019)

Abstract Background Since different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test. Methods We analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants (CNVs) (cohort 1, n = 68), (ii) individuals referred for monogenic multi-gene panels (cohort 2, n = 156), and (iii) 100 prospective, consecutive cases referred to our center for CMA (cohort 3). Bioinformatic tools developed include FindSV, SVDB, Rhocall, Rhoviz, and vcf2cytosure. Results First, we validated our structural variant (SV)-calling pipeline on cohort 1, consisting of three trisomies and 79 deletions and duplications with a median size of 850 kb (min 500 bp, max 155 Mb). All variants were detected. Second, we utilized the same pipeline in cohort 2 and analyzed with monogenic WGS panels, increasing the diagnostic yield to 8%. Next, cohort 3 was analyzed by both CMA and WGS. The WGS data was processed for large (&gt; 10 kb) SVs genome-wide and for exonic SVs and SNVs in a panel of 887 genes linked to intellectual disability as well as genes matched to patient-specific Human Phenotype Ontology (HPO) phenotypes. This yielded a total of 25 pathogenic variants (SNVs or SVs), of which 12 were detected by CMA as well. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7 . Finally, a case of Prader-Willi syndrome with uniparental disomy (UPD) was validated in the WGS data. Important positional information was obtained in all cohorts. Remarkably, 7% of the analyzed cases harbored complex structural variants, as exemplified by a ring chromosome and two duplications found to be an insertional translocation and part of a cryptic unbalanced translocation, respectively. Conclusion The overall diagnostic rate of 27% was more than doubled compared to clinical microarray (12%). Using WGS, we detected a wide range of SVs with high accuracy. Since the WGS data also allowed for analysis of SNVs, UPD, and STRs, it represents a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.