scholarly journals Diverse noncoding mutations contribute to deregulation of cis-regulatory landscape in pediatric cancers

2020 ◽  
Vol 6 (30) ◽  
pp. eaba3064
Author(s):  
Bing He ◽  
Peng Gao ◽  
Yang-Yang Ding ◽  
Chia-Hui Chen ◽  
Gregory Chen ◽  
...  
Keyword(s):  
Joint Analysis ◽  
General Strategy ◽  
Expression Data ◽  
Full Spectrum ◽  
Computational Framework ◽  
Small Indels ◽  
Pediatric Cancers ◽  
Cancer Genomes ◽  
Regulatory Landscape

Interpreting the function of noncoding mutations in cancer genomes remains a major challenge. Here, we developed a computational framework to identify putative causal noncoding mutations of all classes by joint analysis of mutation and gene expression data. We identified thousands of SNVs/small indels and structural variants as putative causal mutations in five major pediatric cancers. We experimentally validated the oncogenic role of CHD4 overexpression via enhancer hijacking in B-ALL. We observed a general exclusivity of coding and noncoding mutations affecting the same genes and pathways. We showed that integrated mutation profiles can help define novel patient subtypes with different clinical outcomes. Our study introduces a general strategy to systematically identify and characterize the full spectrum of noncoding mutations in cancers.

scholarly journals Diverse noncoding mutations contribute to deregulation of cis-regulatory landscape in pediatric cancers

2019 ◽  
Author(s):  
Bing He ◽  
Peng Gao ◽  
Yang-Yang Ding ◽  
Chia-Hui Chen ◽  
Gregory Chen ◽  
...  
Keyword(s):  
Joint Analysis ◽  
General Strategy ◽  
Expression Data ◽  
Full Spectrum ◽  
Computational Framework ◽  
Small Indels ◽  
Pediatric Cancers ◽  
Cancer Genomes ◽  
Regulatory Landscape

AbstractInterpreting the function of noncoding mutations in cancer genomes remains a major challenge. Here we developed a computational framework to identify risk noncoding mutations of all classes by joint analysis of mutation and gene expression data. We identified thousands of SNVs/small indels and structural variants as candidate risk mutations in five major pediatric cancers. We experimentally validated the oncogenic role of CHD4 overexpression via enhancer hijacking in B-ALL. We observed a general exclusivity of coding and noncoding mutations affecting the same genes and pathways. We showed that integrated mutation signatures can help define novel patient subtypes with different clinical outcomes. Our study introduces a general strategy to systematically identify and characterize the full spectrum of noncoding mutations in cancers.

scholarly journals Structural variant detection in cancer genomes: computational challenges and perspectives for precision oncology

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Ianthe A. E. M. van Belzen ◽  
Alexander Schönhuth ◽  
Patrick Kemmeren ◽  
Jayne Y. Hehir-Kwa
Keyword(s):  
Intratumor Heterogeneity ◽  
Precision Oncology ◽  
Single Nucleotide Variants ◽  
Full Spectrum ◽  
Single Nucleotide ◽  
Sequencing Technologies ◽  
Cancer Genomes ◽  
Genomic Aberrations

AbstractCancer is generally characterized by acquired genomic aberrations in a broad spectrum of types and sizes, ranging from single nucleotide variants to structural variants (SVs). At least 30% of cancers have a known pathogenic SV used in diagnosis or treatment stratification. However, research into the role of SVs in cancer has been limited due to difficulties in detection. Biological and computational challenges confound SV detection in cancer samples, including intratumor heterogeneity, polyploidy, and distinguishing tumor-specific SVs from germline and somatic variants present in healthy cells. Classification of tumor-specific SVs is challenging due to inconsistencies in detected breakpoints, derived variant types and biological complexity of some rearrangements. Full-spectrum SV detection with high recall and precision requires integration of multiple algorithms and sequencing technologies to rescue variants that are difficult to resolve through individual methods. Here, we explore current strategies for integrating SV callsets and to enable the use of tumor-specific SVs in precision oncology.

scholarly journals Tackling the challenges of nanomedicines: are we ready?

2021 ◽  
Author(s):  
John B Hertig ◽  
Vinod P Shah ◽  
Beat Flühmann ◽  
Stefan Mühlebach ◽  
Gunar Stemer ◽  
...  
Keyword(s):  
Complex Nature ◽  
Pharmaceutical Sciences ◽  
Patient Benefit ◽  
World Congress ◽  
Clinical Safety ◽  
Hospital Pharmacists ◽  
Drug Products ◽  
Regulatory Bodies ◽  
Regulatory Landscape

Abstract Purpose This review provides an overview of the proceedings of the symposium “Tackling the Challenges of Nanomedicines: Are We Ready?” organized by the International Pharmaceutical Federation (FIP) Hospital Pharmacy Section and Non-Biological Complex Drugs (NBCDs) Working Group at the 2019 FIP World Congress of Pharmacy and Pharmaceutical Sciences. Debate centered on reasons underlying the current complex regulatory landscape for nanomedicines and their follow-on products (referred to as nanosimilars) and the pivotal role of hospital pharmacists in selecting, handling, and guiding usage of nanomedicines and nanosimilars. Summary The evaluation and use of nanomedicines are recognized among scientific, pharmaceutical, and regulatory bodies as complex. Interchangeability and substitutability of nanomedicines and nanosimilars are confounded by a lack of pharmaceutical and pharmacological equivalence, reflecting the inherent complex nature of these drug products and manufacturing processes. Consequences include implications for clinical safety and efficacy and, ultimately, comparability. Local regulatory approvals of some nanomedicines have occurred, but there is no standard to ensure streamlined evaluation and use of consistent measures of therapeutic equivalence of reference products and their nanosimilars. Hospital pharmacists are expected to be experts in the selection, handling, and substitution of nanomedicines and familiarize themselves with the limitations of current methods of assessing pharmaceutical and clinical equivalence of nanosimilars in order to ensure informed formulary decision-making and eventual patient benefit. Conclusion Supportive guidance for pharmacists focusing on the substitutability and/or interchangeability of nanomedicines and their nanosimilars is needed. Current FIP guidance for pharmacists on therapeutic interchange and substitution should be extended to include nanomedicines and nanosimilars.

The Rhetorical Case: Its Roman Precedent and the Current Debate

1989 ◽  
Vol 19 (3) ◽  
pp. 203-226 ◽  
Author(s):  
Michael Mendelson
Keyword(s):  
Problem Solving ◽  
Technical Writing ◽  
Current Debate ◽  
Case Study Method ◽  
Full Spectrum ◽  
Problem Solving Skills ◽  
Early Case ◽  
New Phase

Because of the recent emphasis on rhetorical context in business and technical writing (BTW) instruction, the problem-solving case has become a staple in BTW classrooms. However, a number of critics have voiced concerns about the use of the rhetorical case. These concerns recall an ancient debate among Roman rhetoricians over an early case-study method called declamation. For contemporary theorists, the debate over case study revolves around its value as a stimulant to problem-solving skills, its ability to imitate the realistic circumstances of professional BTW, and its emphasis on persona and audience along with its deemphasis of the teacher. A full spectrum of arguments on these and other issues in the case-study debate indicates that the discipline is entering a new phase in its deliberations over the role of problem-solving and pragmatics in the BTW classroom.

CNS relapse in DLBCL patients below 60 years treated with R-ACVBP, R-CHOEP, or R-CHOP: A joint analysis of LYSA and GLA/DSHNHL.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7543-7543
Author(s):  
Catherine Thieblemont ◽  
Bettina Altmann ◽  
Olivier Casasnovas ◽  
Fabian Frontzek ◽  
Franck Morschhauser ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Risk Groups ◽  
Observation Time ◽  
Joint Analysis ◽  
High Dose ◽  
First Line Therapy ◽  
Cns Relapse ◽  
Prophylactic Measures ◽  
Multicenter Clinical Trials

7543 Background: Central nervous system (CNS) relapse occurs in 2-6% of DLBCL patients (pts) increasing to 10% or more in high-risk groups. Intrathecal (IT) or intravenous high-dose methotrexate (HD MTX) have limited if any prophylactic impact on CNS relapse. To address the role of systemic first-line therapy in pts tolerating intensified strategies (R-ACVBP, R-(Mega)CHOEP, R-CHO(E)P), we compared CNS relapses occurring in a large cohort of pts ≤60 years. Methods: We conducted a retrospective analysis including previously untreated pts with DLBCL by central review, age 18-60 years, from multicenter clinical trials conducted by LYSA and GLA/DSHNHL (Table). We assessed the risk of CNS relapse in matched cohorts based on the aaIPI. Results: A total of 2203 pts were included. Median age was 47 years (18-60). 455 pts were treated with R-ACVBP, 444 with R-(Mega)CHOEP, 1304 with R-CHOP. Distribution of CNS IPI was not significantly different comparing R-ACVBP to R-CHO(E)P groups within aaIPI categories (Table). PFS and OS were comparable according to treatment within aaIPI groups, also adjusted for prognostic factors. No CNS events occured during observation time of 3 years in pts with aaIPI 0. In pts with aaIPI 1, no CNS event occured in the R-ACVPB arm, the 3y-cumulative incidence of CNS relapse for pts treated with R-CHO(E)P group was 1.0% (95%CI 0.3-1.7). In pts with aaIPI 2,3 and intermediate/high CNS IPI, four (1.6%) treated with R-ACVBP experienced relapse in the CNS compared to 15 (3.9%) pts treated with R-(Mega)CHO(E)P (3y-cumulative incidence 1.6% (95%CI 0-3.2) vs. 4.0% (95%CI 2.0-6.0). Conclusions: CNS relapse was extremely rare in younger DLBCL pts with aaIPI 0 or 1; prophylactic measures are not warranted. In pts with aaIPI 2,3 (and intermediate/high CNS-IPI), only 4 (1.6%) CNS relapses were seen with the R-ACVBP while 15 (3.9%) relapses did occur after R-(Mega)CHO(E)P. This analysis underlines the important role of the systemic therapy in controling CNS relapse.[Table: see text]

Microstructural Size Dependency in Nonlinear Lateral Stability of Random Reinforced Microshells via Meshfree-Based Applied Mathematical Modeling

2021 ◽  
pp. 2150164
Author(s):  
Jie-Hua Sun ◽  
Zhi-Dong Zhou ◽  
Saeid Sahmani ◽  
Babak Safaei
Keyword(s):  
Research Work ◽  
Meshfree Method ◽  
Resin Matrix ◽  
Small Scale ◽  
Lateral Stability ◽  
Computational Framework ◽  
Probabilistic Technique ◽  
Prime Objective ◽  
Shear Deformable

The prime objective of this research work is to develop an efficient small scale-dependent computational framework incorporating microstructural tensors of dilatation gradient, rotation gradient, and deviatoric stretch gradient to analyze nonlinear lateral stability of cylindrical microshells. The numerical strategy is established based upon a mixed formation of the third-order shear deformable shell model and modified strain gradient continuum mechanics. The graphene nanoplatelet reinforcements are assumed to be randomly dispersed in a checkerboard scheme within the resin matrix. Accordingly, to extract the effective material properties, the Monte Carlo simulation together with a probabilistic technique are employed. The numerical solution for the microstructural-dependent nonlinear problem is carried out via the moving Kriging meshfree method having the capability to accommodate accurately the essential boundary conditions using proper moving Kriging shape function. It is represented that the role of the stiffening characters related to the effect of microstructural dilatation gradient, rotation gradient, and deviatoric stretch reduces continuously by going to deeper territory of the load-deflection stability path. Moreover, it is indicated that among various microstructural gradient tensors, the stiffening character of the rotation gradient is higher than deviatoric stretch gradient, and the stiffening character of the latter is more considerable than the dilatation gradient tensor.

scholarly journals Collaborative Cross Founder Expression Analysis (CCFEA)

2021 ◽  
Author(s):  
Richard R Green ◽  
Renee C Ireton ◽  
Martin Ferris ◽  
Kathleen Muenzen ◽  
David R Crosslin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Gene Expression Data ◽  
Viral Infections ◽  
Collaborative Cross ◽  
Visualization Tool ◽  
Expression Data ◽  
Individual Gene ◽  
Rnaseq Data

To understand the role of genetic variation in SARS and Influenza infections we developed CCFEA, a shiny visualization tool using public RNAseq data from the collaborative cross (CC) founder strains (A/J, C57BL/6J, 129s1/SvImJ, NOD/ShILtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Individual gene expression data is displayed across founders, viral infections and days post infection.

scholarly journals Fit for Purpose? An Examination of the Jurisdiction of the Health and Disability Commissioner in New Zealand

2021 ◽  
Author(s):  
◽  
Adam Lothian Holloway
Keyword(s):  
New Zealand ◽  
Fit For Purpose ◽  
Regulatory Landscape

<p>This paper examines the role of the Health and Disability Commissioner. It does so by first describing the Commissioner's origins and place in the overall regulatory landscape for doctors in New Zealand. Different frameworks are then described within which the Commissioner's purpose, practice and outcomes can be assessed. Applying these frameworks, an assessment is made of the Commissioner's jurisdiction. Finally, informed by the foregoing assessment, this paper examines the regulatory landscape from a broader perspective, making tentative proposals for reforms.</p>

scholarly journals The pervasive role of pragmatics in early language

2019 ◽  
Author(s):  
Manuel Bohn ◽  
Michael C. Frank
Keyword(s):  
Language Learning ◽  
Common Ground ◽  
Social Cues ◽  
Social Reasoning ◽  
Early Language ◽  
Computational Framework ◽  
Linguistic Pragmatics ◽  
Developmental Continuity ◽  
Pragmatic Reasoning

Language is a fundamentally social endeavor. Pragmatics is the study of how speakers and listeners use social reasoning to go beyond the literal meanings of words to interpret language in context. In this review, we take a pragmatic perspective on language development and argue for developmental continuity between early non-verbal communication, language learning, and linguistic pragmatics. We link phenomena from these different literatures by relating them to a computational framework (the rational speech act framework), which conceptualizes communication as fundamentally inferential and grounded in social cognition. The model specifies how different information sources (linguistic utterances, social cues, common ground) are combined when making pragmatic inferences. We present evidence in favor of this inferential view and review how pragmatic reasoning supports children’s learning, comprehension, and use of language.

scholarly journals Functional cross-talk between allosteric effects of activating and inhibiting ligands underlies PKM2 regulation

2018 ◽  
Author(s):  
Jamie A. Macpherson ◽  
Alina Theisen ◽  
Laura Masino ◽  
Louise Fets ◽  
Paul C. Driscoll ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
High Activity ◽  
Pyruvate Kinase ◽  
Cross Talk ◽  
Glycolytic Enzyme ◽  
Computational Framework ◽  
Allosteric Inhibitor ◽  
Fructose 1,6 Bisphosphate ◽  
Low Activity

ABSTRACTAllosteric regulation is central to the role of the glycolytic enzyme pyruvate kinase M2 (PKM2) in cellular metabolism. Multiple activating and inhibitory allosteric ligands regulate PKM2 activity by controlling the equilibrium between high activity tetramers and low activity dimers and monomers. However, it remains elusive how allosteric inputs upon simultaneous binding of different ligands are integrated to regulate PKM2 activity. Here, we show that, in the presence of the allosteric inhibitor L-phenylalanine (Phe), the activator fructose 1,6-bisphosphate (FBP) can induce PKM2 tetramerisation, but fails to maximally increase enzymatic activity. Guided by a new computational framework we developed to identify residues that mediate FBP-induced allostery, we generated two PKM2 mutants, A327S and C358A, in which activation by FBP remains intact but cannot be attenuated by Phe. Our findings demonstrate a role for residues involved in FBP-induced allostery in enabling the integration of allosteric input from Phe and reveal a mechanism that underlies the co-ordinate regulation of PKM2 activity by multiple allosteric ligands.

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