bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing data protection and governance in health information systems: a novel methodology of Privacy and Ethics Impact and Performance Assessment (PEIPA)
Authors: Di Iorio Concetta Tania , Carinci Fabrizio , Oderkirk Jillian , Smith David , Siano Manuela , de Marco Dorotea Alessandra , de Lusignan Simon , Hamalainen Paivi , Benedetti Massimo Massi 
Published: March 2020

BackgroundData processing of health research databases often requires a Data Protection Impact Assessment to evaluate the severity of the risk and the appropriateness of measures taken to comply with the European Union (EU) General Data Protection Regulation (GDPR). We aimed to define and apply a comprehensive method for the evaluation of privacy, data governance and ethics among research networks involved in the EU Project Bridge Health.MethodsComputerised survey among associated partners of main EU Consortia, using a targeted instrument designed by the principal investigator and progressively refined in collaboration with an international advisory panel. Descriptive measures using the percentage of adoption of privacy, data governance and ethical principles as main endpoints were used for the analysis and interpretation of the results.ResultsA total of 15 centres provided relevant information on the processing of sensitive data from 10 European countries. Major areas of concern were noted for: data linkage (median, range of adoption: 45%, 30%–80%), access and accuracy of personal data (50%, 0%–100%) and anonymisation procedures (56%, 11%–100%). A high variability was noted in the application of privacy principles.ConclusionsA comprehensive methodology of Privacy and Ethics Impact and Performance Assessment was successfully applied at international level. The method can help implementing the GDPR and expanding the scope of Data Protection Impact Assessment, so that the public benefit of the secondary use of health data could be well balanced with the respect of personal privacy.
The summer soundscape of a shallow-water estuary used by beluga whales in the western Canadian Arctic
Authors: Halliday William D. , Scharffenberg Kevin , Whalen Dustin , MacPhee Shannon A. , Loseto Lisa L. , Insley Stephen J. 
Published: March 2020

The soundscape is an important habitat component for marine animals. In the Arctic, marine conditions are changing rapidly due to sea ice loss and increased anthropogenic activities such as shipping, which will influence the soundscape. Here, we assess the contributors to the summer soundscape in the shallow waters of the Mackenzie River estuary within the Tarium Niryutait Marine Protected Area in the western Canadian Arctic, a core summering habitat for beluga whales (Delphinapterus leucas Pallas, 1776). We collected passive acoustic data during the summer over four years, and assessed the influence of physical variables, beluga whale vocalizations, and boat noise on sound pressure levels in three frequency bands (low: 0.2–1 kHz; medium: 1–10 kHz; high: 10–48 kHz) to quantify the soundscape. Wind speed, wave height, beluga vocalizations, and boat noise were all large contributors to the soundscape in various frequency bands. The soundscape varied to a lesser degree between sites, time of day, and with tide height, but remained relatively constant between years. This study is the first detailed description of a shallow summer soundscape in the western Canadian Arctic, an important habitat for beluga whales, and can be used as a baseline to monitor future changes during this season.
Regularization of electroweak monopole by charge screening and BPS energy bound
Authors: Zhang Pengming , Zou Liping , Cho Y. M. 
Published: March 2020

AbstractWe show that the electroweak monopole can be regularized with a non-vacuum electromagnetic permittivity. This allows us to set a new BPS bound for the monopole mass, which implies that the mass may not be smaller than 2.98 TeV, more probably 3.75 TeV. We demonstrate that the same method can also regularize the Dirac monopole, which enhances the possibility to construct the Dirac monopole of mass of a few hundred meV in condensed matters. We discuss the physical implications of our result.
Pancreatic Adenocarcinoma: Unconventional Approaches for an Unconventional Disease
Authors: Gromisch Christopher , Qadan Motaz , Machado Mariana Albuquerque , Liu Kebin , Colson Yolonda , Grinstaff Mark W. 
Published: March 2020

AbstractThis review highlights current treatments, limitations, and pitfalls in the management of pancreatic cancer and discusses current research in novel targets and drug development to overcome these clinical challenges. We begin with a review of the clinical landscape of pancreatic cancer, including genetic and environmental risk factors, as well as limitations in disease diagnosis and prevention. We next discuss current treatment paradigms for pancreatic cancer and the shortcomings of targeted therapy in this disease. Targeting major driver mutations in pancreatic cancer, such as dysregulation in the KRAS and TGFβ signaling pathways, have failed to improve survival outcomes compared with nontargeted chemotherapy; thus, we describe new advances in therapy such as Ras-binding pocket inhibitors. We then review next-generation approaches in nanomedicine and drug delivery, focusing on preclinical advancements in novel optical probes, antibodies, small-molecule agents, and nucleic acids to improve surgical outcomes in resectable disease, augment current therapies, expand druggable targets, and minimize morbidity. We conclude by summarizing progress in current research, identifying areas for future exploration in drug development and nanotechnology, and discussing future prospects for management of this disease.
Disease Monitoring Using Post-induction Circulating Tumor DNA Analysis Following First-Line Therapy in Patients with Metastatic Colorectal Cancer
Authors: Max Ma Xiaoju , Bendell Johanna C. , Hurwitz Herbert I. , Ju Christine , Lee John J. , Lovejoy Alex , Mancao Christoph , Nicholas Alan , Price Richard , Sommer Nicolas , Tikoo Nalin , Yao Lijing , Yaung Stephanie J. , Palma John F. 
Published: March 2020

AbstractPurpose:We assessed plasma circulating tumor DNA (ctDNA) level as a prognostic marker for progression-free survival (PFS) following first-line metastatic colorectal cancer (mCRC) therapy.Experimental Design:The Sequencing Triplet With Avastin and Maintenance (STEAM) was a randomized, phase II trial investigating efficacy of bevacizumab (BEV) plus 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) and 5-fluorouracil/leucovorin/irinotecan (FOLFIRI), administered concurrently or sequentially, versus FOLFOX-BEV in first-line mCRC. Evaluation of biomarkers associated with treatment outcomes was an exploratory endpoint. Patients in the biomarker-evaluable population (BEP) had 1 tissue sample, 1 pre-induction plasma sample, and 1 post-induction plasma sample collected ≤60 days of induction from last drug date.Results:Among the 280 patients enrolled in STEAM, 183 had sequenced and evaluable tumor tissue, 118 had matched pre-induction plasma, and 54 (BEP) had ctDNA-evaluable sequencing data for pre- and post-induction plasma. The most common somatic variants in tumor tissue and pre-induction plasma were TP53, APC, and KRAS. Patients with lower-than-median versus higher-than-median post-induction mean allele fraction (mAF) levels had longer median PFS (17.7 vs. 7.5 months, HR, 0.33; 95% confidence interval, 0.17–0.63). Higher levels of post-induction mAF and post-induction mean mutant molecules per milliliter (mMMPM), and changes in ctDNA (stratified by a 10-fold or 100-fold reduction in mAF between pre- and post-induction plasma), were associated with shorter PFS. Post-induction mAF and mMMPM generally correlated with each other (ρ = 0.987, P &lt; 0.0001).Conclusions:ctDNA quantification in post-induction plasma may serve as a prognostic biomarker for mCRC post-treatment outcomes.
Whole-Exome Sequencing Analysis of the Progression from Non–Low-Grade Ductal CarcinomaIn Situto Invasive Ductal Carcinoma
Authors: Pareja Fresia , Brown David N. , Lee Ju Youn , Da Cruz Paula Arnaud , Selenica Pier , Bi Rui , Geyer Felipe C. , Gazzo Andrea , da Silva Edaise M. , Vahdatinia Mahsa , Stylianou Anthe A. , Ferrando Lorenzo , Wen Hannah Y. , Hicks James B. , Weigelt Britta , Reis-Filho Jorge S. 
Published: March 2020

AbstractPurpose:Ductal carcinoma in situ (DCIS) is a nonobligate precursor of invasive breast cancer. Here, we sought to investigate the level of intralesion genetic heterogeneity in DCIS and the patterns of clonal architecture changes in the progression from DCIS to invasive disease.Experimental Design:Synchronous DCIS (n = 27) and invasive ductal carcinomas of no special type (IDC-NSTs; n = 26) from 25 patients, and pure DCIS (n = 7) from 7 patients were microdissected separately and subjected to high-depth whole-exome (n = 56) or massively parallel sequencing targeting ≥410 key cancer-related genes (n = 4). Somatic genetic alterations, mutational signatures, clonal composition, and phylogenetic analyses were defined using validated computational methods.Results:DCIS revealed genetic alterations similar to those of synchronously diagnosed IDC-NSTs and of non-related IDC-NSTs from The Cancer Genome Atlas (TCGA), whereas pure DCIS lacked PIK3CA mutations. Clonal decomposition and phylogenetic analyses based on somatic mutations and copy number alterations revealed that the mechanisms of progression of DCIS to invasive carcinoma are diverse, and that clonal selection might have constituted the mechanism of progression from DCIS to invasive disease in 28% (7/25) of patients. DCIS displaying a pattern of clonal selection in the progression to invasive cancer harbored higher levels of intralesion genetic heterogeneity than DCIS where no clonal selection was observed.Conclusions:Intralesion genetic heterogeneity is a common feature in DCIS synchronously diagnosed with IDC-NST. DCIS is a nonobligate precursor of IDC-NST, whose mechanisms of progression to invasive breast cancer are diverse and vary from case to case.
Comprehensive Genomic Analysis of Translocation Renal Cell Carcinoma Reveals Copy-Number Variations as Drivers of Disease Progression
Authors: Marcon Julian , DiNatale Renzo G. , Sanchez Alejandro , Kotecha Ritesh R. , Gupta Sounak , Kuo Fengshen , Makarov Vladimir , Sandhu Amar , Mano Roy , Silagy Andrew W. , Blum Kyle A. , Nassau Daniel E. , Benfante Nicole E. , Ortiz Michael V. , Carlo Maria I. , Chan Timothy A. , Motzer Robert J. , Voss Martin H. , Coleman Jonathan , Russo Paul , Reuter Victor , Hakimi A. Ari , Reznik Ed 
Published: March 2020

Abstract

Purpose:
Translocation renal cell carcinoma (tRCC) is a rare, aggressive renal cell carcinoma (RCC) subtype. There is currently limited understanding on the role of molecular alterations in the pathogenesis and progression of these tumors. We investigated the association between somatic alterations and clinical outcomes in two independent cohorts profiled using DNA sequencing.

Experimental Design:
Twenty-two tRCCs underwent targeted sequencing [Memorial Sloan Kettering Cancer Center (MSK)-IMPACT]; a subset was profiled using exome-sequencing and combined with exome data from The Cancer Genome Atlas (TCGA) for analysis. The prognostic value of specific somatic aberrations, tumor mutation burden (TMB), and fraction of copy-number–altered genome (FCNAg) was explored. In TCGA cases, neoantigen prediction and immune cell deconvolution were performed using RNA-sequencing and exome data. Overall survival estimates were computed using the Kaplan–Meier method; time-on-treatment was calculated for 14 MSK-IMPACT patients who underwent systemic therapy. Associations between molecular features and outcomes were evaluated using nonparametric testing.

Results:
Copy-number aberrant tRCCs were associated with poor overall survival (P = 0.03). Pediatric patients had tumors with lower FCNAg (P = 0.01). In one adult case with two chronologically distinct tumor samples sequenced, we confirmed that copy-number events occurred early during evolution. TERT promoter mutations were found exclusively in high-stage tumors. We found that tRCCs displayed distinct angiogenesis and PD-L1 gene expression profiles compared with other RCC subtypes.

Conclusions:
Tumors molecularly defined by increased copy-number variations were associated with aggressive disease in tRCC. A higher burden of genomic events in adults compared with pediatric cases likely reflects a more aggressive clinical course. The unique immunophenotypic characteristics of tRCC merit further exploration.
Wee1 Kinase Inhibitor AZD1775 Effectively Sensitizes Esophageal Cancer to Radiotherapy
Authors: Yang Linlin , Shen Changxian , Pettit Cory J. , Li Tianyun , Hu Andrew J. , Miller Eric D. , Zhang Junran , Lin Steven H. , Williams Terence M. 
Published: March 2020

Abstract

Purpose:
Esophageal cancer is a deadly malignancy with a 5-year survival rate of only 5% to 20%, which has remained unchanged for decades. Esophageal cancer possesses a high frequency of TP53 mutations leading to dysfunctional G1 cell-cycle checkpoint, which likely makes esophageal cancer cells highly reliant upon G2–M checkpoint for adaptation to DNA replication stress and DNA damage after radiation. We aim to explore whether targeting Wee1 kinase to abolish G2–M checkpoint sensitizes esophageal cancer cells to radiotherapy.

Experimental Design:
Cell viability was assessed by cytotoxicity and colony-forming assays, cell-cycle distribution was analyzed by flow cytometry, and mitotic catastrophe was assessed by immunofluorescence staining. Human esophageal cancer xenografts were generated to explore the radiosensitizing effect of AZD1775 in vivo.

Results:
The IC50 concentrations of AZD1775 on esophageal cancer cell lines were between 300 and 600 nmol/L. AZD1775 (100 nmol/L) as monotherapy did not alter the viability of esophageal cancer cells, but significantly radiosensitized esophageal cancer cells. AZD1775 significantly abrogated radiation-induced G2–M phase arrest and attenuation of p-CDK1-Y15. Moreover, AZD1775 increased radiation-induced mitotic catastrophe, which was accompanied by increased γH2AX levels, and subsequently reduced survival after radiation. Importantly, AZD1775 in combination with radiotherapy resulted in marked tumor regression of esophageal cancer tumor xenografts.

Conclusions:
Abrogation of G2–M checkpoint by targeting Wee1 kinase with AZD1775 sensitizes esophageal cancer cells to radiotherapy in vitro and in mouse xenografts. Our findings suggest that inhibition of Wee1 by AZD1775 is an effective strategy for radiosensitization in esophageal cancer and warrants clinical testing.
Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia
Authors: Laurent Anouchka P. , Siret Aurélie , Ignacimouttou Cathy , Panchal Kunjal , Diop M'Boyba , Jenni Silvia , Tsai Yi-Chien , Roos-Weil Damien , Aid Zakia , Prade Nais , Lagarde Stephanie , Plassard Damien , Pierron Gaelle , Daudigeos Estelle , Lecluse Yann , Droin Nathalie , Bornhauser Beat C. , Cheung Laurence C. , Crispino John D. , Gaudry Muriel , Bernard Olivier A. , Macintyre Elizabeth , Barin Bonnigal Carole , Kotecha Rishi S. , Geoerger Birgit , Ballerini Paola , Bourquin Jean-Pierre , Delabesse Eric , Mercher Thomas , Malinge Sebastien 
Published: March 2020

Abstract

Purpose:
Children with Down syndrome (constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse, compared with other children with B-cell acute lymphoblastic leukemia (B-ALL). This highlights the lack of suitable treatment for Down syndrome children with B-ALL.

Experimental Design:
To facilitate the translation of new therapeutic agents into clinical trials, we built the first preclinical cohort of patient-derived xenograft (PDX) models of DS-ALL, comprehensively characterized at the genetic and transcriptomic levels, and have proven its suitability for preclinical studies by assessing the efficacy of drug combination between the MEK inhibitor trametinib and conventional chemotherapy agents.

Results:
Whole-exome and RNA-sequencing experiments revealed a high incidence of somatic alterations leading to RAS/MAPK pathway activation in our cohort of DS-ALL, as well as in other pediatric B-ALL presenting somatic gain of the chromosome 21 (B-ALL+21). In murine and human B-cell precursors, activated KRASG12D functionally cooperates with trisomy 21 to deregulate transcriptional networks that promote increased proliferation and self renewal, as well as B-cell differentiation blockade. Moreover, we revealed that inhibition of RAS/MAPK pathway activation using the MEK1/2 inhibitor trametinib decreased leukemia burden in several PDX models of B-ALL+21, and enhanced survival of DS-ALL PDX in combination with conventional chemotherapy agents such as vincristine.

Conclusions:
Altogether, using novel and suitable PDX models, this study indicates that RAS/MAPK pathway inhibition represents a promising strategy to improve the outcome of Down syndrome children with B-cell precursor leukemia.
Oncogenic Genomic Alterations, Clinical Phenotypes, and Outcomes in Metastatic Castration-Sensitive Prostate Cancer
Authors: Stopsack Konrad H. , Nandakumar Subhiksha , Wibmer Andreas G. , Haywood Samuel , Weg Emily S. , Barnett Ethan S. , Kim Chloe J. , Carbone Emily A. , Vasselman Samantha E. , Nguyen Bastien , Hullings Melanie A. , Scher Howard I. , Morris Michael J. , Solit David B. , Schultz Nikolaus , Kantoff Philip W. , Abida Wassim 
Published: March 2020

Abstract

Purpose:
The genomic underpinning of clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer is unclear.

Experimental Design:
In patients with metastatic castration-sensitive prostate cancer at a tertiary referral center, clinical-grade targeted tumor sequencing was performed to quantify tumor DNA copy number alterations and alterations in predefined oncogenic signaling pathways. Disease volume was classified as high volume (≥4 bone metastases or visceral metastases) versus low volume.

Results:
Among 424 patients (88% white), 213 (50%) had high-volume disease and 211 (50%) had low-volume disease, 275 (65%) had de novo metastatic disease, and 149 (35%) had metastatic recurrence of nonmetastatic disease. Rates of castration resistance [adjusted hazard ratio, 1.84; 95% confidence interval (CI), 1.40–2.41] and death (adjusted hazard ratio, 3.71; 95% CI, 2.28–6.02) were higher in high-volume disease. Tumors from high-volume disease had more copy number alterations. The NOTCH, cell cycle, and epigenetic modifier pathways were the highest-ranking pathways enriched in high-volume disease. De novo metastatic disease differed from metastatic recurrences in the prevalence of CDK12 alterations but had similar prognosis. Rates of castration resistance differed 1.5-fold to 5-fold according to alterations in AR, SPOP (inverse), and TP53, and the cell cycle, WNT (inverse), and MYC pathways, adjusting for disease volume and other genomic pathways. Overall survival rates differed 2-fold to 4-fold according to AR, SPOP (inverse), WNT (inverse), and cell-cycle alterations. PI3K pathway alterations were not associated with prognosis once adjusted for other factors.

Conclusions:
This study identified genomic features associated with prognosis in metastatic castration-sensitive disease that may aid in molecular classification and treatment selection.
An Emerging Landscape for Canonical and Actionable Molecular Alterations in Primary and Metastatic Prostate Cancer
Authors: Dawson Nancy A. , Zibelman Matthew , Lindsay Timothy , Feldman Rebecca A. , Saul Michelle , Gatalica Zoran , Korn W. Michael , Heath Elisabeth I. 
Published: March 2020

Abstract
Patients with prostate cancer with tumors harboring defects in DNA-repair genes (DRD) generally do not respond well to AR-directed therapy. Furthermore, canonical pathways evolve during disease progression and may affect treatment with existing therapies. Due to the limited treatment options after failure of hormonal and taxane therapy, and the tumor heterogeneity induced by DRD, we sought to characterize the alterations in primary and metastatic prostate cancer. Tumors from 1,027 patients with advanced prostate cancer that underwent comprehensive genomic profiling for routine clinical care were reviewed to assess DRD mutation rates (27-gene panel) and co-occurring mutations in select canonical prostate cancer pathways. DRD alterations were identified in 20 genes and in 17% of patients (BRCA2 and ATM most common) occurring with slightly higher frequency in specimens from metastatic biopsy sites and men older than 50 years of age. Microsatellite instability-high (MSI-H) and tumor mutational burden-high occurred with 3% frequency in the overall cohort but were not enriched in metastatic disease. Biomarkers previously associated with antitumor immunity are found at high frequencies in MSI-H patients, including JAK1 (68%) and PTEN (32%). Lastly, mutations in TP53, AR, PTEN, APC, CTNNB1, and PIK3CA were all significantly enriched in metastatic samples. We identified clinically significant subgroups of patients demonstrating (1) defects in DNA-repair pathways, (2) intrinsic prostate cancer signaling pathways that may prevent antitumor immunity, and (3) distinct genomic differences between localized and metastatic prostate cancer. These results lend support that genomic profiling for advanced prostate cancer may identify actionable targets not routinely used in the current metastatic paradigm.
Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models
Authors: Zenke Frank T. , Zimmermann Astrid , Sirrenberg Christian , Dahmen Heike , Kirkin Vladimir , Pehl Ulrich , Grombacher Thomas , Wilm Claudia , Fuchss Thomas , Amendt Christiane , Vassilev Lyubomir T. , Blaukat Andree 
Published: March 2020

Abstract
Physical and chemical DNA-damaging agents are used widely in the treatment of cancer. Double-strand break (DSB) lesions in DNA are the most deleterious form of damage and, if left unrepaired, can effectively kill cancer cells. DNA-dependent protein kinase (DNA-PK) is a critical component of nonhomologous end joining (NHEJ), one of the two major pathways for DSB repair. Although DNA-PK has been considered an attractive target for cancer therapy, the development of pharmacologic DNA-PK inhibitors for clinical use has been lagging. Here, we report the discovery and characterization of a potent, selective, and orally bioavailable DNA-PK inhibitor, M3814 (peposertib), and provide in vivo proof of principle for DNA-PK inhibition as a novel approach to combination radiotherapy. M3814 potently inhibits DNA-PK catalytic activity and sensitizes multiple cancer cell lines to ionizing radiation (IR) and DSB-inducing agents. Inhibition of DNA-PK autophosphorylation in cancer cells or xenograft tumors led to an increased number of persistent DSBs. Oral administration of M3814 to two xenograft models of human cancer, using a clinically established 6-week fractionated radiation schedule, strongly potentiated the antitumor activity of IR and led to complete tumor regression at nontoxic doses. Our results strongly support DNA-PK inhibition as a novel approach for the combination radiotherapy of cancer. M3814 is currently under investigation in combination with radiotherapy in clinical trials.