bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complex Large-Bore Radial percutaneous coronary intervention: rationale of the COLOR trial study protocol
Authors: Meijers Thomas A , Aminian Adel , Teeuwen Koen , van Wely Marleen , Schmitz Thomas , Dirksen Maurits T , van der Schaaf Rene J , Iglesias Juan F , Agostoni Pierfrancesco , Dens Joseph , Knaapen Paul , Rathore Sudhir , Ottervanger Jan Paul , Dambrink Jan-Henk E , Roolvink Vincent , Gosselink A T Marcel , Hermanides Renicus S , van Royen Niels , van Leeuwen Maarten A H 
Published: July 2020

IntroductionThe radial artery has become the standard access site for percutaneous coronary intervention (PCI) in stable coronary artery disease and acute coronary syndrome, because of less access site related bleeding complications. Patients with complex coronary lesions are under-represented in randomised trials comparing radial with femoral access with regard to safety and efficacy. The femoral artery is currently the most applied access site in patients with complex coronary lesions, especially when large bore guiding catheters are required. With slender technology, transradial PCI may be increasingly applied in patients with complex coronary lesions when large bore guiding catheters are mandatory and might be a safer alternative as compared with the transfemoral approach.Methods and analysisA total of 388 patients undergoing complex PCI will be randomised to radial 7 French access with Terumo Glidesheath Slender (Terumo, Japan) or femoral 7 French access as comparator. The primary outcome is the incidence of the composite end point of clinically relevant access site related bleeding and/or vascular complications requiring intervention. Procedural success and major adverse cardiovascular events up to 1 month will also be compared between both groups.Ethics and disseminationEthical approval for the study was granted by the local Ethics Committee at each recruiting center (‘Medisch Ethische Toetsing Commissie Isala Zwolle’, ‘Commissie voor medische ethiek ZNA’, ‘Comité Medische Ethiek Ziekenhuis Oost-Limburg’, ‘Comité d’éthique CHU-Charleroi-ISPPC’, ‘Commission cantonale d'éthique de la recherche CCER-Republique et Canton de Geneve’, ‘Ethik Kommission de Ärztekammer Nordrhein’ and ‘Riverside Research Ethics Committee’). The trial outcomes will be published in peer-reviewed journals of the concerned literature.Trial registration numberNCT03846752.
Decreased Mitochondrial DNA Content Drives OXPHOS Dysregulation in Chromophobe Renal Cell Carcinoma
Authors: Xiao Yi , Clima Rosanna , Busch Jonas , Rabien Anja , Kilic Ergin , Villegas Sonia L. , Timmermann Bernd , Attimonelli Marcella , Jung Klaus , Meierhofer David 
Published: July 2020

Abstract

Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma are closely related, rare kidney tumors. Mutations in complex I (CI)-encoding genes play an important role in dysfunction of the oxidative phosphorylation (OXPHOS) system in renal oncocytoma, but are less frequently observed in chRCC. As such, the relevance of OXPHOS status and role of CI mutations in chRCC remain unknown. To address this issue, we performed proteome and metabolome profiling as well as mitochondrial whole-exome sequencing to detect mitochondrial alterations in chRCC tissue specimens. Multiomic analysis revealed downregulation of electron transport chain (ETC) components in chRCC that differed from the expression profile in renal oncocytoma. A decrease in mitochondrial (mt)DNA content, rather than CI mutations, was the main cause for reduced OXPHOS in chRCC. There was a negative correlation between protein and transcript levels of nuclear DNA- but not mtDNA-encoded ETC complex subunits in chRCC. In addition, the reactive oxygen species scavenger glutathione (GSH) was upregulated in chRCC due to decreased expression of proteins involved in GSH degradation. These results demonstrate that distinct mechanisms of OXPHOS exist in chRCC and renal oncocytoma and that expression levels of ETC complex subunits can serve as a diagnostic marker for this rare malignancy.

Significance:
These findings establish potential diagnostic markers to distinguish malignant chRCC from its highly similar but benign counterpart, renal oncocytoma.
Phase Ib Study of Wnt Inhibitor Ipafricept with Gemcitabine and nab-paclitaxel in Patients with Previously Untreated Stage IV Pancreatic Cancer
Authors: Dotan Efrat , Cardin Dana B. , Lenz Heinz-Josef , Messersmith Wells , O'Neil Bert , Cohen Steven J. , Denlinger Crystal S. , Shahda Safi , Astsaturov Igor , Kapoun Ann M. , Brachmann Rainer K. , Uttamsingh Shailaja , Stagg Robert J. , Weekes Colin 
Published: July 2020

Abstract

Purpose:
The recombinant fusion protein ipafricept blocks Wnt signaling, and in combination with gemcitabine and nab-paclitaxel caused tumor regression in xenografts. This phase Ib study evaluated the combination of ipafricept with nab-paclitaxel + gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma (mPDAC).

Patients and Methods:
Dose escalation started with standard dose nab-paclitaxel + gemcitabine and ipafricept (3.5 mg/kg days 1, 15). Because of fragility fractures seen with different anti-Wnt agents, following cohorts had ≥6 patients treated with ipafricept 3 to 5 mg/kg on day 1, and included bone marker monitoring and prophylactic bisphosphonates as indicated. On the basis of preclinical data, sequential dosing was evaluated in cohort 4 (ipafricept day 1 followed nab-paclitaxel + gemcitabine day 3). Objectives included safety, MTD, recommended phase II dose, pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy.

Results:
A total of 26 patients were enrolled, five in cohort 1 and seven each in cohorts 2–4. ipafricept-related adverse events (AEs) of any grade included fatigue, nausea, vomiting, anorexia, and pyrexia. ipafricept-related AEs grade ≥3 included two events of aspartate aminotransferase elevation, and one each of nausea, rash, vomiting, and leucopenia. No dose-limiting toxicities or fragility fractures were observed. Nine patients (34.6%) had partial response, 12 (46.2%) stable disease as best response, with clinical benefit rate of 81%. Median progression-free survival was 5.9 m [95% confidence interval (CI), 3.4–18.4], median overall survival was 9.7 m (95% CI, 7.0–14). The study was terminated by the sponsor due to bone-related toxicity within this therapeutic program and concerns for commercial viability. One patient remains on therapy under compassionate use.

Conclusions:
Ipafricept can be administered with nab-paclitaxel + gemcitabine with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.
Clinical Evaluation of (4S)-4-(3-[18F]Fluoropropyl)-L-glutamate (18F-FSPG) for PET/CT Imaging in Patients with Newly Diagnosed and Recurrent Prostate Cancer
Authors: Park Sonya Youngju , Na Sae Jung , Kumar Meena , Mosci Camila , Wardak Mirwais , Koglin Norman , Bullich Santiago , Mueller Andre , Berndt Mathias , Stephens Andrew W. , Cho Yong Mee , Ahn Hanjong , Chae Sun Young , Kim Hye Ok , Moon Dae Hyuk , Gambhir Sanjiv S. , Mittra Erik S. 
Published: July 2020

Abstract

Purpose:
(4S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid (18F-FSPG) is a radiopharmaceutical for PET imaging of system xC− activity, which can be upregulated in prostate cancer. We present data on the first evaluation of patients with newly diagnosed or recurrent prostate cancer with this radiopharmaceutical.

Experimental Design:
Ten patients with primary and 10 patients with recurrent prostate cancer were enrolled in this prospective multicenter study. After injection of 300 MBq of 18F-FSPG, three whole-body PET/CT scans were obtained. Visual analysis was compared with step-section histopathology when available as well as other imaging studies and clinical outcomes. Metabolic parameters were measured semiquantitatively. Expression levels of xCT and CD44 were evaluated by IHC for patients with available tissue samples.

Results:
18F-FSPG PET showed high tumor-to-background ratios with a relatively high tumor detection rate on a per-patient (89%) and per-lobe (87%) basis. The sensitivity was slightly higher with imaging at 105 minutes in comparison with 60 minutes. The maximum standardized uptake values (SUVmax) for cancer was significantly higher than both normal (P &lt; 0.005) and benign pathology (P = 0.011), while there was no significant difference between normal and benign pathology (P = 0.120). In the setting of recurrence, agreement with standard imaging was demonstrated in 7 of 9 patients (78%) and 13 of 18 lesions (72%), and revealed true local recurrence in a discordant case. 18F-FSPG accumulation showed moderate correlation with CD44 expression.

Conclusions:
18F-FSPG is a promising tumor imaging agent for PET that seems to have favorable biodistribution and high cancer detection rate in patients with prostate cancer. Further studies are warranted to determine the diagnostic value for both initial staging and recurrence, and how it compares with other investigational radiotracers and conventional imaging modalities.
Genomic and Clinicopathologic Characterization ofATM-deficient Prostate Cancer
Authors: Kaur Harsimar , Salles Daniela C. , Murali Sanjana , Hicks Jessica L. , Nguyen Minh , Pritchard Colin C. , De Marzo Angelo M. , Lanchbury Jerry S. , Trock Bruce J. , Isaacs William B. , Timms Kirsten M. , Antonarakis Emmanuel S. , Lotan Tamara L. 
Published: July 2020

AbstractPurpose:The ATM (ataxia telangiectasia mutated) gene is mutated in a subset of prostate cancers, and ATM mutation may confer specific therapeutic vulnerabilities, although ATM-deficient prostate cancers have not been well-characterized.Experimental Design:We genetically validated a clinical grade IHC assay to detect ATM protein loss and examined the frequency of ATM loss among tumors with pathogenic germline ATM mutations and genetically unselected primary prostate carcinomas using tissue microarrays (TMAs). Immunostaining results were correlated with targeted somatic genomic sequencing and clinical outcomes.Results:ATM protein loss was found in 13% (7/52) of primary Gleason pattern 5 cancers with available sequencing data and was 100% sensitive for biallelic ATM inactivation. In a separate cohort with pathogenic germline ATM mutations, 74% (14/19) had ATM protein loss of which 70% (7/10) of evaluable cases had genomic evidence of biallelic inactivation, compared with zero of four of cases with intact ATM expression. By TMA screening, ATM loss was identified in 3% (25/831) of evaluable primary tumors, more commonly in grade group 5 (17/181; 9%) compared with all other grades (8/650; 1%; P &lt; 0.0001). Of those with available sequencing, 80% (4/5) with homogeneous ATM protein loss and 50% (6/12) with heterogeneous ATM protein loss had detectable pathogenic ATM alterations. In surgically treated patients, ATM loss was not significantly associated with clinical outcomes in random-effects Cox models after adjusting for clinicopathologic variables.Conclusions:ATM loss is enriched among high-grade prostate cancers. Optimal evaluation of ATM status requires both genomic and IHC studies and will guide development of molecularly targeted therapies.
A Phase I Study of DLYE5953A, an Anti-LY6E Antibody Covalently Linked to Monomethyl Auristatin E, in Patients with Refractory Solid Tumors
Authors: Tolaney Sara M. , Do Khanh T. , Eder Joseph P. , LoRusso Patricia M. , Weekes Colin D. , Chandarlapaty Sarat , Chang Ching-Wei , Chen Shang-Chiung , Nazzal Denise , Schuth Eva , Brunstein Flavia , Carrasco-Triguero Montserrat , Darbonne Walter C. , Giltnane Jennifer M. , Flanagan William M. , Commerford S. Renee , Ungewickell Alexander , Shapiro Geoffrey I. , Modi Shanu 
Published: July 2020

Abstract

Purpose:
DLYE5953A is an antibody–drug conjugate consisting of an anti-LY6E antibody covalently linked to the cytotoxic agent monomethyl auristatin E. This study characterized the safety, pharmacokinetics, immunogenicity, potential biomarkers, and antitumor activity of DLYE5953A in patients with metastatic solid tumors.

Patients and Methods:
This was a phase I, open-label, 3+3 dose-escalation, and dose-expansion study of DLYE5953A administered intravenously every 21 days (Q3W) in patients with locally advanced or metastatic solid malignancies.

Results:
Sixty-eight patients received DLYE5953A (median, four cycles; range, 1–27). No dose-limiting toxicities were identified during dose escalation (0.2–2.4 mg/kg; n = 20). The recommended phase II dose (RP2D) of 2.4 mg/kg Q3W was based on overall safety and tolerability. Dose-expansion cohorts for HER2-negative metastatic breast cancer (HER2-negative MBC; n = 23) and non–small cell lung cancer (NSCLC; n = 25) patients were enrolled at the RP2D. Among patients receiving DLYE5953A 2.4 mg/kg (n = 55), the most common (≥30%) related adverse events (AEs) included alopecia, fatigue, nausea, and peripheral neuropathy. Grade ≥3 related AEs occurred in 14 of 55 (26%) patients, with neutropenia being the most common (13%). DLYE5953A demonstrated linear total antibody pharmacokinetics at doses of ≥0.8 mg/kg with low unconjugated monomethyl auristatin E levels in blood. Partial response was confirmed in eight of 68 (12%) patients, including three of 29 patients with MBC (10%) and five of 25 patients with NSCLC (20%) at the RP2D. Stable disease was the best response for 37 of 68 (54%) patients.

Conclusions:
DLYE5953A administered at 2.4 mg/kg has acceptable safety. Preliminary evidence of antitumor activity in patients with HER2-negative MBC and NSCLC supports further investigation of LY6E as a therapeutic target.
A Phase Ib/IIa Study of the Pan-BET Inhibitor ZEN-3694 in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer
Authors: Aggarwal Rahul R. , Schweizer Michael T. , Nanus David M. , Pantuck Allan J. , Heath Elisabeth I. , Campeau Eric , Attwell Sarah , Norek Karen , Snyder Margo , Bauman Lisa , Lakhotia Sanjay , Feng Felix Y. , Small Eric J. , Abida Wassim , Alumkal Joshi J. 
Published: July 2020

AbstractPurpose:ZEN-3694 is a bromodomain extraterminal inhibitor (BETi) with activity in androgen-signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide was evaluated in a phase Ib/IIa study in metastatic castration-resistant prostate cancer (mCRPC).Patients and Methods:Patients had progressive mCRPC with prior resistance to abiraterone and/or enzalutamide. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN-3694 at 48 and 96 mg orally once daily, respectively).Results:Seventy-five patients were enrolled (N = 26 and 14 in dose expansion at low- and high-dose ZEN-3694, respectively). Thirty (40.0%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 to 144 mg daily without reaching an MTD. Fourteen patients (18.7%) experienced grade ≥3 toxicities, including three patients with grade 3 thrombocytopenia (4%). An exposure-dependent decrease in whole-blood RNA expression of BETi targets was observed (up to fourfold mean difference at 4 hours post–ZEN-3694 dose; P ≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months [95% confidence interval (CI), 4.6–12.9] and composite median radiographic or clinical progression-free survival (PFS) was 5.5 months (95% CI, 4.0–7.8). Median duration of treatment was 3.5 months (range, 0–34.7+). Lower androgen receptor (AR) transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months).Conclusions:ZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity.
Multicenter Phase I/II Trial of Napabucasin and Pembrolizumab in Patients with Metastatic Colorectal Cancer (EPOC1503/SCOOP Trial)
Authors: Kawazoe Akihito , Kuboki Yasutoshi , Shinozaki Eiji , Hara Hiroki , Nishina Tomohiro , Komatsu Yoshito , Yuki Satoshi , Wakabayashi Masashi , Nomura Shogo , Sato Akihiro , Kuwata Takeshi , Kawazu Masahito , Mano Hiroyuki , Togashi Yosuke , Nishikawa Hiroyoshi , Yoshino Takayuki 
Published: July 2020

Abstract

Purpose:
This is a phase I/II trial to assess the efficacy and safety of napabucasin plus pembrolizumab for metastatic colorectal cancer (mCRC).

Patients and Methods:
Phase I was conducted to determine the recommended phase 2 dose (RP2D) in a dose escalation design of napabucasin (240 to 480 mg twice daily) with 200 mg pembrolizumab every 3 weeks. Phase II included cohort A (n = 10, microsatellite instability high, MSI-H) and cohort B (n = 40, microsatellite stable, MSS). The primary endpoint was immune-related objective response rate (irORR). PD-L1 combined positive score (CPS), genomic profiles, and the consensus molecular subtypes (CMS) of colorectal cancer were assessed.

Results:
A total of 55 patients were enrolled in this study. In phase I, no patients experienced dose-limiting toxicities, and napabucasin 480 mg was determined as RP2D. The irORR was 50.0% in cohort A and 10.0% in cohort B. In cohort B, the irORR was 0%, 5.3%, and 42.9% in CPS &lt; 1, 1≤ CPS &lt;10, and CPS ≥ 10, respectively. Patients with objective response tended to have higher tumor mutation burden than those without. Of evaluable 18 patients for CMS classification in cohort B, the irORR was 33.3%, 0%, 33.3%, and 33.3% in CMS1, CMS2, CMS3, and CMS4, respectively. The common grade 3 or higher treatment-related adverse events included fever (10.0%) in cohort A and decreased appetite (7.5%) and diarrhea (5.0%) in cohort B.

Conclusions:
Napabucasin with pembrolizumab showed antitumor activity with acceptable toxicities for patients with MSS mCRC as well as MSI-H mCRC, although it did not meet the primary end point. The impact of related biomarkers on the efficacy warrants further investigations in the additional cohort.
See related commentary by Nusrat, p. 5775
Promise in Preaching and Pop Culture: in Search of a Sermon for Latin American Vulnerable Life
Authors: Adam Júlio Cézar 
Published: July 2020

Abstract
This article aims to reflect on homiletics and Christian preaching as a voice of promise in the Brazilian and Latin American context. Initially it will reflect upon three characteristic types of relationship between preaching and promise: the eschatological and transcendentalist preaching that locates the promise in an afterlife or the end of times; the humanistic and liberating preaching that places the promise in the dimension of the socio-political struggle for transformation in the present; and, thirdly, the individualistic and prosperity-oriented preaching that projects promise as material achievement and hedonistic satisfaction. Finally, faced with this reality, we seek ways in literature (Two Words, by Isabel Allende) and in popular culture (Central do Brasil, a movie by Walter Salles) to help us in creating a sermon that announces the promise amid the daily and vulnerable life in order to contribute not merely to individual, ecclesial or ideological satisfaction, but to point to human and cultural transformations.
Franz Magnis-Suseno, Dialogue Ethics and Public Reasoning of Religions
Authors: Hardiman Fransisco Budi 
Published: July 2020

Abstract
The return of religion in politics is an important issue in a contemporary democracy. Franz Magnis-Suseno, a Jesuit, ethician and interfaith figure in Indonesia, provides a raft of interesting insights for interreligious dialogues in a pluralistic democracy. Through his publications, he seeks to assist Muslims and Christians to build an ethics of citizenship in a pluralistic democracy with the second Vatican theology of religions as his intellectual foundation. In this article, the author attempts to reconstruct the important points of Magnis-Suseno’s thoughts on dialogue ethics and identifies their relationships to the public reasoning of religions in a political public sphere. He comments that Magnis-Suseno demands more of religions than do Rawls and Habermas in terms of moderating their doctrinal positions vis-à-vis other religions.
Public Theology and the Anthropocene: Exploring Human-Animal Relations
Authors: van Urk Eva 
Published: July 2020

Abstract
Given that the current ecological crises are largely human-caused, it is an issue of public concern to promote views which appreciate non-human animals (and creation at large) as inherently and independently valuable, and which stimulate efforts to reverse trends towards mass extinction. This article examines how theologians may critically explore the Bible’s relevance in the Anthropocene. It will show that theology can both critically incorporate new attitudes towards non-human animals, as well as dig into its own reservoirs, like biblical stories for the sake of an appropriate response. Such ‘digging’ needs to consist of a willingness both to discover and actualize a biblical ecological wisdom and to unmask possible anthropocentric tendencies. It is assumed that theology will continue to prove itself to be an indispensable conversation partner in public spheres.
A Second-Order Closure Turbulence Model: New Heat Flux Equations and No Critical Richardson Number
Authors: Cheng Y. , Canuto V. M. , Howard A. M. , Ackerman A. S. , Kelley M. , Fridlind A. M. , Schmidt G. A. , Yao M. S. , Del Genio A. , Elsaesser G. S. 
Published: July 2020

Abstract
We formulate a new second-order closure turbulence model by employing a recent closure for the pressure–temperature correlation at the equation level. As a result, we obtain new heat flux equations that avoid the long-standing issue of a finite critical Richardson number. The new, structurally simpler model improves on the Mellor–Yamada and Galperin et al. models; a key feature includes enhanced mixing under stable conditions facilitating agreement with observational, experimental, and high-resolution numerical datasets. The model predicts a planetary boundary layer height deeper than predicted by models with low critical Richardson numbers, as demonstrated in single-column model runs of the GISS ModelE general circulation model.
Predicting Rainy Season Onset in the Ethiopian Highlands for Agricultural Planning
Authors: Lala Jonathan , Tilahun Seifu , Block Paul 
Published: July 2020

ABSTRACTThe Kiremt rainy season is the foundation of agriculture in the Ethiopian Highlands and a key driver of economic development as well as the instigator of famines that have plagued the country’s history. Despite the importance of these rains, relatively little research exists on predicting the season’s onset; even less research evaluates statistical modeling approaches, in spite of their demonstrated utility for decision-making at local scales. To explore these methods, predictions are generated conditioned on three definitions of onset, at three lead times, using partial least squares (PLS) regression and random forest classification. Results illustrate moderate prediction skill and an ability to avoid false onsets, which may guide planting decisions; however, they are highly sensitive to how onset is defined, suggesting that future prediction approaches should additionally consider local agricultural definitions of onset.