bluuebunny/crossref_metadata_2025_split huggingface dataset:
The first six months of the Advanced LIGO’s and Advanced Virgo’s third observing run with GRANDMA
Authors: Antier S , Agayeva S , Aivazyan V , Alishov S , Arbouch E , Baransky A , Barynova K , Bai J M , Basa S , Beradze S , Bertin E , Berthier J , Blažek M , Boër M , Burkhonov O , Burrell A , Cailleau A , Chabert B , Chen J C , Christensen N , Coleiro A , Cordier B , Corre D , Coughlin M W , Coward D , Crisp H , Delattre C , Dietrich T , Ducoin J-G , Duverne P-A , Marchal-Duval G , Gendre B , Eymar L , Fock-Hang P , Han X , Hello P , Howell E J , Inasaridze R , Ismailov N , Kann D A , Kapanadze G , Klotz A , Kochiashvili N , Lachaud C , Leroy N , Le Van Su A , Lin W L , Li W X , Lognone P , Marron R , Mo J , Moore J , Natsvlishvili R , Noysena K , Perrigault S , Peyrot A , Samadov D , Sadibekova T , Simon A , Stachie C , Teng J P , Thierry P , Thöne C C , Tillayev Y , Turpin D , de Ugarte Postigo A , Vachier F , Vardosanidze M , Vasylenko V , Vidadi Z , Wang X F , Wang C J , Wei J , Yan S Y , Zhang J C , Zhang J J , Zhang X H 
Published: November 2019

ABSTRACT
We present the Global Rapid Advanced Network Devoted to the Multi-messenger Addicts (GRANDMA). The network consists of 21 telescopes with both photometric and spectroscopic facilities. They are connected together thanks to a dedicated infrastructure. The network aims at coordinating the observations of large sky position estimates of transient events to enhance their follow-up and reduce the delay between the initial detection and optical confirmation. The GRANDMA programme mainly focuses on follow-up of gravitational-wave alerts to find and characterize the electromagnetic counterpart during the third observational campaign of the Advanced LIGO and Advanced Virgo detectors. But it allows for follow-up of any transient alerts involving neutrinos or gamma-ray bursts, even those with poor spatial localization. We present the different facilities, tools, and methods we developed for this network and show its efficiency using observations of LIGO/Virgo S190425z, a binary neutron star merger candidate. We furthermore report on all GRANDMA follow-up observations performed during the first six months of the LIGO–Virgo observational campaign, and we derive constraints on the kilonova properties assuming that the events’ locations were imaged by our telescopes.
General relativistic magnetohydrodynamic dynamo in thick accretion disks: fully nonlinear simulations
Authors: Tomei N , Del Zanna L , Bugli M , Bucciantini N 
Published: November 2019

Abstract
The recent imaging of the M87 black hole at millimeter wavelengths by the Event Horizon Telescope (EHT) collaboration has triggered a renewed interest in numerical models for the accretion of magnetized plasma in the regime of general relativistic magnetohydrodynamics (GRMHD). Here non-ideal simulations, including both the resistive effects and, above all, the mean-field dynamo action due to sub-scale, unresolved turbulence, are applied for the first time to such systems in the fully nonlinear regime. Combined with the differential rotation of the disk, the dynamo process is able to produce an exponential growth of any initial seed magnetic field up to the values required to explain the observations, when the instability tends to saturate even in the absence of artificial quenching effects. Before reaching the final saturation stage we observe a secondary regime of exponential growing, where the magnetic field increases more slowly due to accretion, which is modifying the underlying equilibrium. By varying the dynamo coefficient we obtain different growth rates, though the field seems to saturate at approximately the same level, at least for the limited range of parameters explored here, providing substantial values for the MAD parameter for magnetized accretion. For reasonable values of the central mass density and the commonly employed recipes for synchrotron emission by relativistically hot electrons, our model is able to reproduce naturally the observed flux of Sgr A*, the next target for EHT.
Scale-invariance in the repeating fast radio burst 121102
Authors: Lin Hai-Nan , Sang Yu 
Published: November 2019

Abstract
The statistical properties of the repeating fast radio burst FRB 121102 are investigated. We find that the cumulative distributions of fluence, flux density, total energy and waiting time can be well fitted by the bent power law. In addition, the probability density functions of fluctuations of fluence, flux density and total energy well follow the Tsallis q-Gaussian distribution. The q values keep steady around q ∼ 2 for different scale intervals, indicating a scale-invariant structure of the bursts. The statistical properties of FRB 121102 are very similar to that of the soft gamma repeater SGR J1550-5418. The underlying physical implications need to be further investigated.
Stress response pathways in the male germ cells and gametes
Authors: Santiago J , Santos M A S , Fardilha M , Silva J V 
Published: November 2019

AbstractThe unfolded protein response (UPR) is a conserved and essential cellular pathway involved in protein quality control that is activated in response to several cellular stressors such as diseases states, ageing, infection and toxins. The cytosol, endoplasmic reticulum (ER) and mitochondria are continuously exposed to new proteins and in situations of aberrant protein folding; one of three lines of defence may be activated: (i) heat-shock response, (ii) mitochondrial UPR and (iii) ER UPR. These pathways lead to different signal transduction mechanisms that activate or upregulate transcription factors that, in turn, regulate genes that increase the cell's ability to correct the conformation of poorly folded proteins or, ultimately, lead to apoptosis. Despite the recent progress in understanding such biological processes, few studies have focused on the implications of the UPR in male infertility, highlighting the need for a first approach concerning the presence of these components in the male reproductive system. In testis, there is a high rate of protein synthesis, and the UPR mechanisms are well described. However, the presence of these mechanisms in spermatozoa, apparently transcriptionally inactive cells, is contentious, and it is unclear how sperm cells deal with stress. Here, we review current concepts and mechanisms of the UPR and highlight the relevance of these stress response pathways in male fertility, especially the presence and functional activation of those components in male germinal cells and spermatozoa.
Exposome-Explorer 2.0: an update incorporating candidate dietary biomarkers and dietary associations with cancer risk
Authors: Neveu Vanessa , Nicolas Geneviève , Salek Reza M , Wishart David S , Scalbert Augustin 
Published: November 2019

Abstract
Exposome-Explorer (http://exposome-explorer.iarc.fr) is a database of dietary and pollutant biomarkers measured in population studies. In its first release, Exposome-Explorer contained comprehensive information on 692 biomarkers of dietary and pollution exposures extracted from the analysis of 480 peer-reviewed publications. Today, Exposome-Explorer has been further expanded and contains a total of 908 biomarkers. Two additional types of information have been collected. First, 185 candidate dietary biomarkers having 403 associations with food intake (as measured by metabolomic studies) have been identified and added. Second, 1356 associations between dietary biomarkers and cancer risk in epidemiological studies, which were collected from 313 publications, have also been added to the database. Classifications for both foods and compounds have been revised, and new classifications for biospecimens, analytical methods and cancers have been implemented. Finally, the web interface has been redesigned to significantly improve the user experience.
Exploring trophoblast-specific Tead4 enhancers through chromatin conformation capture assays followed by functional screening
Authors: Tomikawa Junko , Takada Shuji , Okamura Kohji , Terao Miho , Ogata-Kawata Hiroko , Akutsu Hidenori , Tanaka Satoshi , Hata Kenichiro , Nakabayashi Kazuhiko 
Published: November 2019

Abstract
Tead4 is critical for blastocyst development and trophoblast differentiation. We assayed long-range chromosomal interactions on the Tead4 promoter in mouse embryonic stem (ES) cells and trophoblast stem (TS) cells. Using luciferase reporter assays with ES and TS cells for 34 candidate enhancer regions, we identified five genomic fragments that increased Tead4 promoter activity in a TS-specific manner. The five loci consisted of three intra- and two inter-chromosomal loci relative to Tead4 on chromosome 6. We established five mouse lines with one of the five enhancer elements deleted and evaluated the effect of each deletion on Tead4 expression in blastocysts. By quantitative RT-PCR, we measured a 42% decrease in Tead4 expression in the blastocysts with a homozygous deletion with a 1.5 kb genomic interval on chromosome 19 (n = 14) than in wild-type blastocysts. By conducting RNA-seq analysis, we confirmed the trans effect of this enhancer deletion on Tead4 without significant cis effects on its neighbor genes at least within a 1.7 Mb distance. Our results demonstrated that the genomic interval on chromosome 19 is required for the appropriate level of Tead4 expression in blastocysts and suggested that an inter-chromosomal enhancer-promoter interaction may be the underlying mechanism.
ATIM-04. PHASE I IMMUNOVIROTHERAPY TRIAL OF IL-12 EXPRESSING HSV-1 (M032) IN PET DOGS WITH SPONTANEOUS HIGH GRADE GLIOMAS: A PRELIMINARY REPORT
Authors: Renee Chambers M , Crossman David , Foote Jeremy , Koehler Jey , Markert James , Platt Simon , Mitchell Self D , Shores Andy , Waters Alicia , Yanke Amy , Yancey Gillespie G 
Published: November 2019

Abstract
Malignant gliomas are the most common primary brain tumors in humans, accounting for approximately 30% of all primary central nervous system (CNS) tumors in adults. Incidence and outcomes of gliomas in pet dogs are similar to humans. Previous methods of studying gliomas in rodent models do not adequately represent several features that define human cancers, most notably the sporadic nature of tumor development. Murine models lack intra-tumoral heterogeneity or hosts do not have an intact immune system. To overcome these rodent model deficiencies, many investigators have used canine models to study human diseases. We describe a prospective, phase I clinical trial in canine patients with sporadic high-grade gliomas to evaluate M032, a mutant HSV-1 expressing IL-12, alone or combined with a checkpoint inhibitor (Indoximod) to assess safety, tolerability and efficacy. M032 has been shown to infect and kill glioma cells, producing a virus and tumor cell antigen-rich debris field; will provide an increased adjuvant effect from released viral DNA recognized by TLR-9 receptors; and express IL-12 locally, stimulating activation of TH1 lymphocytes. The intratumoral inflammatory cell infiltration is expected to result in immune-related anti-viral responses with cross-epitope spreading to tumor antigens. Indoximod immunomodulation will be tested in latter cohorts to prolong anti-tumor responses. To date, six canines with high-grade gliomas have received intratumoral M032 without virus-related toxicities. Resected tumor and serial blood samples are being cryopreserved for analysis of lymphoid and monocyte/myeloid subset markers. This same virus is being tested in a phase 1 clinical trial in humans with high-grade malignant gliomas; eight human patients have received treatment at this writing without virus-related toxicities. The concurrent prosecution of both trials allows unprecedented real time comparison of safety and efficacy of immunovirotherapy as a stringent test of suitability of the dog as a valid and informative model of human brain tumors.
ATIM-06. TREATMENT OF RECURRENT/REFRACTORY (R/R) ANAPLASTIC ASTROCYTOMA (AA, WHO GRADE 3) PATIENTS WITH ANTI-TGFß2 RNA THERAPEUTIC OT-101 VERSUS TEMOZOLOMIDE IS ASSOCIATED WITH IMPROVED OVERALL SURVIVAL
Authors: Uckun Fatih , Qazi Sanjive , Nam David , Hwang Larn , Trieu Vuong 
Published: November 2019

Abstract

BACKGROUND
OT-101 is a first-in-class RNA therapeutic designed to disrupt the immunosuppressive action of TGFß2. During Phase 1 clinical trials, OT-101 induced partial responses in R/R AA patients. We now report our clinical results from a randomized Phase IIB study (NCT00431561) that further evaluated its single agent activity in R/R AA patients in side-by-side comparison with the standard chemotherapy drug temozolomide (TMZ).

METHODS
OT-101 was administered via high-flow microperfusion with an intratumoral catheter using a convection enhanced delivery (CED) system. 26 AA patients (12: 2.5 mg/cycle; 14: 19.8 mg/cycle) received 7-day cycles of OT-101 every other week via continuous infusion for 4–11 cycles. Response determinations were based on central review of MRI scans by an independent review committee according to standard as well as modified McDonald criteria. 11 patients in the active control arm were treated with TMZ (150–200 mg/m2, 5 days/28-day cycles x up to 6 treatment cycles). Standard statistical methods were applied for the analysis of data.

RESULTS
14 of 26 patients (53.8%) treated with 4–11 cycles of OT-101 had either a CR (N=2) or PR (N=12) as their best overall response. The average time until 99% reduction of their tumor volumes ranged from 9.9 to 115.4 (median: 23.7) months. In contrast, only 1 of 10 evaluable patients (10%) treated with TMZ achieved an objective response which was a PR (Fisher’s exact test, 2-tailed, P-value = 0.0002). The median overall survival (OS) was 1154 days (95% CI: 811 - >1743) for the OT-101 group and 590 days (95% CI: 287 - >1137) days for the TMZ group (Log Rank Chi Square = 7.55, P-value = 0.006).

CONCLUSION
Our results confirm and extend previous studies and provide early evidence that the anti-TGFß2 RNA therapeutic OT-101 is at least as active as TMZ in salvage therapy of R/R AA patients.
ATIM-08. TRIAL IN PROGRESS: CA209-9Y8 PHASE 2 TRIAL OF TUMOR TREATING FIELDS (TTFS), NIVOLUMAB PLUS/MINUS IPILIMUMAB FOR BEVACIZUMAB-NAÏVE, RECURRENT GLIOBLASTOMA
Authors: Odia Yazmin , Iwamoto Fabio 
Published: November 2019

Abstract
Recurrent glioblastoma has limited therapeutic options. The EF11 trial of TTFs vs. physician’s choice chemotherapy showed an objective response rate (ORR) of 14%, but no survival (OS) benefit. CheckMate 143 randomized phase 3, open-label trial of nivolumab vs. bevacizumab failed to show an OS benefit, though nivolumab led to ORR of 7.8% with more durable response than bevacizumab (11.1 vs. 5.3 months). Preclinical studies suggest synergism between TTFs and immunotherapy. TTFs expose calreticulin on cell surfaces, causing HMGB1 and ATP secretion—hallmarks of anticancer immunogenic cell death. Observed trends in a glioma cohort also suggest synergism: 77% of glioma patients treated with TTFs received concurrent temozolomide (16, 31%), nitrosourea (4,8%), bevacizumab (19,37%), or immunotherapy (28,54%). Only 2 (4%) experienced skin toxicity requiring TTFs hold. For TTFs plus immunotherapy vs. chemotherapy, there was a trend toward increased OS (8.3 vs. 6.5 months,p=0.32) and ORR (26% vs. 13%), with significant increase in PFS for glioblastomas (4.6 vs. 3.5 months,p=0.04). ORR was >14% in EF11 or < 5- 10% in meta-analyses of immunotherapy for recurrent glioblastoma. This open-label, phase 2 trial with 2 parallel arms uses a 2-stage Minimax design with stopping rules for futility. We will enroll 30 (15/Arm) to 60 (30/Arm) evaluable subjects. The primary endpoint is ORR by modified RANO. Secondary objectives are OS, PFS, safety, compliance, and biomarker correlations. Adults with glioblastoma at first or second recurrence and no prior CTLA inhibitor or bevacizumab are eligible. All receive TTFs with nivolumab for ≤24 months and ipilimumab for ≤4 doses. Arm A (no prior PD1/PDL1 inhibitor) receive nivolumab only and add ipiliumumab at progression. Arm B (prior PD1/PDL1 inhibitor) receive nivolumab and ipilumimab. Nivolumab is dosed IV q2weeks 240mg as monotherapy and 3mg/kg with ipilumimab IV 1mg/kg q6weeks. TTFs starts by 1 month and worn for ≥75% over ≤24 months.
ATIM-09. CLINICAL TRIAL IN PROGRESS: A STUDY OF NEOADJUVANT AND ADJUVANT VB-111 FOR TREATMENT OF RECURRENT GBM
Authors: Cloughesy Timothy , Butowski Nicholas , Harats Dror , Rachmilewitz Minei Tamar , Wen Patrick 
Published: November 2019

Abstract

BACKGOUND
Ofranergene obadenovec (VB-111) is a targeted anti-cancer viral based gene therapy with a dual mechanism: a broad antiangiogenic effect and induction of a tumor directed immune response. Previous study demonstrated a survival benefit for patients with recurrent glioblastoma (rGBM) treated with VB-111 monotherapy that was continued upon progression with combination treatment of VB-111 and bevacizumab. Glioblastoma is an immunologically “cold” microenvironment which fosters immunosuppression and antagonizes anti-tumor immune responses. The role of T-cell infiltration in combating cancer has been increasingly recognized and associated with improved participant outcomes. Based on these observations, this study will assess the hypothesis that neoadjuvant use of VB-111 will lead to a statistically significant increase in tumor infiltrating T lymphocyte (TIL) density within the tumor and enhanced systemic tumor-specific T cell responses.

METHODS
This is a multicenter, randomized, blinded, placebo-controlled, phase 2 surgical trial to evaluate early immunologic pharmacodynamic parameters for the viral cancer therapy VB-111 in rGBM. 45 participants with rGBM indicated for resection will randomized to one of three treatment arms: Neoadjuvant Arm: intravenous VB-111 prior to resection, and VB-111 every 6 weeks after resection. Adjuvant Arm: placebo prior to resection, and VB-111 every 6 weeks afterwards. The control arm will receive placebo prior to resection followed by standard of care. Upon evidence of contrast-enhancing progression, bevacizumab may be initiated as needed for supportive care and VB-111 will continue until progression is supported at two consecutive time points. Tumor samples will be obtained and archived at the time of surgery, and blood samples will be obtained as pharmacodynamic markers throughout the study to allow DNA sequencing of T cells. The primary endpoint is influence of neoadjuvant VB-111 on TIL density. Other endpoints include safety and tolerability, peripheral T cell response, tumor/microenvironment transcriptomic alteration, and PFS/OS. Study will open for enrolment in 2019.
ATIM-11. TUMOR-INFILTRATING LYMPHOCYTES EXPRESSING ANTI-PD-1 ANTIBODY EXHIBIT A PROMISING EFFICACY AND SURVIVAL BENEFIT IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME
Authors: Tang Chao , Zhang Zhi , Chen Di , Ji Kai , Ji Chunxia , Liu Xiao , Chen Ling , Lu Qiqi , Chu Wen , Qin Wen , Xu Fei , Jin Hua , Qian Qi , Yao Yu , Zhou Liang 
Published: November 2019

Abstract
Adoptive cell therapies utilizing autologous tumor-infiltrating lymphocytes (TIL) have been demonstrated to be safe and promising in anti-tumor activities; However, their efficiency was still low in treating glioblastoma multiforme (GBM) because of immunosuppression microenvironment. In this study, we proposed a new strategy to enhance the anti-tumor immune response by using modified TIL expressing anti-PD-1 antibody (anti-PD1-TIL), which could reverse immunosuppression in tumor microenviroment. From April 2017 to April 2018，a total of 8 patients with recurrent GBM were enrolled and received more than one cycles of anti-PD1-TIL immunotherapy after surgery and chemotherapy with a median follow-up of 20 months. The anti-PD1-TIL immunotherapy was well tolerated. Two patients suffered grade 1 and 2 adverse events, including fatigue, mucosal/cutaneous toxicities. The median overall survival time was 16.1（95% CL: 15.4–16.7）months. By iRANO criteria, one patient experienced a partial response (PR), and three patients experienced stable disease (SD) after anti-PD-1-TIL immunotherapy. Genomic analysis by whole exome sequencing revealed an enrichment of MUC12 mutation in responders (p< 0.01), and an enrichment of TMEM125 (p< 0.01) and HIST2H3A/C amplification (p< 0.05) associated with immunosuppressive signature in non-responders. Taken together, the anti-PD1-TIL immunotherapy is a safe and promising strategy with durable efficacy to treat patients with recurrent GBM. Clinicaltrials.gov identifier: NCT 03347097.
ATIM-17. A PHASE I TRIAL OF HYPOFRACTIONATED STEREOTACTIC IRRADIATION (HFSRT) COMBINED WITH NIVOLUMAB (NIVO), IPILIMUMAB (IPI) AND BEVACIZUMAB (BEV) IN PATIENTS (PTS) WITH RECURRENT HIGH GRADE GLIOMAS
Authors: Sahebjam Solmaz , Forsyth Peter , Tran Nam , Etame Arnold , Arrington John , Jaglal Michael , Mokhtari Sepideh , MacAulay Robert , Wicklund Melissa , Evernden Brittany , Gatewood Tyra , Robinson Timothy , Raval Raju , Yu Michael 
Published: November 2019

Abstract

BACKGROUND
There is strong pre-clinical evidence that combining CTLA4 and PD-1/PDL-1 blockade with antiangiogenic agents and HFSRT independently enhance anti-tumor immune responses and tumor regression.

METHODS
This phase I study includes a safety cohort of 6 pts followed by dose expansion cohort of 26 pts. Pts with Bev naïve recurrent WHO grade III or IV gliomas (maximum diameter of enhancing brain lesion ≤ 4 cm) are eligible. An interval of at least 6 months after the end of prior RT is required unless there is a new recurrence outside of the previous RT treatment field. Eligible pts are treated with HFSRT to the recurrent tumor (30 Gy in 5 fractions) and 4 cycles of Nivo (3 mg/kg), Ipi (1 mg/kg) and Bev (15 mg/kg) every 3 weeks followed by Nivo 240 mg and Bev 10 mg/kg every 2 weeks for 4 months. After 4 months, Nivo is administered every 4 weeks at 480 mg flat dose and Bev is continued at every 2 week schedule. The primary study objectives are to determine safety and tolerability of above treatment. Secondary endpoints include response rate, 6 and 9-months survival rates, and exploring tissue and imaging biomarkers.

RESULTS
As of June 2019, safety cohort has been completed and accrual to dose expansion cohort is ongoing. Combination of HFSRT, Nivo, Ipi and Bev as above is well tolerated. The most common toxicities were grade 1 anorexia, grade 1 diarrhea, grade 1 elevation of alanine aminotransferase, grade 1 elevation of lipase and grade 1 infusion related reaction. One patient had grade 3 confusion which was reversible with use of corticosteroids. No dose limiting toxicity has been observed.

CONCLUSIONS
Combination of HFSRT with Nivo, Ipi and Bev was considered safe to be studied in expansion cohort. Updated safety and efficacy data will be presented.