bluuebunny/crossref_metadata_2025_split huggingface dataset:
DREAMM-5 platform trial: Belantamab mafodotin in combination with novel agents in patients with relapsed/refractory multiple myeloma (RRMM).
Authors: Richardson Paul G. , Biswas Swethajit , Holkova Beata , Jackson Nicola , Netherway Thelma , Paul Sofia , Ferron-Brady Geraldine , Yeakey Anne , Shelton Chris , Montes de Oca Rocio , Ahlers Christoph Matthias , Ballas Marc S. , Paul Elaine Marie , Gupta Ira , Opalinska Joanna , Luptakova Katarina 
Published: May 2020

TPS8552 Background: Single-agent belantamab mafodotin (GSK2857916), a B-cell maturation antigen targeting immunoconjugate, induced deep and durable responses in patients with RRMM, with a manageable safety profile (DREAMM-2, NCT03525678, Lancet Oncol.2020). A platform trial design allows efficient evaluation of belantamab mafodotin in combination with other anti-myeloma agents, such as a humanized wild-type IgG1 anti-OX40 agonist, an IgG4 inducible T-cell costimulatory (ICOS) agonist, and a gamma-secretase inhibitor. The unique, multimodal mechanisms of action (MoAs) of belantamab mafodotin, in combination with MoAs of these agents, has the potential to achieve synergistic effects in MM, to further enhance anti-myeloma activity without compromising safety. Methods: DREAMM-5 (NCT04162210) utilizes a master protocol with separate sub-studies comprised of sequential dose exploration (DE) and cohort expansion (CE) phases, to identify promising, effective belantamab mafodotin combinations when compared with a shared belantamab mafodotin monotherapy control arm (CE phase only). DE phases consist of multiple dosing cohorts with belantamab mafodotin combinations where patients are assigned to treatment slots by predetermined algorithmic approach (modified toxicity probability interval; N≤10 per cohort). Recommended phase 2 doses (RP2D) will be based on dose-limiting toxicities, safety, and pharmacokinetics. Interim analyses, based on overall response rate (ORR), determine if a RP2D is moved forward to a CE phase (N≥35 per cohort). Patients in the CE (stratified by number of prior therapies) will be randomized equally to open sub-studies. Eligible patients will have received ≥3 prior therapy lines which must include ≥1 immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody. The primary objectives are to identify RP2D for each combination (DE phase) and ORR (≥partial response, CE phase). Sub-studies 1 (combination with GSK3174998, OX40 agonist antibody) and 2 (combination with GSK3359609, ICOS agonist antibody) are currently enrolling. Sub-study 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics]) is projected to begin enrollment in the first half of 2020. Additional sub-studies will be explored based on scientific rationale and/or preclinical combination study results. Funding: GlaxoSmithKline (207495). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04162210 .
A phase Ib/II study of niraparib plus temozolomide plus atezolizumab versus atezolizumab as maintenance therapy in extensive-stage small cell lung cancer (TRIO-US L-06).
Authors: Cummings Amy Lauren , Kim David Dae-Young , Rosen Lee S. , Garon Edward B. , Wainberg Zev A. , Slamon Dennis J. , Goldman Jonathan Wade 
Published: May 2020

TPS9084 Background: Maintenance therapy is a promising therapeutic approach for extensive-stage small cell lung cancer (ES-SCLC), especially in light of IMpower 133 (Horn NEJM 2018). SCLC models of poly (ADP-ribose) polymerase (PARP) protein 1 and 2 inhibition suggested synergy with temozolomide (TMZ) (Wainberg AACR 2016). Combining PARP inhibition and TMZ with atezolizumab after first-line therapy for ES-SCLC may improve disease control. Methods: This is a phase 1b/2, randomized, open-label study of TMZ plus niraparib, a PARP inhibitor, with atezolizumab versus atezolizumab as maintenance therapy in adult patients with ES-SCLC after completion of platinum-based first-line chemotherapy. The primary outcome for phase 1b is the RP2D of TMZ in combination with niraparib, and for phase 2, progression-free survival (PFS). Secondary endpoints include safety, objective response rate, and overall survival. Exploratory endpoints include adverse events and patient-reported outcomes, including health-related quality of life. Phase 1b participants are required to have an advanced and incurable solid malignancy. Part one of phase 1b includes an accelerated lead-in of 12 participants treated in cohorts of 6 with an initial dose level of niraparib 200 mg po daily in 28-day cycles and low-dose TMZ 40 mg po daily on days 1-5 of each cycle. Part two includes a safety lead-in of 6 patients receiving standard-of-care atezolizumab, to which R2PD niraparib and TMZ will be added. For phase 2, participants are required to have ES-SCLC with a complete response or partial response per RECIST 1.1 following 4 to 6 cycles of platinum-based chemotherapy and ability to proceed to randomization within 7 weeks after day 1 of the last cycle of prior chemotherapy. Prophylactic WBRT is allowed prior to study. 52 participants will be stratified by a history of brain metastases and randomized 1:1 to atezolizumab with or without RP2D niraparib plus TMZ. There will be no cross-over between arms. To date, cohort 1 had two DLTs. Enrollment to dose level -1 and an intermediate dose have been completed without a DLT. The atezolizumab safety lead-in begins enrollment in March 2020. Clinical trial information: NCT03830918.
A phase II randomized study of telaglenastat, a glutaminase (GLS) inhibitor, versus placebo, in combination with pembrolizumab (Pembro) and chemotherapy as first-line treatment for KEAP1/NRF2-mutated non-squamous metastatic non-small cell lung cancer (mNSCLC).
Authors: Skoulidis Ferdinandos , Neal Joel W. , Akerley Wallace L. , Paik Paul K. , Papagiannakopoulos Thales , Reckamp Karen L. , Riess Jonathan W. , Jenkins Yonchu , Holland Sacha , Parlati Francesco , Shen Yijing , Whiting Sam H. , Rizvi Naiyer A. 
Published: May 2020

TPS9627 Background: Mutational activation of the KEAP1/NRF2 pathway occurs in >20% of NSCLC patients (pts). KEAP1/NRF2 activation protects tumor cells from diverse forms of oxidative stress and promotes tumor growth and survival. In pts w/ advanced NSCLC, mutation of the KEAP1/NRF2 pathway is associated w/ dramatically reduced survival and poor outcomes following standard-of-care therapy. These tumors have increased dependence on GLS-mediated conversion of glutamine to glutamate due to upregulation of NRF2 target genes involved in glutamine metabolism. Telaglenastat (CB-839), an investigational, first-in-class, potent, oral GLS inhibitor, has demonstrated preclinical activity in KEAP1/NRF2-mutated NSCLC cell lines and xenograft models. This study will evaluate the safety and efficacy of telaglenastat + standard-of-care pembro and chemotherapy as 1L therapy for KEAP1/NRF2-mutated non-squamous mNSCLC (NCT04265534). Methods: This phase II, randomized, multicenter, double-blind study will enroll ~120 pts with histologically or cytologically documented stage IV non-squamous NSCLC w/ KEAP1 or NRF2 mutation, no prior systemic therapy for mNSCLC, measurable disease (RECIST v1.1), ECOG PS 0-1, and no EGFR, ALK, ROS, or other actionable mutation w/ available approved therapy in 1L setting. KEAP1 or NRF2 mutations will be determined by next generation sequencing (NGS), and study-provided liquid biopsy NGS will be available. Pts will be randomized 1:1 to receive telaglenastat (800 mg BID PO) or placebo, in combination with pembro, carboplatin, and pemetrexed at standard doses on day 1 of each 21-day cycle. Pts will be stratified by STK11/LKB1 mutational status and M stage of cancer (M1a-b vs M1c). The study will include an initial safety run-in period (n=12; 1 cycle). Co-primary endpoints are safety and investigator-assessed progression-free survival (RECIST v1.1). Secondary endpoints include overall response rate, duration of response, overall survival, and efficacy analysis in the subgroup of pts w/ biochemical confirmation of KEAP1/NRF2 pathway activation. Findings of this novel NGS biomarker-selected study will inform the efficacy and safety profile of telaglenastat + standard-of-care chemoimmunotherapy for 1L treatment of KEAP1/NRF2-mutated, non-squamous mNSCLC. Clinical trial information: NCT04265534 .
Phase III trial of sitravatinib plus nivolumab vs. docetaxel for treatment of NSCLC after platinum-based chemotherapy and immunotherapy (SAPPHIRE).
Authors: Percent Ivor John , Reynolds Craig H. , Konduri Kartik , Whitehurst Matthew Thomas , Nidhiry Emmanuel A. , Yanagihara Ronald H. , Nagasaka Misako , Schreeder Marshall T , Uyeki James , Azzi Georges , Pachipala Krishna Kishore , Comer Jason C. , Lerner Rachel E. , Leal Ticiana , Alvarez Delia , Neuteboom Saskia T.C. , Reddinger Natasha , yan xiaohong , Shazer Ronald L. , Waterhouse David Michael 
Published: May 2020

TPS9635 Background: Sitravatinib is an oral spectrum-selective tyrosine kinase inhibitor that targets the TAM (TYRO3/AXL/MERTK) and split (VEGFR2/KIT) family receptor tyrosine kinases (RTKs), as well as MET. Inhibition of TAM RTKs may promote the depletion of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) and repolarize tumor associated macrophages towards the pro-inflammatory M1 phenotype. Inhibition of the split RTKs may reduce immunosuppressive regulatory T cells in addition to MDSCs within the TME. Given these pleiotropic immune-stimulating effects, sitravatinib may reverse resistance to checkpoint inhibitor therapy (CIT) and augment the antitumor immune response of nivolumab in patients (pts) with non-small cell lung cancer (NSCLC). An ongoing Phase 2 study (MRTX-500) demonstrates clinical activity of this combination in pts with metastatic non-squamous NSCLC after progression on or after CIT. Methods: Global, randomized, open-label, Phase 3 study of sitravatinib in combination with nivolumab vs docetaxel in pts with advanced non-squamous NSCLC who have progressed on or after CIT. Pts must have also received platinum-based chemotherapy either in combination with CIT or prior to CIT. Pts are randomized (1:1) to receive oral sitravatinib 120 mg once daily in continuous 28-day cycles combined with nivolumab IV 240 mg every 2 weeks or 480 mg every 4 weeks vs treatment with docetaxel 75 mg/m2 IV every 3 weeks. Patients are stratified based on number of prior treatment regimens in the advanced setting, ECOG performance status, and presence of brain metastases. Key eligibility criteria include duration of treatment of CIT of at least 4 months, discontinuation of prior treatment with CIT < 90 days prior to the date of randomization, and absence of symptomatic or uncontrolled brain metastases. The primary endpoint is overall survival (OS). Key secondary endpoints include safety and tolerability, ORR, PFS, PROs, and PK. OS will be analyzed using Kaplan-Meier methods and the stratified log-rank test to estimate and compare the median OS between the two treatment arms with 95% CI. An IDMC will review safety at regular intervals and efficacy at a planned interim analysis based on OS. Enrollment is ongoing. Clinical trial information: NCT03906071 .
TRIDENT-1: A global, multicenter, open-label Phase II study investigating the activity of repotrectinib in advanced solid tumors harboring ROS1 or NTRK1-3 rearrangements.
Authors: Doebele Robert Charles , Lin Jessica Jiyeong , Nagasaka Misako , Zhu Viola Weijia , Gabrail Nashat Y. , Bazhenova Lyudmila , Anderson Peter Meade , Solomon Benjamin J. , Dudek Arkadiusz Z. , Pippas Andrew William , Shirinian Mihran , Baik Christina S , Stopatschinskaja Shanna , Camidge D. Ross , Cho Byoung Chul , Drilon Alexander E. 
Published: May 2020

TPS9637 Background: Repotrectinib is a next-generation ROS1/TRK inhibitor with > 90-fold greater potency than crizotinib against ROS1 and > 100-fold greater potency than larotrectinib against TRK. Preclinical studies demonstrated inhibitory activity of repotrectinib against ROS1 resistance mutations, including the solvent-front mutation (SFM) G2032R. In the phase 1 portion of the study, repotrectinib was found to be well tolerated with encouraging antitumor activity including a 91% confirmed overall response (cORR) in TKI-naïve ROS1+ NSCLC pts. In ROS1+ NSCLC pts who received 1 prior chemo and 1 prior TKI, the cORR was 57% at the clinical dose of 160 mg QD or above. Intra-cranial (IC) activity was observed in ROS1+ NSCLC pts with measurable CNS disease (100% IC-ORR in TKI-naïve and 75% IC-ORR in patients with 1 prior TKI). Encouraging antitumor activity was observed in pts with NTRK+ solid tumors. Methods: A global phase 2 study was initiated and is actively enrolling. The primary endpoint for the Phase 2 study is cORR assessed by BICR (Blinded Independent Central Review) using RECIST v1.1, in each expansion cohort in pts with advanced solid tumors that harbor a ROS1 or NTRK1/2/3 gene fusion. Secondary endpoints include duration of response (DOR), progression-free survival (PFS), overall survival (OS), IC-ORR, IC-PFS, and quality of life assessments. All pts need to have RECIST 1.1 measurable disease confirmed by BICR and ECOG performance score ≤1. Repotrectinib is administered at 160 mg QD for 14 days and, if tolerated, the dose can be increased to 160 mg BID. Approximately 320 pts (≥12 years old) will be enrolled into 6 defined expansion cohorts, depending on the status of previous treatment with TKIs and cancer types (see table below). Clinical trial information: NCT03093116 . [Table: see text]
Development and Validation of Criteria for Sparing Confirmatory Tests in Diagnosing Primary Aldosteronism
Authors: Wang Kanran , Hu Jinbo , Yang Jun , Song Ying , Fuller Peter J , Hashimura Hikaru , He Wenwen , Feng Zhengping , Cheng Qingfeng , Du Zhipeng , Wang Zhihong , Ma Linqiang , Yang Shumin , Li Qifu 
Published: May 2020

Abstract

Context
The Endocrine Society Guidelines for the diagnosis of primary aldosteronism (PA) suggest that confirmatory tests (CFT) are not required when the following criteria are met: plasma aldosterone concentration (PAC) is &gt;20 ng/dL, plasma renin is below detection levels, and hypokalemia is present. The evidence for the applicability of the guideline criteria is limited.

Objective
To develop and validate optimized criteria for sparing CFT in the diagnosis of PA.

Design and Setting
The optimized criteria were developed in a Chinese cohort using the captopril challenge test, verified by saline infusion test (SIT) and fludrocortisone suppression test (FST), and validated in an Australian cohort.

Participants
Hypertensive patients who completed PA screening and CFT.

Main Outcome Measure
Diagnostic value of the optimized criteria.

Results
In the development cohort (518 PA and 266 non-PA), hypokalemia, PAC, and plasma renin concentration (PRC) were selected as diagnostic indicators by multivariate logistic analyses. The combination of PAC &gt;20 ng/dL plus PRC &lt;2.5 μIU/mL plus hypokalemia had much higher sensitivity than the guideline criteria (0.36 vs 0.11). The optimized criteria remained superior when the SIT or FST were used as CFT. Non-PA patients were not misdiagnosed by either criteria, but the percentage of patients in whom CFT could be spared was higher with the optimized criteria. In the validation cohort (125 PA and 81 non-PA), the sensitivity of the optimized criteria was also significantly higher (0.12 vs 0.02).

Conclusions
Hypertensive patients with PAC &gt;20 ng/dL, PRC &lt;2.5 μIU/mL, plus hypokalemia can be confidently diagnosed with PA without confirmatory tests.
Expression of SOAT1 in Adrenocortical Carcinoma and Response to Mitotane Monotherapy: An ENSAT Multicenter Study
Authors: Weigand Isabel , Altieri Barbara , Lacombe Amanda M F , Basile Vittoria , Kircher Stefan , Landwehr Laura-Sophie , Schreiner Jochen , Zerbini Maria C N , Ronchi Cristina L , Megerle Felix , Berruti Alfredo , Canu Letizia , Volante Marco , Paiva Isabel , Della Casa Silvia , Sbiera Silviu , Fassnacht Martin , Fragoso Maria Candida B V , Terzolo Massimo , Kroiss Matthias 
Published: May 2020

Abstract

Context
Objective response rate to mitotane in advanced adrenocortical carcinoma (ACC) is approximately 20%, and adverse drug effects are frequent. To date, there is no marker established that predicts treatment response. Mitotane has been shown to inhibit sterol-O-acyl transferase 1 (SOAT1), which leads to endoplasmic reticulum stress and cell death in ACC cells.

Objective
To investigate SOAT1 protein expression as a marker of treatment response to mitotane.

Patients
A total of 231 ACC patients treated with single-agent mitotane as adjuvant (n = 158) or advanced disease therapy (n = 73) from 12 ENSAT centers were included. SOAT1 protein expression was determined by immunohistochemistry on formalin-fixed paraffin-embedded specimens.

Setting
Retrospective study at 12 ACC referral centers.

Main outcome measure
Recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS).

Results
Sixty-one of 135 patients (45%) with adjuvant mitotane treatment had recurrences and 45/68 patients (66%) with mitotane treatment for advanced disease had progressive disease. After multivariate adjustment for sex, age, hormone secretion, tumor stage, and Ki67 index, RFS (hazard ratio [HR] = 1.07; 95% confidence interval [CI], 0.61-1.85; P = 0.82), and DSS (HR = 1.30; 95% CI, 0.58-2.93; P = 0.53) in adjuvantly treated ACC patients did not differ significantly between tumors with high and low SOAT1 expression. Similarly, in the advanced stage setting, PFS (HR = 1.34; 95% CI, 0.63-2.84; P = 0.45) and DSS (HR = 0.72; 95% CI, 0.31-1.70; P = 0.45) were comparable and response rates not significantly different.

Conclusions
SOAT1 expression was not correlated with clinical endpoints RFS, PFS, and DSS in ACC patients with mitotane monotherapy. Other factors appear to be relevant for mitotane treatment response and ACC patient survival.
A tájhasználat változása a Hódmezővásárhelyi kistérségben a földhasználat és a felszínborítás változásának tükrében
Authors: Kis Krisztián 
Published: May 2020

The proportion of the land use categories reflects the quality and intensity of the landscape use. According to the data the land use of the micro-region mostly defined by arable land, grassland (meadow/pasture), forest and uncultivated land, which are amounted to 99% of the area of the micro-region during the examined period. In spite of the short examined period it can be concluded from the examination that considerable changes took place in the landscape use of the micro-region which can be derived from the land use and land cover changes. It can be assessed as favourably change that forest areas increased but the increase of uncultivated land at the same time can be less favourable assessed. The proportion of forest and semi-natural areas, wetlands and water bodies also increased as the positive result of the land use change.
Asymmetry between galaxies with different spin patterns: A comparison between COSMOS, SDSS, and Pan-STARRS
Authors: Shamir Lior 
Published: May 2020

Abstract
Previous observations of a large number of galaxies show differences between the photometry of spiral galaxies with clockwise spin patterns and spiral galaxies with counterclockwise spin patterns. In this study the mean magnitude of a large number of clockwise galaxies is compared to the mean magnitude of a large number of counterclockwise galaxies. The observed difference between clockwise and counterclockwise spiral galaxies imaged by the space-based COSMOS survey is compared to the differences between clockwise and counterclockwise galaxies imaged by the Earth-based SDSS and Pan-STARRS around the same field. The annotation of clockwise and counterclockwise galaxies is a fully automatic process that does not involve human intervention, and in all experiments both clockwise and counterclockwise galaxies are separated from the same fields. The comparison shows that the same asymmetry was identified by all three telescopes, providing strong evidence that the rotation direction of a spiral galaxy is linked to its luminosity as measured from Earth. Analysis of the luminosity difference using a large number of galaxies from different parts of the sky shows that the difference between clockwise and counterclockwise galaxies changes with the direction of observation, and oriented around an axis.
Two mixed-ligand coordination polymers based on 2,5-thiophenedicarboxylic
acid and flexible N-donor ligands: the protective effect on periodontitis via
reducing the release of IL-1β and TNF-α
Authors: Wu Shao-Hsuan , Huang Jun-Hui 
Published: May 2020

Abstract
Two novel mixed-ligand coordination polymers, {[Co(tdc)(btrp)]·0.67DMF}
n
(1) and
{[Zn2(bimb)2(tdc)2]·2H2O}
n
(2) involving 2,5-thiophenedicarboxylate (H2tdc), and bitopic
flexible N-donor ligands, 1,3-bis(1,2,4-triazol-1-yl)propane (btrp) and
1,4-bis((1H-benzo[d]imidazol-1-yl)methyl)benzene
(bimb), have been synthesized by the hydrothermal method and characterized via IR,
elemental analysis, thermal analysis, and powder X-ray diffraction. The biological
functional studies were performed; the treatment activity of the compounds on
periodontitis and the specific mechanism was explored. First, the real-time RT-PCR
was carried out to determine the inflammatory genes nf-κb and
p53 relative expression in periodontal mucosal cells after
treating with compounds 1 and 2. Then, the level of the
inflammatory cytokine in the gingival crevicular fluid after treating with compounds
was also determined by the ELISA detection kit.
On some extension of Paley Wiener theorem
Authors: N’Da Ettien Yves-Fernand , Kangni Kinvi 
Published: May 2020

Abstract
Paley Wiener theorem characterizes the class of functions which are Fourier transforms of ℂ∞ functions of compact support on ℝ
n
by relating decay properties of those functions or distributions at infinity with analyticity of their Fourier transform. The theorem is already proved in classical case : the real case with holomorphic Fourier transform on L
2(ℝ), the case of functions with compact support on ℝ
n
from Hörmander and the spherical transform on semi simple Lie groups with Gangolli theorem.
Let G be a locally compact unimodular group, K a compact subgroup of G, and δ an element of unitary dual ̑K of K. In this work, we’ll give an extension of Paley-Wiener theorem with respect to δ, a class of unitary irreducible representation of K, where G is either a semi-simple Lie group or a reductive Lie group with nonempty discrete series after introducing a notion of δ-orbital integral. If δ is trivial and one dimensional, we obtain the classical Paley-Wiener theorem.
From ℋ∞ to 𝒩. Pointwise properties and algebraic structure in the Nevanlinna class
Authors: Massaneda Xavier , Thomas Pascal J. 
Published: May 2020

Abstract
This survey shows how, for the Nevanlinna class 𝒩 of the unit disc, one can define and often characterize the analogues of well-known objects and properties related to the algebra of bounded analytic functions ℋ∞: interpolating sequences, Corona theorem, sets of determination, stable rank, as well as the more recent notions of Weak Embedding Property and threshold of invertibility for quotient algebras. The general rule we observe is that a given result for ℋ∞ can be transposed to 𝒩 by replacing uniform bounds by a suitable control by positive harmonic functions. We show several instances where this rule applies, as well as some exceptions. We also briefly discuss the situation for the related Smirnov class.