tbuckley/cabot-search huggingface dataset:
IMMU-46. A siRNA APPROACH FOR TARGETING IMMUNOSUPPRESSIVE IDO1 IN PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Alicia Lenzen, Matthew Genet, Kristen Lauing, Lijie Zhai, Rishi Lulla, Rintaro Hashizume, Alexander Stegh, Derek Wainwright
Journal: Neuro-Oncology (2017)

The purpose of our project is to delineate the role of indoleamine 2,3 dioxygenase 1 (IDO1) in pediatric diffuse intrinsic pontine glioma (DIPG), and develop therapeutic potential of IDO1 inhibition through small inhibitory (si)RNA oligonucleotides and spherical nucleic acids (SNAs). Our specific aims are: (1) confirm the gene expression of IDO1 in different human DIPG cell lines; (2) generate and characterize siRNA oligonucleotides specifically targeting human IDO1 for an in vitro targeted approach to validate knockdown of IDO1 expression; and (3) generate and characterize gold nanoparticles for further targeted approach to inhibit IDO1. Unique patient-derived DIPG cell lines were grown in culture, stimulated with increasing concentrations of IFN-γ, and analyzed by levels of mRNA. IDO1 small inhibitory (si)RNA were created to target IDO1 specifically, and transfected into cells. Using the best siRNA for IDO1 inhibitions, SNAs were generated. IDO1 is expressed in different human pediatric DIPG cells at the mRNA level. We created siRNA that specifically targets IDO1 and preliminary results show overall decrease of IDO1 at the mRNA level. Generation of SNA is ongoing for targeted approach and improved blood brain barrier penetration & stability, with preliminary results showing siIDO1-SNAs inhibit IDO1 expression. Discussion/Significance of Impact: The overall poor prognosis of children with DIPG combined with the lack of effective therapies, emphasizes the importance of understanding the IDO1 pathway and the potential effects of IDO1 inhibition for therapeutically-modulating these devastating tumors. Our research confirms IDO1 presence in DIPG, and the use of nanotechnology and development of siRNA-SNAs for IDO1 inhibition has the capability of direct translatability of therapeutically-valuable data.
Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome
Authors: Orrin Devinsky, J. Helen Cross, Linda Laux, Eric Marsh, Ian Miller, Rima Nabbout, Ingrid E. Scheffer, Elizabeth A. Thiele, Stephen Wright
Journal: New England Journal of Medicine (2017)

The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome.In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period.The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, -22.8 percentage points; 95% confidence interval [CI], -41.1 to -5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient's overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375 .).
Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription
Authors: Kenia Ubieta, Mireia Garcia, Bettina Grötsch, Steffen Uebe, Georg F. Weber, Merle Stein, Arif Ekici, Georg Schett, Dirk Mielenz, Aline Bozec
Journal: The Journal of Experimental Medicine (2017)

The role of AP-1 transcription factors in early B cell development and function is still incompletely characterized. Here we address the role of Fra-2 in B cell differentiation. Deletion of Fra-2 leads to impaired B cell proliferation in the bone marrow. In addition, IL-7-stimulated pro-B cell cultures revealed a reduced differentiation from large pre-B cells to small B cells and immature B cells. Gene profiling and chromatin immunoprecipitation sequencing analyses unraveled a transcriptional reduction of the transcription factors Foxo1, Irf4, Ikaros, and Aiolos in Fra-2-deficient B cells. Moreover, expression of IL7Rα and Rag 1/2, downstream targets of Irf4 and Foxo1, were also reduced in the absence of Fra-2. Pro-B cell proliferation and small pre-B cell differentiation were fully rescued by expression of Foxo1 and Irf4 in Fra-2-deficient pro-B cells. Hence, Fra-2 is a key upstream regulator of Foxo1 and Irf4 expression and influences proliferation and differentiation of B cells at multiple stages.
Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon–Induced Up‐Regulation of Interferon Regulatory Factor 1
Authors: Jianhua Liu, Celine C. Berthier, J. Michelle Kahlenberg
Journal: Arthritis & Rheumatology (2017)

Objective The inflammasome complex is a driver of organ damage in patients with systemic lupus erythematosus (SLE). Although type I interferons (IFNs) are well established as mediators of SLE pathogenesis, their role in inflammasome activation in SLE has not been assessed. The aim of this study was to examine type I IFNs as regulators of the inflammasome. Methods SLE patients fulfilled ≥4 American College of Rheumatology criteria and were recruited from the University of Michigan Lupus Cohort. Primary monocytes were isolated from SLE patients or healthy controls by negative selection, treated with inflammasome activators in the presence or absence of IFNα, and IL‐1β secretion was measured by enzyme‐linked immunosorbent assay. Expression levels of IFN and inflammasome‐related molecules were assessed by real‐time polymerase chain reaction and Western blotting. IFN regulatory factor 1 (IRF‐1) expression was specifically down‐regulated by small interfering RNA (siRNA) transfection and a chemical inhibitor. Results Monocytes from patients with SLE exhibited increased expression and enhanced activation of the inflammasome by ATP when compared with control monocytes. Expression of inflammasome and IFN‐regulated genes was significantly correlated in monocytes from SLE patients but not in control monocytes. Inflammasome activity was increased after prolonged exposure to IFNα. Reduction of IRF‐1 expression via siRNA blocked caspase 1 up‐regulation after treatment with IFNα. Importantly, hyperactivity of the inflammasome in the monocytes of SLE patients was significantly reduced after knockdown or inhibition of IRF‐1. Conclusion Prolonged type I IFN exposure, as seen in SLE patients, primes monocytes for robust inflammasome activation in an IRF‐1–dependent manner. IRF‐1 inhibition may serve as a novel target for treatment of SLE‐associated inflammation and organ damage.
Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production
Authors: Anja Brehm, Yin Liu, Afzal Sheikh, Bernadette Marrero, Ebun Omoyinmi, Qing Zhou, Gina Montealegre, Angelique Biancotto, Adam L Reinhardt, Adriana Almeida De Jesus, Martin Pelletier, Wanxia L. Tsai, Elaine F. Remmers, Lela Kardava, Suvimol Hill, Hanna Kim, Helen J. Lachmann, Andre Megarbane, Jae Jin Chae, Jilian Brady, Rhina D. Castillo, Diane Brown, Angel Vera Casano, Ling Gao, Dawn Chapelle, Yan Huang, Deborah Stone, Yongqing Chen, Franziska Sotzny, Chyi Chia Richard Lee, Daniel L. Kastner, Antonio Torrelo, Abraham Zlotogorski, Susan Moir, Massimo Gadina, Phil McCoy, Robert Wesley, Kristina I. Rother, Peter W. Hildebrand, Paul Brogan, Elke Krüger, Ivona Aksentijevich, Raphaela Goldbach-Mansky
Journal: Journal of Clinical Investigation (2016)

The authors recently became aware that the IL-1R mice used for the original Supplemental Figure 7, A and B, were incorrectly genotyped and were heterozygous rather than homozygous knockout animals.The experiment with IL1r -/-animals was repeated, and the correct Supplemental Figure 7 is now available online.The correct text describing the experiments in the Results and Discussion sections appears below. ResultsLung CFUs also were reduced to the same extent in vaccinated Il18r -/-and wild-type mice (Supplemental Figure 7B).In contrast, IL-17-producing T cells recruited to the lungs of IL1r -/-mice were reduced, and the mice failed to acquire resistance in comparison with vaccinated wild-type controls.Thus, IL-18R, but not IL-1R, is dispensable in the development of T17 cells and vaccine resistance.Moreover, failed T17 differentiation of 1807 cells in Myd88 -/-mice is not due to impaired IL-18R signaling, but is likely due to impaired signaling via TLRs and IL-1R.
MEDU-17. SEXUALLY DIMORPHIC ROLES OF STAT3 IN MEDULLOBLASTOMA
Authors: Christine White, Samantha Jayasekara, Daniel Picard, Marc Remke, Jason Cain, Daniel Gough
Journal: Neuro-Oncology (2017)

Medulloblastoma is the most common childhood malignant brain tumour, and represents 20% of all paediatric central nervous system neoplasms. Although advances in surgery, radiation and chemotherapy have improved overall survival, the lifelong sequelae of these treatments represents a major health care burden for patients, parents, and society. Recent progress in the molecular subtyping of medulloblastoma have revealed at least four distinct subsets of tumours with dramatically different biology. Additionally, medulloblastoma predominately occurs in males and maleness correlates with worse outcome. However, the drivers of this sexual dimorphism in medulloblastoma are unclear. We have identified that STAT3 is one such factor. Deletion of STAT3 from granule cell precursors in a mouse model of SHh medulloblastoma driven by the loss of one PTCH1 allele results in complete protection of males, but has no effect in females. Stratification of transcriptomics data from a cohort of SHh medulloblastoma patients on the basis of STAT3 expression shows that male patients with low STAT3 expression have improved overall survival - an outcome not observed in females. Additionally, we identified STAT3-dependent genes, specific to males which correlate with overall survival. This is one of the first observations of a gene that could, in part, explain the sex dimorphism in medulloblastoma and offer insights into altered treatment options for patients on the basis of their sex and/or STAT3 expression.
HGG-01. A COMBINED PERFUSION AND DIFFUSION MRI BIOMARKER TO DISTINGUISH PEDIATRIC GLIOMA GRADE
Authors: Kathleen Schmainda, Melissa Pray, Jose Palomares, Mohit Maheshwari, Sean Lew, Teresa Kelly
Journal: Neuro-Oncology (2017)

BACKGROUND AND PURPOSE: This study aims to evaluate the effectiveness of perfusion MRI (pMRI) and diffusion MRI (DWI) parameters individually and in combination for distinguishing low-grade and high-grade pediatric brain tumors. MATERIALS AND METHODS: This IRB-approved study was performed in patients aged newborn to 18 years of age with newly diagnosed untreated brain lesions. A total of 38 patients were studied (22 females and 16 males). All MRI examinations were performed on a 1.5 T MRI scanner. Surgically resected and non-resected tumors were classified according to WHO tumor grades I, II (LG) and III, IV (HG). Pilocytic astrocytomas and optic pathway gliomas were grouped separately (PA+OPG). ROIs were selected using the tumor boundaries apparent on the FLAIR sequence with peritumoral edematous regions excluded if present. The rCBV determined as both standardized and normalized rCBV (sRCBV, nRCBV) as well as diffusion (ADC) mean values were determined. Statistical analysis included the Wilcoxon-Mann-Whitney t-test using an alpha=0.05 as the level of significance. RESULTS: This study demonstrates that the combined parameter, determined from the ratio of sRCBV to ADC has a greater statistical power for distinguishing HG, LG, PA+OPG lesions than ADC or rCBV alone. CONCLUSION: This study presents the ratio of sRCBV to ADC as a novel imaging biomarker able to distinguish low-grade from high-grade pediatric brain tumor and further distinguish PA+OPG from high-grade tumors. Tumor subclassification by imaging alone would be beneficial for treatment monitoring, may help to reduce invasive interventions and important for nonsurgical candidates.
MEDU-33. PLK1 INHIBITION IN COMBINATION WITH STANDARD THERAPIES FOR MYC-DRIVEN MEDULLOBLASTOMA
Authors: Ilango Balakrishnan, Sujatha Venkataraman, Angela M Pierce, Irina Alimova, Eric Prince, Daniel C. Moreira, Susan Fosmire, Krishna Madhavan, Nicholas Foreman, Rajeev Vibhakar
Journal: Neuro-Oncology (2017)

In the recent past, polo-like kinase (PLK1) has gained considerable attention as a potential therapeutic target in medulloblastoma. Volasertib (BI6727), highly specific and potent PLK1 inhibitor, is under clinical trials. However, volasertib exhibits varied clinical efficacies and only few patients respond well to single-agent volasertib. Therefore, we tested whether combination of BI6727 with other standard chemotherapy drugs could show promise in the treatment of highly aggressive Myc driven medulloblastoma. We evaluated the cellular effects of BI6727 in combination with other drugs in a panel of high and low cMyc expressing medulloblastoma cell lines. Of all the drugs tested, we found pairing the kinase inhibitor, BI6727, with the topoisomerase inhibitor, topotecan, showed synergistic effect in inhibiting tumor cell growth and enhanced tumor cell killing. Combination treatment resulted in a significant increase in apoptosis when compared with either drug alone. BI6727 in combination with topotecan induced both S and G2/M phase cell cycle arrest. In addition, BI6727 treatment caused a marked induction of tumor suppressor proteins, p53 and p21, when combined with topotecan. Interestingly we found that high-myc expressing medulloblastoma cell lines displayed increased sensitivity to BI6727 in combination with topotecan treatment when compared to low-myc cell lines. Using ChIP-PCR we found that Myc binds to the PLK1 promoter to induce expression of PLK1 and conversely volesertib suppresses Myc driven transcriptomic programs suggesting a positive feedback loop between PLK1 and Myc. In summary our study suggests that a combination, topotecan, and volasertib will synergize to potentiate cell death in high-Myc medulloblastoma patients.
Anticancer effect of PBI-0110 in combination with gemcitabine in intradermal and orthotopic pancreatic cancer
Authors: Lyne Gagnon, Lilianne Geerts, Francois Sara-Bournet, Liette Gervais, Brigitte Grouix, Mouna Lagraoui
Journal: Cancer Research (2008)

5670  Carcinoma of the exocrine pancreas has a particularly poor prognosis. Five-year survival is only 3-5%. Radical pancreaticoduodenectomy, especially for minimal disease, is currently the only chance of cure. Although chemotherapy has led to improvement in survival in patients with locally advanced disease, the overall effect is small. Also, surgery or radiotherapy of locally advanced unresectable pancreatic cancer does not lead to significantly prolonged survival. Therefore, novel therapeutic strategies are required. PBI-0110 is a well-defined low molecular weight orally active molecule. PBI-0110 has been shown to induce in vitro cell cytotoxicity towards Panc02 cell line and suppress tumor growth in the intradermal and orthotopic Panc02 tumor model. The antitumor efficacy of oral administration of PBI-0110 (100 mg/kg) was studied in combination with the standard therapy, gemcitabine (iv, 50 mg/kg), in intradermal pancreatic Panc02 cancer. Mice were treated every day with oral administration of vehicle (negative control), or PBI-0110 and with intraperitoneal injection of gemcitabine (50 mg/kg) once a week. Tumors were palpable, in general, 3-5 days post-inoculation. Gemcitabine induced a significant inhibition (p
Impact of chemotherapy dose and schedule on progression and survival in metastatic breast cancer: A systematic review.
Authors: Marek S. Poniewierski, Eva Culakova, Adane Fekadu Wogu, David C. Dale, Jeffrey Crawford, Gary H. Lyman
Journal: Journal of Clinical Oncology (2014)

6521 Background: Metastatic breast cancer (MBC) is a responsive but heterogeneous disease with generally a poor prognosis. The clinical importance of chemotherapy dosing and schedule in this setting has been questioned. Methods: A systematic review of randomized control trials (RCTs) of chemotherapy in MBC was conducted via searching PubMed (1990-2013) and meetings abstracts (2010-2012). RCTs comparing regimens that utilized the same agents or those studying impact of addition of agents were eligible. Relative risks of progression and mortality were based on event rates at 6, 12, 24 months. Heterogeneity was assessed by inconsistency index I2. Meta-analyses were based on fixed effects models. Results: Among 2626 studies identified, 70 eligible RCTs involving 15,181 patients were analyzed. Average median time to progression and overall survival were 7.5 and 19.8 months, respectively. RCTs were divided into four a priori defined groups based on trial design: higher vs lower dose intensity (DI) (n=30), addition of ≥1 agents (n=26), continuation of treatment vs observation (n=7), and sequential (A→B) vs concurrent (AB) schedule (n=7). More intense regimens were associated with reduced progression at 6 and, to a lesser extent, 12 months, as well as reduced mortality at 1 year with the greatest effect in the added drug group. At 2 years, a trend for reduced mortality was observed with the greatest reduction in sequentially treated patients (Table). Conclusions: Chemotherapy can be an effective treatment for MBC with results suggesting better efficacy with higher DI and multidrug regimens, with stronger early effects diminishing by 2 years. The question of optimal treatment in MBC requires additional studies. Relative risk and 95% confidence interval. Groups Progression 6 months Progression 1 year Mortality 1 year Mortality 2 years Higher vs lower DI 0.89 (0.84-0.94) 0.97 (0.94-1.00) 0.94 (0.87-1.01) 0.96 (0.92-1.01) Continued tx. vs observation 0.68 (0.61-0.76) 0.89 (0.85-0.94) 0.91 (0.77-1.08) 0.93 (0.85-1.01) More vs fewer agents 0.74 (0.70-0.78) 0.91 (0.88-0.93) 0.86 (0.81-0.92) 0.97 (0.94-1.01) Sequential vs concurrent 1.00 (0.85-1.19) 0.98 (0.92-1.06) 0.96 (0.77-1.20) 0.88 (0.79-0.98)
Association of calcium channel blocker use with prostate cancer aggressiveness, progression-free survival, and overall survival.
Authors: Michael Adam Poch, Diana Mehedint, Alexandra Curtis, Kristopher Attwood, Gregory E. Wilding, Rochelle Payne Ondracek, Willie Underwood, Thomas Schwaab, Khurshid Guru, James Mohler, Hannelore Heemers
Journal: Journal of Clinical Oncology (2012)

e15204 Background: Epidemiological studies indicate that the use of calcium channel blockers (CCB) is inversely related to prostate cancer (PCa) incidence. The goal of this study was to examine the association between CCB use and PCa aggressiveness at the time of radical prostatectomy (RP) or outcome after RP. Methods: Information on medication use, PCa aggressiveness and outcome after RP was retrieved from a prospective database that contains clinical and follow-up (FU) data for all men that have undergone RP at the Department of Urology at Roswell Park Cancer Institute since 1992. The database was queried for anti-hypertensive medication use at the time of diagnosis for all patients with ≥ 1 year FU. Prostate cancer aggressiveness (risk status) and recurrence were defined using NCCN guideline definitions. Cox regression models were performed to compare the distribution of progression-free survival (PFS) and overall survival (OS) with adjustment for covariates. Chi-Square test was used to assess the relationship between CCB use and PCa aggressiveness. Results: 875 men were included in the study. At diagnosis, mean age was 60 (SD ± 7) years and mean serum PSA value was 7.4 (SD ±7.4) ng/ml. 48%, 37%, and 15% of patients had low risk, intermediate risk, or high risk PCa, respectively. 104 (12%) had a history of CCB use. CCB users and non-users were similar by PSA at diagnosis (p=0.97) and tumor aggressiveness (p=0.88). Patients taking CCB were more likely to be older (p=0.023), have a higher BMI (p=0.006) and use additional anti-hypertensive medications (p&lt;0.01). Margin status after radical prostatectomy was similar (p=0.30) between the two groups. Median FU was 42 months. PFS (p=0.82, HR 95% CI: 0.63-1.44) and OS (p=0.72, HR 95% CI: 0.42-3.52) did not differ between the 2 groups. Adjusting for age and PCa aggressiveness did not alter the results observed for PFS (p=0.44, HR 95% CI: 0.62–1.41) and OS (p=0.50, HR 95% CI: 0.04-3.48). PCa aggressiveness was associated with PFS (p=0.001) in the multivariate model. Conclusions: CCB use does not affect PCa aggressiveness at time of diagnosis or improve PFS or OS.
A trust approach for sharing research reagents
Authors: Aled Edwards, Max Morgan, Arij Al Chawaf, Kerry Andrusiak, Rachel Charney, Zarya Cynader, Ahmed ElDessouki, Yunjeong Lee, Andrew Moeser, Simon Stern, William J. Zuercher
Journal: Science Translational Medicine (2017)

The core feature of trusts—holding property for the benefit of others—is well suited to constructing a research community that treats reagents as public goods.