bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pilot study of tazemetostat and MK-3475 (pembrolizumab) in advanced urothelial carcinoma (ETCTN 10183).
Authors: Meeks Joshua J. , Shilatifard Ali , Miller Stephen D. , Morgans Alicia K. , VanderWeele David James , Kocherginsky Masha , Hussain Maha H. A. 
Published: February 2020

TPS607 Background: Few patients with metastatic urothelial carcinoma (UC) achieve a durable response despite early stabilization with chemotherapy or immunotherapy. Mutations in the COMPASS-related proteins KMT2D, KMT2C, and KDM6A are found in 66% of patients with UC, suggesting disruption of histone regulation may be an acquired mechanism of tumor viability. Using a carcinogen-derived mouse model of UC in which 80% of animals have alterations in Kmt2d, Kmt2d or both, we found regression of tumors when treated an enzymatic inhibitor of EZH2 (Tazemetostat). In vivo administration of Tazemetostat enhanced the immune response with more necrosis when combined with an anti-PD1 antibody. Therefore, we hypothesized that treatment of UC with an Tazemetostat may further improve the activity of immunotherapy as only 21% of cisplatin refractory (KN45) and 24% of cisplatin ineligible (KN52) patients achieve an objective response. We hypothesized that restoration of the epigenetic imbalance, combined with immunotherapy may improve survival in patients with metastatic UC. Methods: ETCTN10183 (NCT03854474) is a Phase I/II trial evaluating the efficacy of Tazemetostat at 800 mg BID + Pembrolizumab 200 mg IV every 3 weeks in patients with either cisplatin-refractory (Cohort A) or cisplatin-ineligible (Cohort B) metastatic UC. The safety lead-in portion of the trial will follow a “3+3” design with one dose de-escalation level (800mg or 600mg BID Tazemetostat) and will enroll 6-12 patients to establish the recommended phase II dose (RP2D) of Tazemetostat. All DLTs will be reviewed and if tolerated, two dose expansion cohorts will be initiated and will include 24 patients with 12 in each cohort (cisplatin refractory and ineligible). The primary objectives are to identify the RP2D of Tazemetostat in combination with Pembrolizumab, and secondary objectives are to determine the objective disease response in patients with either cisplatin-refractory or unresponsive UC per RECIST criteria, safety, tolerability and progression-free survival. Translational objectives include evaluation of tumor mutations in COMPASS genes, total mutation burden, T cell infiltration, TCR clonality, tumor subtyping and PD-L1 expression. Clinical trial information: NCT03854474.
PROSPER: Phase III randomized study comparing perioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).
Authors: Harshman Lauren Christine , Puligandla Maneka , Allaf Mohamad E. , McDermott David F. , Drake Charles G. , Signoretti Sabina , Cella David , Gupta Rajan T. , Shuch Brian M. , Lara Primo , Kapoor Anil , Heng Daniel Yick Chin , Leibovich Bradley , Michaelson M. Dror , Choueiri Toni K. , Master Viraj A. , Jewett Michael A.S. , Maskens Deb , Haas Naomi B. , Carducci Michael Anthony ,   On behalf of the PROSPER RCC Investigators
Published: February 2020

TPS765 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of October 18, 2019, 317 patients have been enrolled. Clinical trial information: NCT03055013.
A phase III study (COSMIC-313) of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in patients (pts) with previously untreated advanced renal cell carcinoma (aRCC) of intermediate or poor risk.
Authors: Choueiri Toni K. , Albiges Laurence , Powles Thomas , Scheffold Christian , Wang Fong , Motzer Robert J. 
Published: February 2020

TPS767 Background: C inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER), and may promote an immune-permissive tumor environment, resulting in enhanced response to immune checkpoint inhibitors. C has shown preliminary clinical activity and tolerability in combination with the PD-1 inhibitor N and as part of a triplet combination with N and the CTLA-4 inhibitor I in pts with aRCC (Nadal et al. ASCO 2018). C is approved for pts with aRCC, and N+I is approved as a combination therapy in pts with previously untreated aRCC of intermediate or poor risk. We present the study design of a phase 3 trial of C+N+I vs N+I in previously untreated pts with aRCC of IMDC intermediate or poor risk (NCT03937219). Methods: This randomized, double-blind, controlled phase 3 study evaluates the efficacy and safety of C+N+I vs N+I in previously untreated pts with IMDC intermediate or poor risk aRCC. Eligible pts are randomized 1:1 to receive C+N+I or N+I in combination with placebo, stratified by IMDC prognostic score and geographic region. Pts receive C (40 mg oral QD) + N (3 mg/kg IV Q3W) x 4 doses + I (1 mg/kg IV Q3W) x 4 doses, followed by C (40 mg oral QD) + N (480 mg IV flat dose Q4W). Control pts receive C-matched placebo and the same treatment regimen for N+I as the experimental arm. N will be administered for a maximum of 2 years. Eligibility criteria include histologically confirmed metastatic or aRCC with a clear cell component, intermediate or poor risk RCC per IMDC criteria, measurable disease per RECIST 1.1, KPS ≥70%, adequate organ and marrow function and age ≥18 years. Exclusion criteria include prior systemic therapy for aRCC and uncontrolled significant illnesses. The primary endpoint is PFS per RECIST 1.1 by BICR; the secondary endpoint is OS. Additional endpoints include ORR, safety, correlation of biomarkers with outcomes, and pharmacokinetics of C in combination with N+I. The first patient was enrolled in June 2019 and enrollment is ongoing. Clinical trial information: NCT03937219.
Higher Circulating Adiponectin Concentrations Predict Incident Cancer in Type 2 Diabetes – The Adiponectin Paradox
Authors: Lee Chi Ho , Lui David T W , Cheung Chloe Y Y , Fong Carol H Y , Yuen Michele M A , Chow Wing Sun , Woo Yu Cho , Xu Aimin , Lam Karen S L 
Published: February 2020

Abstract

Introduction
Despite the beneficial cardiometabolic effects of adiponectin demonstrated in preclinical studies, paradoxically higher circulating adiponectin concentrations have been found in epidemiological studies to be associated with incident cardiovascular events, renal outcomes, and mortality in patients with diabetes. On the other hand, diabetes is also associated with an increased risk of cancer. Here, we investigated prospectively the association between circulating adiponectin concentrations and incident cancer using a cohort of exclusively individuals with type 2 diabetes.

Materials and Methods
Baseline serum adiponectin concentrations were measured in 5658 participants recruited from the Hong Kong West Diabetes Registry. The associations of circulating adiponectin concentrations with incident cancer and cancer-related deaths were evaluated using multivariable Cox regression analysis, with hazard ratio (HR) for adiponectin referring to the respective risk per doubling of serum adiponectin concentration.

Results
Over a median-follow up of 6.5 years, 7.53% and 3% of participants developed cancer and had cancer-related deaths, respectively. Serum adiponectin concentrations were significantly higher in those who had incident cancer (9.8 μg/mL vs 9.1 μg/mL, P &lt; 0.001) and cancer-related deaths (11.5 μg/mL vs 9.3 μg/mL, P &lt; 0.001) compared with those without. Moreover, in multivariable analyses, serum adiponectin concentration was independently associated with both incident cancer (hazard ratio, 1.19; 95% confidence interval, 1.05–1.35; P = 0.006) and cancer-related deaths (hazard ratio, 1.23; 95% confidence interval, 1.03–1.47; P = 0.024).

Conclusions
Higher serum adiponectin concentration was independently associated with incident cancer and cancer-related deaths in type 2 diabetes, indicating that adiponectin paradox can be observed in another major diabetic complication in addition to cardiovascular and kidney diseases.
Bone Metastases in Medullary Thyroid Carcinoma: High Morbidity and Poor Prognosis Associated With Osteolytic Morphology
Authors: Vogel Theresa , Wendler Julia , Frank-Raue Karin , Kreissl Michael C , Spitzweg Christine , Fassnacht Martin , Raue Friedhelm , Kroiss Matthias 
Published: February 2020

Abstract

Context
The clinical relevance of bone metastases (BM) in advanced medullary thyroid carcinoma (MTC) is poorly described.

Objective
The objectives of this work are to describe the prevalence of BM, frequency of skeletal related events (SREs), and impact of BM morphology and SREs on prognosis, and to assess the role of antiresorptive treatment (ART).

Design
A retrospective cohort study was conducted.

Setting
This study was conducted at 4 German referral centers.

Patients
A total of 1060 MTC patients were included.

Main Outcome Measure
Main outcome measures include descriptive statistics, overall survival (OS) by the Kaplan-Meier method, and risk factors by Cox proportional hazards modeling.

Results
A total of 120 of 416 patients (29%) with metastatic MTC had BM, of which 97% had concurrent nonosseous metastases. BM occurred 2.1 years (median, range –0.1 to 20.6 years) after initial diagnosis, were multifocal in 79%, and were located preferentially in the spine (86%) and pelvis (60%). BM morphology was osteolytic in 32%, osteoblastic in 25%, and mixed in 22% of cases (unknown: 21%). Within a median observation period of 26.6 months (range, 0-188 months) after BM diagnosis, 47% of patients experienced one or more SREs (bone radiation 50%, pathological fractures 32%), of which 42% occurred in osteolytic and 17% in osteoblastic BM (P = .047). Presence of osteolytic metastases (hazard ratio 3.85, 95% CI 1.52-9.77, P = .005) but not occurrence of SREs was associated with impaired OS. Among the 36 patients who received ART (no ART: n = 71), SREs were significantly less frequent than in untreated patients (P = .04).

Conclusion
BM are common in metastatic MTC and most often with an osteolytic morphology and an unfavorable prognosis. The majority of SREs occur in osteolytic metastases and may be prevented by ART.
Normocalcemic Hyperparathyroidism: Study of its Prevalence and Natural History
Authors: Schini Marian , Jacques Richard M , Oakes Eleanor , Peel Nicola F A , Walsh Jennifer S , Eastell Richard 
Published: February 2020

Abstract

Context
Normocalcemic hyperparathyroidism (NPHPT) is characterized by persistently normal calcium levels and elevated parathyroid hormone (PTH) values, after excluding other causes of secondary hyperparathyroidism. The prevalence of the disease varies greatly and the data on the natural history of this disease are sparse and inconclusive.

Objectives
The objectives of this study are to describe the prevalence of NPHPT and its natural history in a referral population and to compare the variability of serum calcium with a group of patients with primary hyperparathyroidism (PHPT).

Design
A retrospective study was conducted over 5 years.

Setting
The setting for this study was a metabolic bone referral center.

Patients
A total of 6280 patients were referred for a bone mineral density measurement (BMD).

Main Outcome Measures
The prevalence and natural history of NPHPT and variability of calcium were the main outcome measures.

Results
We identified NPHPT patients using data from the day of the BMD measurement. We excluded patients with low estimated glomerular filtration rate (eGFR) or vitamin D, or with no measurements available. Based on the evaluation of their medical files, we identified 11 patients with NPHPT (prevalence 0.18%). Only 4 patients had consistent normocalcemia throughout their follow-up, with only 2 also having consistently high PTH. None had consistently normal eGFR or vitamin D.
Intermittent hypercalcemia was present in 7 of the 11 NPHPT patients. The mean adjusted calcium was found to be significantly lower in the NPHPT group compared with the PHPT group but higher than the control group. PTH was similar for NPHPT and PHPT. These 2 groups had similar variability in serum calcium.

Conclusions
NPHPT patients often have episodes of hypercalcemia. We believe that NPHPT is a mild form of PHPT.
Corticotropin-releasing factor protects against ammonia neurotoxicity in isolated larval zebrafish brains
Authors: Williams Tegan A. , Bernier Nicholas J. 
Published: February 2020

ABSTRACTThe physiological roles of corticotropin-releasing factor (CRF) have recently been extended to cytoprotection. Here, to determine whether CRF is neuroprotective in fish, the effects of CRF against high environmental ammonia (HEA)-mediated neurogenic impairment and cell death were investigated in zebrafish. In vivo, exposure of 1 day post-fertilization (dpf) embryos to HEA only reduced the expression of the determined neuron marker neurod1. In contrast, in 5 dpf larvae, HEA increased the expression of nes and sox2, neural progenitor cell markers, and reduced the expression of neurog1, gfap and mbpa, proneuronal cell, radial glia and oligodendrocyte markers, respectively, and neurod1. The N-methyl-d-aspartate (NMDA) receptor inhibitor MK801 rescued the HEA-induced reduction in neurod1 in 5 dpf larvae but did not affect the HEA-induced transcriptional changes in other neural cell types, suggesting that hyperactivation of NMDA receptors specifically contributes to the deleterious effects of HEA in determined neurons. As observed in vivo, HEA exposure elicited marked changes in the expression of cell type-specific markers in isolated 5 dpf larval brains. The addition of CRF reversed the in vitro effects of HEA on neurod1 expression and prevented an HEA-induced increase in cell death. Finally, the protective effects of CRF against HEA-mediated neurogenic impairment and cell death were prevented by the CRF type 1 receptor selective antagonist antalarmin. Together, these results provide novel evidence that HEA has developmental time- and cell type-specific neurotoxic effects, that NMDA receptor hyperactivation contributes to HEA-mediated impairment of determined neurons, and that CRF has neuroprotective properties in the larval zebrafish brain.
Universality, spectrality, proximity: The cinematic faces of Europe's other
Authors: Pantev Boris 
Published: February 2020

Abstract
For a number of scholars, the crisis of European identity is a result of the asymmetry between Europe's universal normative claims and its particular ethnic, cultural and racial contexts. This asymmetry is epitomized by the EU's failure to ratify its legally binding constitution. For others, the same asymmetry constitutes the very condition of being a European. Those envision Europeanness beyond its regulative idea as the ethical injunction of a promise to 'the other'. This article probes the validity of each of these arguments by juxtaposing two groups of films. Gianfraco Rosi's Fire at Sea (2016) and Ai Weiwei's Human Flow (2017) remain committed to the idea of human rights as a universal norm, an idea whose most prominent advocate is Jürgen Habermas. As an alternative to this view, Guido Hendrikx's Stranger in Paradise (2016) and Christian Petzold's Transit (2018) are taken to demonstrate what Jacques Derrida describes as 'hospitality' and 'spectrality'. Based on this analysis, the paper finds both models inadequate to hold together the irreconcilable modalities of the political and the ethical. To address this deficiency, it revisits Levinas' account of 'justice beyond the face' to propose an extension of the ethical view of Europeanness into the spheres of international law and public institutions.
Laju Pertumbuhan dan Pertumbuhan Mutlak Karang Lunak Cladiella sp. pada Substrat yang Berbeda
Authors: Fitriani Diah Putri , Zainuri Muhammad , Nugraha Wahyu Andy 
Published: February 2020

Soft corals have a soft textured skeletal like tiny spikes made of calcium carbonate present in their tissues. In general, soft corals are attached to hard substrates in the bottom of the waters. This study aims to determine the survival rate, relative and absolute growth rate, and comparison of soft coral growth rates on different substrates. The survival rate obtained was 100%, or 20 soft coral fragments lived until the end of the study. The growth rate and absolute growth of soft coral is relatively varied due to environmental and water quality, with the highest growth rate and absolute growth found in rubble substrate. week and 2,875 cm / week. There was no significant difference in growth rate of soft coral Cladiella sp. on the different substrate. In transplantation or soft coral cultivation activities, the selection of substrates becomes very important, and it is recommended to use rubble or dead coral substrates. Karang lunak mempunyai tekstur kerangka yang lunak berupa duri-duri kecil dari kalsium karbonat yang ada dalam jaringan tubuhnya. Pada umumnya karang lunak melekat pada substrat yang keras di dasar perairan. Penelitian ini bertujuan untuk mengetahui tingkat kelangsungan hidup, laju pertumbuhan relatif dan mutlak, dan perbandingan laju pertumbuhan karang lunak pada substrat yang berbeda. Tingkat kelangsungan hidup yang didapatkan yaitu 100 % atau 20 fragmen karang lunak dapat hidup sampai akhir penelitian. Laju pertumbuhan karang lunak relatif bervariasi karena pengaruh lingkungan dan kualitas air. Laju pertumbuhan dan pertumbuhan mutlak karang lunak Cladiella sp. relatif bervariasi karena pengaruh perbedaan substrat yang berbeda, dengan laju pertumbuhan dan pertumbuhan mutlak tertinggi ditemukan pada substrat rubble. Tidak ada perbedaan yang nyata pada laju pertumbuhan karang lunak Cladiella sp. pada substrat yang berbeda. Pada kegiatan transplantasi ataupun budidaya karang lunak, pemilihan substrat menjadi sangat penting, dan disarankan untuk menggunakan substrat rubble atau karang mati.
Simultaneous Impacts of Fe3O4{\text{Fe}_{3}}{\text{O}_{4}} Particles and Thermal Radiation on Natural Convection of Non-Newtonian Flow Between Two Vertical Flat Plates Using ADM
Authors: Gabli Ameur , Kezzar Mohamed , Zighed Lilia , Sari Mohamed Rafik , Tabet Ismail 
Published: February 2020

Abstract
The main aim of this research work is to show the simultaneous effects of ferro-particles (

Fe

3

O

4

{\text{Fe}_{3}}{\text{O}_{4}}

) and thermal radiation on the natural convection of non-Newtonian nanofluid flow between two vertical flat plates. The studied nanofluid is created by dispersing ferro-particles (

Fe

3

O

4

{\text{Fe}_{3}}{\text{O}_{4}}

) in sodium alginate (SA), which is considered as a non-Newtonian base fluid. Resolution of the resulting set of coupled non-linear second order differential equations characterizing dynamic and thermal distributions (velocity/temperature) is ensured via the Adomian decomposition method (ADM). Thereafter the obtained ADM results are compared to the Runge–Kutta–Feldberg based shooting data. In this investigation, a parametric study was conducted showing the influence of varying physical parameters, such as volumic fraction of

Fe

3

O

4

{\text{Fe}_{3}}{\text{O}_{4}}

nanoparticles, Eckert number (

E

c

{E_{c}}

) and thermal radiation parameter (N), on the velocity distribution, the skin friction coefficient, the heat transfer rate and the temperature distribution. Results obtained also show the advantages of ferro-particles over other types of standard nanoparticles. On the other hand, this investigation demonstrates the accuracy of the adopted analytical ADM technique.
Smell terms are not rara: A semantic investigation of odor vocabulary in Thai
Authors: Wnuk Ewelina , Laophairoj Rujiwan , Majid Asifa 
Published: February 2020

AbstractLarge lexica of basic smell terms are considered to be restricted to a handful of small languages of non-industrialized societies. Accordingly, they are thought to belong to the sphere of rara within lexical typology (Plank 2001.Das grammatische Raritätenkabinett. Konstanz: University of Konstanz.https://typo.uni-konstanz.de/rara/intro/index.php(accessed 3 October 2017)). However, smell lexica might in fact be more common than previously suggested. In this article, we discuss the case of Thai – a language with a population of tens of millions of speakers – which defies this assumption. We show Thai has a sizeable lexicon of terms for olfactory qualities, and investigate their semantics using a multi-method approach. In particular, we demonstrate a novel use of exemplar listing where – in addition to giving insights into the terms’ extensions – exemplar data is used to reveal the structure of the lexicon. Additionally, we use corpus data to provide complementary information on meaning and usage, thereby showing the advantage of multi-method approaches. Overall, the findings suggest smell lexica are not rara, and their distribution in the world’s languages goes beyond the stereotypical cases of languages spoken by small-scale societies.