bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of BRCA1, BRCA2, and ATM Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound
Authors: Chi Kim N. , Barnicle Alan , Sibilla Caroline , Lai Zhongwu , Corcoran Claire , Barrett J. Carl , Adelman Carrie A. , Qiu Ping , Easter Ashley , Dearden Simon , Oxnard Geoffrey R. , Agarwal Neeraj , Azad Arun , de Bono Johann , Mateo Joaquin , Olmos David , Thiery-Vuillemin Antoine , Harrington Elizabeth A. 
Published: August 2022

Abstract

Purpose:
Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing. Furthermore, samples may fail because of difficulties within the testing procedure. Optimization of screening techniques may reduce failure rates; however, a need remains for additional testing methods to detect cancers with alterations in homologous recombination repair genes. We evaluated the utility of plasma-derived circulating tumor DNA (ctDNA) in identifying deleterious BRCA1, BRCA2 (BRCA), and ATM alterations in screened patients with mCRPC from the phase III PROfound study.

Patients and Methods:
Tumor tissue samples were sequenced prospectively at Foundation Medicine, Inc. (FMI) using an investigational next-generation sequencing (NGS) assay based on FoundationOne®CDx to inform trial eligibility. Matched ctDNA samples were retrospectively sequenced at FMI, using an investigational assay based on FoundationOne®Liquid CDx.

Results:
81% (503/619) of ctDNA samples yielded an NGS result, of which 491 had a tumor tissue result. BRCA and ATM status in tissue compared with ctDNA showed 81% positive percentage agreement and 92% negative percentage agreement, using tissue as reference. At variant-subtype level, using tissue as reference, concordance was high for nonsense (93%), splice (87%), and frameshift (86%) alterations but lower for large rearrangements (63%) and homozygous deletions (27%), with low ctDNA fraction being a limiting factor.

Conclusions:
We demonstrate that ctDNA can greatly complement tissue testing in identifying patients with mCRPC and BRCA or ATM alterations who are potentially suitable for receiving targeted PARP inhibitor treatments, particularly patients with no or insufficient tissue for genomic analyses.
Abstract IA19: Impact of single checkpoint inhibitors and biomarkers of response
Authors: El-Khoueiry Anthony 
Published: September 2022

Abstract
Single agent anti PD-1 antibodies have shown consistent safety and efficacy for the treatment of advanced hepatocellular carcinoma (HCC). Response rates range between 15 and 20% and the rate of grade 3 and 4 adverse events is generally below 25%. Recently, the HIMALAYA trial showed that durvalumab was non-inferior to sorafenib for first-line treatment of HCC. Further, Keynote-394 showed that pembrolizumab improved survival compared to placebo in second line treatment of HCC. Nivolumab was evaluated in a dedicated cohort of Checkmate 040 in patients with child pugh B cirrhosis and determined to have a manageable safety profile, similar to that in child pugh A. Given the fact that immunotherapy-based combinations are the current standard of care for advanced HCC, and given the absence of biomarkers for patient selection, the use of single agent anti PD-1 or PD-L1 antibodies in advanced first line HCC treatment is limited to patients who are not candidates for combination therapy or patients with compromised liver function. Single agent anti PD-1/PD-L1 antibodies are being evaluated in the adjuvant setting and in combination with liver directed therapy. Emerging biomarker data suggest an association between T cell inflammation signature and outcome with single agent anti PD-1 and PD-L1 agents. Further research is needed to validate the early biomarker data.
Citation Format: Anthony El-Khoueiry. Impact of single checkpoint inhibitors and biomarkers of response [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA19.
Abstract IA24: IDH Inhibitors: Rationale, Molecular Mechanisms and Benefit
Authors: Zhu Andrew X. 
Published: September 2022

Abstract
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are the most frequently mutated metabolic genes across human cancers including cholangiocarcinoma. These hotspot gain-of-function mutations will lead to the IDH enzyme to aberrantly produce high levels of R-2-hydroxyglutarate (2-HG), which is thought to be the oncometabolite. 2-HG can competitively inhibit enzymes that regulate epigenetics, DNA repair, metabolism, and it can also modulate tumor immune microenvironment. IDH-1 mutations are particularly common in intrahepatic cholangiocarcinoma (iCCA), and their frequency varies depending on the geographic location and underlying etiology. Many inhibitors targeting mutant IDH (mIDH) are under active clinical development. Results from the phase III ClarIDHy trial have demonstrated that ivosidenib-a first-in-class, oral, small-molecule inhibitor of mutant IDH1, was well tolerated and could improve progression-free survival and a favorable overall survival benefit versus placebo, leading to the regulatory approval of ivosidenib in mIDH1 cholangiocarcinoma. The author will discuss the rationale, current clinical development, unanswered questions including the mechanism of resistance, and the optimal combination strategies that can more effectively harness mIDH as a therapeutic target.
Citation Format: Andrew X. Zhu. IDH Inhibitors: Rationale, Molecular Mechanisms and Benefit [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA24.
Abstract IA28: Advances in the pathogenesis and classification of pediatric hepatocellular neoplasms
Authors: Lopez-Terrada Dolores (Lola) 
Published: September 2022

Abstract
Hepatocellular neoplasms are the most common primary liver malignancies in children, with hepatoblastoma (HB) accounting for more than two-thirds of all cases. HB is a histologically heterogeneous embryonal tumor often recapitulating liver developmental stages, more commonly diagnosed during the first three years of life. HB classification has been historically challenged by its rarity and the lack of a systematic review of diagnostic tumor specimens. Recent international initiatives resulted in the development of international datasets (CHIC) and muti-consortia therapeutic trials (PHITT) that required a new pediatric liver tumors consensus classification. Meanwhile, genomic profiling is quickly advancing our understanding of HB and its biological heterogeneity, and allowing for the identification of biomarkers and biological subgroups of potential clinical relevance. Preliminary biological annotation of the International Consensus Classification, including diagnostic and prognostically relevant tumor subtypes, is ongoing. Molecular profiling of high-risk tumors, such as those in the HCN-NOS provisional category, is revealing histological and molecular features which are important to recognize to correctly diagnose and risk-stratify this group of patients. Current initiatives, including those led by clinical consortia participating in the International Pediatric Liver Tumors Trial (PHITT), are validating potential diagnostic and risk-stratifying biomarkers and engaged in exploratory studies, such genomic tumor profiling and investigation of novel therapeutic strategies, to be considered in upcoming trials.
Citation Format: Dolores (Lola) Lopez-Terrada. Advances in the pathogenesis and classification of pediatric hepatocellular neoplasms [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA28.
Abstract IA29: Present and future of precision oncology in hepatoblastoma
Authors: Armengol Carolina 
Published: September 2022

Abstract
Pediatric liver cancer is rare (~1 case/1 million) with increasing incidence. The commonest tumor seen usually in young children and infants without underlying liver disease is hepatoblastoma (HB). Despite significant advances during last decades thanks to improvements in chemotherapeutic regimens and efficient surgical approaches, treatment options remain limited for ~20% of patients with aggressive resistant tumours and more than 40% survivors have long-term effects derived from treatment toxicity. Because of the rarity of the disease, global international efforts on clinical, pathological and biological fields are crucial to improve the current clinical management of HB. In this talk, current clinical patient stratification (Children's Hepatic tumors International Collaboration Hepatoblastoma Stratification, CHIC-HS) and treatment of patients with HB (Pediatric Hepatic International Tumor Trial, PHITT) will be exposed. The main clinical, pathological and biological prognostic factors used at present will be also explained. Since it is well-known that therapy response in oncology is intimately associated with cancer biology, the need to improve the current CHIC stratification by incorporating biological data will be emerged as a way to significant move forward towards precision medicine in pediatric liver cancer patients. Moreover, a summary of the latest advances in genomic, transcriptomic and methylation studies and the diagnostic/prognostic biomarkers as well as newest therapeutic targets/drugs will be exposed. As a rare disease, the unmet need for banking human samples, patient-derived cell lines and animal models to enable and boost translational research of childhood liver tumors will be stressed. Finally, Dr. Armengol will explain the latest advances on biological and pathological studies associated to PHITT in Europe, ranging from sample collection to identification and validation of diagnostic/prognostic biomarkers. The ongoing PHITT patient cohort and its associated biorepositories will be exposed as an exceptional opportunity to validate a panel of diagnostic and prognostic biomarkers and novel therapeutic strategies that could be incorporated in the upcoming clinical trial (PHITT-2). Nowadays, ongoing international efforts at clinical, pathological and biological level from the three main childhood liver study groups of Europe (SIOPEL), United States (COG) and Japan (JCCG) are being conducted and will move forward precision medicine in HB, impacting on the quality of life and survival of patients with HB in a near future.
Citation Format: Carolina Armengol. Present and future of precision oncology in hepatoblastoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA29.
Abstract PO019: Gas6/Axl signaling induces PRAME expression in hepatocellular carcinoma
Authors: Hedrich Viola , Chen Doris , Huber Heidemarie , Mikulits Wolfgang 
Published: September 2022

Abstract
The receptor tyrosine kinase Axl, binding to its ligand Gas6, fosters oncogenic effects during the progression of hepatocellular carcinoma (HCC) which is accompanied by increased mortality of patients. The specific role of Gas6/Axl signaling in neoplastic hepatocytes and its pathophysiological consequences are poorly understood at the current stage of research. We aimed at identifying and functionally analyzing targets of Gas6/Axl signaling in HCC by exploiting well-characterized human HCC tumor models. HCC cells transformed by epithelial to mesenchymal transition (EMT) and expressing high levels of Axl or harboring CRISPR/Cas9-mediated Axl deficiency, the latter in absence or presence of Axl reconstitution, were subjected to Gas6 stimulation and subsequent RNA-seq analysis. Bioinformatics and VENN relations were applied to identify novel targets of the Gas6/Axl axis. Expression of Gas6/Axl targets was assessed in publicly available HCC patient datasets and in HCC tissue microarrays. In vitro analysis was performed including gain and loss of functions studies to unravel target genes contribution to EMT and HCC progression. RNA-seq analyses revealed PRAME (preferentially expressed antigen in melanoma) and C15orf48 among others as novel targets of Gas6/Axl. Notably, these target genes showed elevated expression levels in Axl-stratified HCC patients and significant impact on patient survival. Pharmacological or genetic interference with Axl signaling resulted in strongly reduced expression of PRAME and C15orf48, suggesting bona fide targets of Gas6/Axl signaling. PRAME expression positively regulated 2D cell migration and invasion of 3D hepatospheres while proliferation and survival of HCC cells remained unaffected by altered PRAME levels. In accordance, PRAME expression strongly associated with a mesenchymal-like phenotype in human HCC. Intriguingly, HCC patients expressing PRAME correlated with Axl expression and vascular invasion in a large proportion of HCC patients. Our study demonstrates that PRAME is a novel target of Gas6/Axl signaling in HCC linked to EMT. Translation of in vitro findings into the HCC patient situation provides first insights that PRAME plays a crucial role in HCC progression.
Citation Format: Viola Hedrich, Doris Chen, Heidemarie Huber, Wolfgang Mikulits. Gas6/Axl signaling induces PRAME expression in hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO019.
Hábitos de vida saludable en estudiantes del sur de Chile
Authors: Infante-Grandón Matías , Cerda Cristian , León-Herrera Miriam 
Published: September 2022

(analítico)Clasificar estudiantes según hábitos de vida saludable podría contribuir a optimizar programas de salud escolar, dado que existe escasa evidencia al respecto en Chile. Se determinaron grupos de estudiantes chilenos del sur, según hábitos de vida saludable. Se extrajeron datos de 1183 sujetos, desde una encuesta aplicada en 2017 en Lautaro. Se realizó un análisis de conglomerado jerárquico y se identificaron tres grupos. El primero presentó mayor actividad física y conducta alimentaria saludable (p < 0.05). El segundo presentó mayor tiempo de pantalla y conducta alimentaria menos saludable (p < 0.05). El tercero presentó menor tiempo de actividad física y menor conducta alimentaria (p < 0.05). Los estudiantes que practican más actividad física se alimentan mejor y quienes se mueven menos se alimentan menos. Estos hallazgos resultan útiles para el gobierno local.
Palabras clave: Estudiantes; actividad física; conducta alimentaria; tiempo de pantalla; análisis por conglomerados; Chile.
Neurostigma xanthopterum New, 1980 (Psocodea: Psocoptera: Epipsocidae): updated diagnosis, description of a female specimen, morphological variations and a checklist of all known species of the genus
Authors: Reategui Natália Soares , Rafael José Albertino , Silva-Neto Alberto Moreira da 
Published: September 2022

The holotype of the Neurostigma xanthopterum New, 1980 is here illustrated based on photographs. We also describe and illustrate a previously unknown female individual that is assigned to this species. New records for five localities in the Brazilian state of Amazonas, one in the Brazilian state of Acre and another in the Brazilian state of Amapá, are presented. The mouthparts of both sexes are here describe and illustrate. Thirteen types of variation and anomalies in the fore-hindwing veins were found. We found unique patterns in the number and shape of transverse veins in the pterostigma between individuals. We also identified a large variation in the denticles present in the lacinia. Therefore, we suggest these variable characteristics (fore-hindwing veins and lacinia denticles) are not to be used for the diagnosis of species of this genus. A revised diagnosis of N. Xanthopterum is also presented.
FAIR Equivalency with Regulatory Framework for Digital Health in Uganda
Authors: Basajja Mariam , Van Reisen Mirjam , Oladipo Francisca 
Published: August 2022

Abstract
This study explores the possibility of opening a policy window for the adoption of the FAIR Guidelines— that data be Findable, Accessible, Interoperable, and Reusable (FAIR)—in Uganda's eHealth sector. Although the FAIR Guidelines were not mentioned in any of the policy documents relevant to Uganda's eHealth sector, the study found that 83% of the documents mentioned FAIR Equivalent efforts, such as the adoption of the National Identification Number (NIN) as a unique identifier in Uganda's national Electronic Health Management Information System (eHMIS) (findability), the planned/ongoing integration of various information systems (interoperability), and the alignment of various projects with international best practices/standards (reusability). A FAIR Equivalency Score (FE-Score), devised in this study as an aggregate score of the mention of the equivalent of FAIR facets in the policy documents, showed that the documents at the core of Uganda's digital health/eHealth policy have the highest score of all the documents analysed, indicating that there is a degree of alignment between Uganda's National eHealth Vision and the FAIR Guidelines. Therefore, it can be concluded that favourable conditions exist for the adoption and implementation of the FAIR Guidelines in Uganda's eHealth sector. Hence, it is recommended that the FAIR community adopt a capacity building strategy through organisations with a worldwide mandate, such as the World Health Organization, to promote the adoption of the FAIR Guidelines as part of international best practices.
Nuremberg’s Enduring Legacy to International Justice
Authors: Lobo de Souza I.M. 
Published: August 2022

Abstract
The historic Nuremberg trial represented a first step toward an adequate response by the international society to grave crimes under international law committed by individuals in position of governmental authority. This article discusses three particular ways in which the Nuremberg trial has advanced international justice. From a normative perspective, it has helped crystallise the principle of individual criminal responsibility for crimes under international law. Furthermore, the Nuremberg tribunal’s extraordinary jurisdiction paved the way for domestic and international courts’ jurisdiction over crimes under international law, while instigating the evolution of relevant law concerning immunity from jurisdiction. Finally, in associating international crimes with the maintenance of international peace and security, it allowed the UN system of collective security to consider situations involving the commission of those crimes as a threat to international peace and security, preventing impunity and promoting the efficacy of international humanitarian law.
Pupil maximum constriction velocity predicts post-induction hypotension in patients with lower ASA status: a prospective observational study
Authors: Shao Luyi , Zhou Yaqing , Yue Zichuan , Gu Zhongya , Zhang Jie , Hui Kangli , Xiong Jingwei , Xu Miaomiao , Duan Manlin 
Published: August 2022

AbstractBackgroundIndividuals affected by autonomic dysfunction are at a higher risk of developing hypotension following anesthesia induction. Dynamic pupillometry has previously been employed as a means of assessing autonomic function. This prospective observational study was developed to determine whether pupillary light reflex (PLR) parameters can reliably predict post-induction hypotension (PIH).MethodsThis study enrolled patients with lower ASA status (I-II) undergoing elective surgery. PLR recordings for these patients prior to anesthesia induction were made with an infrared pupil camcorder, with a computer being used to assess Average Constriction Velocity (ACV), Maximum Constriction Velocity (MCV), and Constriction Ratio (CR). PIH was defined by a > 30% reduction in mean arterial pressure (MAP) or any MAP recording < 65 mmHg for at least 1 min from the time of induction until 10 minutes following intubation. Patients were stratified into PIH and non-PIH groups based on whether or not they developed hypotension.ResultsThis study enrolled 61 total patients, of whom 31 (50.8%) exhibited one or more hypotensive episodes. Patients in the PIH group exhibited significantly smaller ACV (P = 0.003) and MCV values (P < 0.001), as well as a higher CR (P = 0.003). Following adjustment for certain factors (Model 2), MCV was identified as a protective factor for PIH (Odds Ratio: 0.369). Receiver operating characteristic (ROC) analyses revealed that relative to CR (AUC: 0.695, 95% CI: 0.563–0.806;P = 0.004), the reciprocal of MCV (1/MCV) offered greater value as a predictor of PIH (AUC: 0.803,95%CI: 0.681–0.894;P < 0.001).ConclusionThese results indicate that pupil maximum constriction velocity is a reliable predictor of post-induction hypotension in individuals of ASA I-II status undergoing elective surgery.Trial registrationThis study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR2200057164, registration date: 01/03/2022).
Bridging the resources gap: deep learning for fluorescein angiography and optical coherence tomography macular thickness map image translation
Authors: Abdelmotaal Hazem , Sharaf Mohamed , Soliman Wael , Wasfi Ehab , Kedwany Salma M. 
Published: September 2022

Abstract
Background
To assess the ability of the pix2pix generative adversarial network (pix2pix GAN) to synthesize clinically useful optical coherence tomography (OCT) color-coded macular thickness maps based on a modest-sized original fluorescein angiography (FA) dataset and the reverse, to be used as a plausible alternative to either imaging technique in patients with diabetic macular edema (DME).

Methods
Original images of 1,195 eyes of 708 nonconsecutive diabetic patients with or without DME were retrospectively analyzed. OCT macular thickness maps and corresponding FA images were preprocessed for use in training and testing the proposed pix2pix GAN. The best quality synthesized images using the test set were selected based on the Fréchet inception distance score, and their quality was studied subjectively by image readers and objectively by calculating the peak signal-to-noise ratio, structural similarity index, and Hamming distance. We also used original and synthesized images in a trained deep convolutional neural network (DCNN) to plot the difference between synthesized images and their ground-truth analogues and calculate the learned perceptual image patch similarity metric.

Results
The pix2pix GAN-synthesized images showed plausible subjectively and objectively assessed quality, which can provide a clinically useful alternative to either image modality.

Conclusion
Using the pix2pix GAN to synthesize mutually dependent OCT color-coded macular thickness maps or FA images can overcome issues related to machine unavailability or clinical situations that preclude the performance of either imaging technique.

Trial registration
ClinicalTrials.gov Identifier: NCT05105620, November 2021. “Retrospectively registered”.