tbuckley/cabot-search huggingface dataset:
Complementary Activation of Ccnd, MYC, RAS and NFkB By Mutations in Multiple Myeloma
Authors: Kristine Misund, Niamh Keane, Yan W Asmann, Scott Van Wier, Daniel Riggs, Gregory Ahmann, Marta Chesi, K. Martin Körtum, Rafael Fonseca, A. Keith Stewart, Esteban Braggio, P. Leif Bergsagel
Journal: Blood (2016)
Hepatitis B Virus Reactivation Associated With Direct-Acting Antiviral Therapy for Chronic Hepatitis C Virus: A Review of Cases Reported to the U.S. Food and Drug Administration Adverse Event Reporting System
Authors: Susan J. Bersoff-Matcha, Kelly Cao, Mihaela Jason, Adebola Ajao, S. Christopher Jones, Tamra Meyer, Allen Brinker
Journal: Annals of Internal Medicine (2017)

Direct-acting antiviral agents (DAAs) are used increasingly to treat hepatitis C virus (HCV) infection. Reports were published recently on hepatitis B virus (HBV) reactivation (HBV-R) in patients with HBV-HCV co-infection. Hepatitis B virus reactivation, defined as an abrupt increase in HBV replication in patients with inactive or resolved HBV infection, may result in clinically significant hepatitis.To assess whether HBV-R is a safety concern in patients receiving HCV DAAs.Descriptive case series.U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).29 patients with HBV-R receiving HCV DAAs.Clinical and laboratory data.The FDA identified 29 unique reports of HBV-R in patients receiving DAAs from 22 November 2013 to 15 October 2016. Two cases resulted in death and 1 case in liver transplantation. Patients in whom HBV-R developed were heterogeneous regarding HCV genotype, DAAs received, and baseline HBV characteristics. At baseline, 9 patients had a detectable HBV viral load, 7 had positive results on hepatitis B surface antigen (HBsAg) testing and had an undetectable HBV viral load, and 3 had negative results on HBsAg testing and had an undetectable HBV viral load. For the remaining 10 patients, data points were not reported or the data were uninterpretable. Despite provider knowledge of baseline HBV, HBV-R diagnosis and treatment were delayed in 7 cases and possibly 7 others.The quality of information varied among reports. Because reporting is voluntary, HBV-R associated with DAAs likely is underreported.Hepatitis B virus reactivation is a newly identified safety concern in patients with HBV-HCV co-infection treated with DAAs. Patients with a history of HBV require clinical monitoring while receiving DAA therapy. Studies would help determine the risk factors for HBV-R, define monitoring frequency, and identify patients who may benefit from HBV prophylaxis and treatment. DAAs remain a safe and highly effective treatment for the management of HCV infection.None.
Abstract 19: Microrna-19b Enhances Cardiac Cell Survival After Ischemic Injury
Authors: Bas Molenaar, Charlotte Demkes, Hester Ruiter, de, Danielle Versteeg, Monika Gladka-de Vries, Ricardo Korporaal, Else Deel, van, Hillary M Semus, Eva van Rooij
Journal: Circulation Research (2015)

Ischemia/reperfusion (I/R) injury in cardiac tissue results in substantial loss of cardiomyocytes, leading to a functional decline. The release of several cytokines increases cardiomyocyte survival after ischemic injury by activating the janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway. However, this pathway is inhibited by Suppressor of cytokine signaling (SOCS)1 and SOCS3, which act as endogenous negative regulators of cardiomyocyte survival by blocking JAK activity. MicroRNAs (miRNAs) are small, non-coding RNAs that can repress gene expression by binding to recognition sequences within target genes. In a bioinformatic screen, we identified conserved binding sites in SOCS1 and 3 for miR-19b. Using a luciferase reporter assay, we were able to confirm direct binding of miR-19b to the 3’-UTR of both SOCS1 and 3 in vitro . In addition, we found that miR-19b downregulates SOCS1 in cardiac-like cells and isolated neonatal cardiomyocytes. In vivo , we observed a downregulation of miR-19b in both rodent and human cardiac tissues after ischemic injury, which corresponds to an upregulation of both SOCS1 and 3. Since inhibition of SOCS1 and 3 could enhance cardiac JAK-STAT signaling, miRNA-based inhibition could lead to an increase in cardiomyocyte survival. Here we show that cardiomyocyte-specific overexpression of miR-19b lowers SOCS1 and SOCS3 expression and enhances JAK-STAT signaling during ischemia reperfusion, which corresponds to a decrease in the pro-apoptotic proteins Bad, Bax and P53. Additional genes that are decreased by miR-19b during ischemic injury are Rnf11 and TNFAIP3, both repressors NF-kB signaling. To further explore the cardioprotective effects of miR-19b, we are currently investigating the therapeutic benefits of administering synthetic miR-19b mimics through intracardiac injection after I/R injury in mice. Our study indicates a conserved mechanism by which miR-19b targets both SOCS1 and 3 and to increase the activation of JAK/STAT signaling to decrease cardiomyocyte apoptosis. Administration of miR-19b mimics might be of therapeutic interest to enhance cardiomyocyte cells survival and preserve heart function in the setting of ischemic injury.
A phase I study of axitinib (AG-013736), a potent inhibitor of VEGFRs, in combination with gemcitabine (GEM) in patients (pts) with advanced pancreatic cancer
Authors: J. Spano, M. Moore, S. Kim, K. F. Liau, B. Hee, P. Bycott, P. Boissaye, S. Francis, D. Peters, O. Rixe
Journal: Journal of Clinical Oncology (2006)

13092 Background: Axitinib (AG-013736) is a novel small molecule inhibitor of the receptor tyrosine kinases with picomolar potency against VEGFR 1, 2 &amp; 3 and nanomolar potency against PDGFR-beta and KIT. A phase I study in solid tumors identified 5 mg BID as the therapeutic dose; a phase II study in renal cell cancer demonstrated significant efficacy with a response rate (RR) of 46% (Rini et al, ASCO 2005). This study examined the safety, PK and preliminary efficacy of AG-013736 (AG) in combination with gemcitabine (GEM) as first-line therapy for advanced pancreatic cancer. Methods: A randomized phase II study was preceded by a phase I component. All patients (pts) in the phase I portion received 1000 mg/m 2 GEM by 30-minute infusion on days 1, 8, and 15 followed by one week of rest from treatment. AG 5 mg p.o. BID was given beginning Cycle 1, Day 3 (C1D3). Eligible pts had no prior chemotherapy for advanced disease, ECOG 0–2, and no previous treatment with VEGF/VEGFR inhibitors, or anti-angiogenesis treatment. Full PK profiles were collected on C1D1 (GEM alone), C1D14 (steady state, AG alone), and C1D15 (GEM + AG). In the phase II trial, pts are randomized to AG or AG plus GEM beginning C1D1. Results: 8 pts were treated on the phase I portion of this trial. Toxicity: The primary Gr. 3/4 toxicity was hematologic: Gr. 4 anemia and Gr.3 thrombocytopenia in 1 pt and Gr. 3 neutropenia in 1 pt requiring a dose reduction for GEM in Cycle 3. Gr. 2 non-hematologic adverse events include pruritus (1 pt), abdominal pain (2 pts), epigastric pain (1 pt), melena (1 pt), and asthenia (2 pts). Gr. 2 hypertension was observed in 3 pts. Efficacy: Radiological assessment suggests 2 pts with partial response and 4 pts with stable disease: response assessments are ongoing. The median number of cycles is 3 [1,6]. Treatment for 4 pts is still ongoing: Cycle 6 (2 pts) and Cycle 2 (2 pts). Conclusions: This combination is safe and appears to be an effective treatment for advanced pancreatic cancer with significant tumor regression observed in 2 pts. Therapy was well tolerated with manageable toxicity. Additional investigation of AG-013736 in combination with GEM in the phase II setting for advanced pancreatic cancer is warranted. [Table: see text]
MUC1-C Inhibition Leads to Decrease in PD-L1 Levels Via up-Regulation of Micro RNAs
Authors: Athalia Rachel Pyzer, Dina Stroopinsky, Jacalyn Rosenblatt, Eleni Anastasiadou, Hasan Rajabi, Abigail J. Washington, Ashujit Tagde, Maxwell Douglas Coll, Leandra Cole, Kristen Anna Palmer, Poorvi Somaiya, Rebecca Karp Leaf, Myrna R. Nahas, Arie Apel, Salvia Jain, Robin Joyce, Jon Arnason, Frank Slack, Donald Küfe, David E. Avigan
Journal: Blood (2016)
P03.15 Detection of 1p19q co-deletion in oligodendrogliomas with droplet digital PCR
Authors: M. Lysiak, K. Radke, A. Malmström, O. Jönsson, A. L. Hallbeck, C. Bratthäll, M. Strandeus, P. Milos, M. Hallbeck, P. Söderkvist
Journal: Neuro-Oncology (2017)

Introduction: Complete 1p19q co-deletion is a molecular marker with favorable prognostic and predictive value in oligodendrogliomas (ODG) and is together with mutations in IDH1/2 the most abundant alteration. Moreover, the new WHO classification of tumors of the central nervous system emphasizes the importance of molecular testing for diagnostic purposes. The most commonly used methods for detection of 1p19q co-deletion are FISH, MLPA or microsatellite analysis. All are burdened with some flaws, for instance susceptibility to subjective evaluation, complicated analysis or necessity of parallel testing of blood samples. We propose a new method which uses droplet digital PCR (ddPCR) technology characterized by very high sensitivity and specificity. Materials and Methods: Tumors from Linköping University Hospital, by the neuro-pathologist diagnosed as being of oligodendroglial differentiation, were analyzed. Using the ddPCR approach and copy number variation analysis in regard to a reference gene with stable 2 copies, we analyzed 8 selected genes distributed along the chromosomal arms 1p and 19q (TP73, CDKN2C, FUBP1, LRIG2 on 1p and NLRP9, ERCC1, CEBPA, CCNE1 on 19q). For complete loss of both arms, deletion of all gene markers had to be stated. Sanger sequencing and pyrosequencing were used for IDH1/2 mutation detection. Survival was calculated from date of first surgery. Results: Eighty four ODGs collected between 2000 and 2013 and histologically reviewed as ODG grade II-IV (28 ODGs grade II, 50- grade III, 5- grade IV and 1 oligoastrocytoma) were analyzed for 1p19q co-deletion and IDH1/2 mutation. 55% of patients were male and the median age was 57 years. In 35 samples (42%) complete co-deletion of chromosomal arms 1p and 19q was found. In 20 cases (24%) no chromosomal arm was completely deleted, however local deletions of genes were present. Deletion of 1p only was observed in one sample and only 19q loss was found in 28 samples (33%). In 47 (56%) tumors mutations in IDH1 or IDH2 were detected and 24 of the 35 (69%) patients with co-deleted tumor were IDH mutated. Kaplan-Meier analysis showed significantly longer survival for patients with co-deletion (77 vs. 41 months, p=0.000) and those with mutated IDH (92 vs. 29 months). In the multivariate analysis co-deletion, IDH mutation and age were independent factors influencing survival (HR=0.502, CI=0.255–0.987, p=0.046, HR=0.184, CI=0.084–0.404, p=0.000 and HR=1.069, CI=1.043–1.096, p=0.000, respectively). Conclusions: The ddPCR based method provides a good alternative for 1p19q co-deletion detection. It can be successfully used on FFPE samples, it is relatively fast, with short hands-on time requirement, simple analysis, high sensitivity and specificity. We could confirm that survival of ODG patients depends on co-deletion of 1p/19q, presence of IDH mutations and age at diagnosis, as has been shown previously.
P08.44 Preoperative serum microRNA profiles as a diagnostic tool in glioma.
Authors: A. Morokoff, I. Bennett, L. Paradiso, R. Luwor, R. Koldej, J. Li, C. Ma, K. Drummond, A. Kaye, T. Siegal
Journal: Neuro-Oncology (2017)

Introduction: Current diagnosis of glioma is based on clinical suspicion, magnetic resonance imaging (MRI) and surgical biopsy based on WHO criteria for neuropathology. Blood sampling for circulating assessment of biomarkers is a potentially valuable method that could add to diagnostic and prognostic accuracy. We previously showed that miR-10b and miR-21 were significantly upregulated in high-grade glioma patients compared to healthy controls. We hypothesized that large-scale miRNA profiling could improve diagnostic discrimination across all grades of glioma. Materials and Methods: Pre-operative serum samples from 91 glioma patients (45 GBM, 46 Low Grade Glioma, LGG) from the Royal Melbourne and Melbourne Private Hospitals between 2009 and 2013 were included in the cohort and compared to 20 healthy controls. miRNA profiling was performed by Nanostring v.3 analysis of isolated total serum RNA. Statistical output was generated using nSolver and R packages. Results: miR-320e, miR-16-5p and miR-223-3p differed significantly between GBM, LGG and healthy controls. Highly differentially expressed serum miRs in GBM vs LGG included miR-520f-3p, miR-223-3p and miR-150-5p and these were also associated with overall survival. A 9-miRNA gene classifier incorporating miRs with p<0.01 and log-fold change >0.5 in either direction was able to discriminate between GBM and LGG. Conclusions: Profiling of miRNA expression levels in serum shows promise for discovery of diagnostic and prognostic circulating biomarkers in glioma. These preliminary results require validation in prospective data sets including sequential post-operative serum samples.
Mark Arnold Wainberg
Authors: Barbara Kermode-Scott
Journal: BMJ (2017)

Canadian HIV researcher and campaigner



Credit: McGill University

The death of Mark Wainberg leaves a huge void, not only for his family, friends, and the Jewish community in Montreal, but also, according to his colleagues in the specialty, for all those engaged in ridding the world of HIV and AIDS. During his career Wainberg changed the study and treatment of HIV and AIDS, helping to improve and save the lives of millions. At the age of 71 he was still a busy researcher and mentor, as well as an outspoken advocate for patients with the infection. 

At the time of his death he was professor of microbiology and immunology, paediatrics, and medicine at McGill University in Montreal, Canada; editor in chief of the Journal of the International AIDS Society ; and editor of Retrovirology . He was also director of McGill’s AIDS centre and the lead investigator at the Lady Davis Institute for Medical Research …
Continued Excellent Outcomes in Previously Untreated Follicular Lymphoma Patients after Treatment with CHOP Plus Rituximab or CHOP Plus (131) Iodine-Tositumomab - Long Term Follow-up of Phase III Randomized Study SWOG S0016
Authors: Mazyar Shadman, Hongli Li, Lisa Rimsza, John P. Leonard, Mark S Kaminski, Rita M Braziel, Catherine M. Spier, Ajay K Gopal, David G Maloney, Bruce Cheson, Shaker Dakhil, Michael LeBlanc, Sonali M. Smith, Richard I. Fisher, Jonathan W. Friedberg, Oliver Press
Journal: Blood (2016)
P08.64 A NF-κB in vivo reporter system allows molecular insights into glioma progression and therapy response
Authors: R. Xie, M. Ratliff, G. Solecki, K. Karimian, D. Hänggi, W. Wick, F. Winkler
Journal: Neuro-Oncology (2017)

Introduction: Glioblastoma is the most common primary malignant brain tumor in adults. It is highly resistant to available treatment options as the invasiveness of the tumor limits complete resection, as well as the dynamic tumor genome, multiple pathways driving the malignant phenotype, and the blood brain barrier, which limits the availability of drugs to the tumor. Evidence suggests a significant role for NF-κB in the gliomagenesis and the mechanism of treatment resistance in glioblastoma making NF-κB a potentially potent target for treatment. However, increasing evidence suggest a great cellular heterogeneity in glioma, making it important to understand which glioma cell types are dynamically driven by certain molecular pathways, and how that relates to their function in glioma progression and resistance. Therefore, we established an in vivo reporter system based on NF-κB responsive promoter elements driving green fluorescent protein (GFP) to monitor the expression of this transcription factor. Materials and Methods: Ten tandem repeats of the NF-κB transcription responsive element were designed, annealed and ligated into the HIV-1 based lentiviral vector pLVXPuro by replacing the CMV promoter with NF-κB elements. GFP was subcloned into the multiple cloning site of pLVXPuro. The integrity of the plasmid was verified by sequencing analysis. Its reliability as a NF-κB reporter was verified in vivo and in vitro. Using a chronic cranial window mouse model two-photon microscopy allows for consecutive in vivo imaging to observe different biological processes such as tumor growth, angiogenesis, and tumor repair after laser ablation and radiotherapy. Results: While cells grown under stem like conditions in vitro were highly NF-κB reporter positive, only few cells were positive in the established tumor in vivo, and that this changed dynamically depending on distinct states of tumor progression, and in response to lesions in the tumor area that were repopulated - “repaired” - by tumor cells. Furthermore, we were able to show that TNFα induced NF-κB reporter activity significantly in vitro. Radiotherapy led to a significant increase in reporter GFP expression in vivo as well as in vitro, to the extent that most cells became reporter positive. Pre-existing reporter-positive cells differed from reporter negative cells with respect to resistance against cytotoxic stress. NF-κB reporter positivity did not colocalize with established “stem cell” markers Mushashi, Nestin and Sox2 on tumor slices grown in our mouse model. DISCUSSION: Our results suggest a role for NF-κB expression during GBM resistance to treatment and progression after radiation in a heterogeneous manner. We will further analyze cell fate and morphology during irradiation and tumor “repair” with regard to their NF-κB positivity, and will include this data in the presentation, including inhibitory strategies of the NF-κB pathway.
Exercise patterns and quality of life among survivors of aggressive lymphoma.
Authors: Raina Mahajan Ferzoco, James Robert Cerhan, Matthew John Maurer, Cristine Allmer, Kathleen J. Yost, Thomas Matthew Habermann, Stephen Maxted Ansell, David James Inwards, Thomas E. Witzig, Luis F. Porrata, Grzegorz S. Nowakowski, William R Macon, Jessica N Towns, Umar Farooq, Brian K. Link, Carrie A. Thompson
Journal: Journal of Clinical Oncology (2015)

8555 Background: Aerobic exercise has been associated with improved QOL in the general population, but has not been studied in non-Hodgkin lymphoma (NHL) survivors. Methods: Newly diagnosed patients with aggressive lymphoma were prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource and systematically followed. Patient reported exercise patterns and QOL (FACT-G) were assessed at 3 years after diagnosis; patients with active disease or recent treatment were excluded from this analysis. QOL scores were normalized to a 0-100 scale for analysis. Results: From 2002-2009, 625 eligible patients completed the 3 year questionnaire.Themedian age was 62 years (range 18-87), 59% were male, and diagnoses included DLBCL (60%), FL grade III (11%), mantle cell (12%), other B-cell (7%), and T-cell (10%) lymphomas. Overall, 49% of 3-year survivors met CDC exercise recommendations defined as 30 minutes of moderate activity at least 5 days/week, which was comparable to the general population estimate (50%). Since their diagnosis of lymphoma, 10% of patients reported an increase in exercise and 49% reported a decrease in exercise. Males were more likely to meet exercise recommendations than females (54% v 41%, p = 0.002). Young patients (18-39 years) were more likely to increase physical activity after diagnosis than patients age > 70 (16% vs. 4%; p = 0.002). Those meeting exercise recommendations had higher median functional well-being (WB) (89 vs.75), physical WB (93 vs. 88), emotional WB (88 vs. 83), social/family WB (89 vs. 86), and overall QOL (89 vs. 80) (all p < 0.0001). Similarly, compared to those who reported decrease in exercise since diagnosis, patients with increased physical activity had higher median functional WB (89 vs. 75), physical WB (96 vs. 86), emotional WB (88 vs. 83), social/family WB (88 vs. 86) and total QOL (90 vs. 81) (all p < 0.0001). Conclusions: In this cohort, half of aggressive lymphoma survivors are meeting recommendations for exercise, similar to the general population. Meeting exercise recommendations and increasing exercise are associated with significantly higher QOL. Lymphoma patients should be counseled on exercise, and studies of activity interventions and outcomes are needed.
P01.13 The role of non-coding RNAs in GBM stem-like cells subtype identity maintenance and transition
Authors: J. Godlewski, A. K. Rooj
Journal: Neuro-Oncology (2017)

Decades of research on protein coding genes (2% of the genome) led to only incremental improvements of outcomes in glioblastoma multiforme (GBM) patients. Meanwhile, research on non-protein-coding genes, which constitute the vast majority of the human transcriptome, have received comparatively little attention to date. Large scale transcriptomic profiling of GBM into four subtypes has provided remarkable insight about the pathobiology and heterogeneous nature of this disease, including the mechanisms of subtype maintenance and adaptation to tumor anatomic niche and microenvironmental challenges. The co-existence of several molecular subtypes of differentiated tumor cells and GBM stem-like cells (GSCs) within individual tumors is further complicated by their complex speciation, inter-subtype transitions and hybrid stages. The role of non-coding RNAs (such as microRNAs and long, non-coding RNAs) in these processes is poorly understood. Through their unique capability of targeting multiple mRNA targets, microRNAs, whose expression is often de-regulated in cancers, play pivotal role in pathophysiology of tumor. Subtype-specific expression of microRNA-128 (miR-128) affects complex subpopulation dynamics within the heterogeneous GBM tumors. Alterations in miR-128 levels, acting through de-regulation of multiple mRNA targets that control epigenetic landscape, are a potent mechanism of bi-directional transitions between proneural and mesenchymal GSC subpopulations resulting in intermediate hybrid stages and emphasizing highly intricate intra-tumoral networking. Long non-coding RNAs (lncRNAs) have an undefined role in the pathobiology of GBM. Hypoxia Inducible Factor 1 Alpha-Anti Sense RNA 2 (HIF1A-AS2) was identified as a subtype-specific hypoxia-inducible lncRNA, upregulated in mesenchymal GSCs. Knockdown of HIF1A-AS2 affected GSC growth, self-renewal, and hypoxia-dependent molecular reprogramming, leading to delayed growth of mesenchymal GSC tumors, survival benefits, and impaired expression of downstream genes. Our data demonstrate that HIF1A-AS2 contributes to GSCs’ speciation and adaptation to hypoxia within the tumor microenvironment, acting directly through its interactome and targets and indirectly by modulating responses to hypoxic stress depending on the subtype-specific genetic context. These examples highlight immense, yet not fully appreciated, role of non-coding RNAs in pathophysiology of GBM.