scholarly journals Pre-clinical validation of an RNA-based precision oncology platform for patient-therapy alignment in a diverse set of human malignancies resistant to standard treatments

2021 ◽  
Author(s):  
Prabhjot S. Mundi ◽  
Filemon S. Dela Cruz ◽  
Adina Grunn ◽  
Daniel Diolaiti ◽  
Audrey Mauguen ◽  
...  
Keyword(s):  
Predictive Power ◽  
De Novo ◽  
Objective Response ◽  
Joint Analysis ◽  
Precision Oncology ◽  
Action Analysis ◽  
Low Passage ◽  
Negative Controls ◽  
Protein Treatment

Predicting tumor sensitivity to antineoplastics remains an elusive challenge, with no methods demonstrating predictive power. Joint analysis of tumors-from patients with distinct malignancies who had progressed on multiple lines of therapy-and drug perturbation transcriptional profiles predicted sensitivity to 28 of 350 drugs, 26 of which (93%) were confirmed in low-passage, patient-derived xenograft (PDX) models. Drugs were prioritized based on their ability to either invert the activity of individual Master Regulator proteins, with available high-affinity inhibitors, or of the modules they comprise (Tumor-Checkpoints), based on de novo mechanism of action analysis. Of 138 PDX mice enrolled in 16 single and 18 multi-protein treatment arms, a disease control rate (DCR) of 68% and 91%, and an objective response rate (ORR) of 12% and 17%, were achieved respectively, compared to 6% and 0% in the negative controls arm, with multi-protein drugs achieving significantly more durable responses. Thus, these approaches may effectively complement and expand current precision oncology approaches, as also illustrated by a case study.

Deep Reinforcement Learning for Multiparameter Optimization in de novo Drug Design

2019 ◽  
Author(s):  
Niclas Ståhl ◽  
Göran Falkman ◽  
Alexander Karlsson ◽  
Gunnar Mathiason ◽  
Jonas Boström
Keyword(s):  
Reinforcement Learning ◽  
Short Term Memory ◽  
De Novo ◽  
De Novo Drug Design ◽  
Generative Process ◽  
New Methods ◽  
Multiparameter Optimization ◽  
Long Short Term Memory ◽  
New Compounds

<p>In medicinal chemistry programs it is key to design and make compounds that are efficacious and safe. This is a long, complex and difficult multi-parameter optimization process, often including several properties with orthogonal trends. New methods for the automated design of compounds against profiles of multiple properties are thus of great value. Here we present a fragment-based reinforcement learning approach based on an actor-critic model, for the generation of novel molecules with optimal properties. The actor and the critic are both modelled with bidirectional long short-term memory (LSTM) networks. The AI method learns how to generate new compounds with desired properties by starting from an initial set of lead molecules and then improve these by replacing some of their fragments. A balanced binary tree based on the similarity of fragments is used in the generative process to bias the output towards structurally similar molecules. The method is demonstrated by a case study showing that 93% of the generated molecules are chemically valid, and a third satisfy the targeted objectives, while there were none in the initial set.</p>

scholarly journals Status epilepticus from GABABR antibody positive encephalitis due to de novo mixed small cell and adenocarcinoma of the prostate

2020 ◽  
Vol 13 (11) ◽  
pp. e238172 ◽  
Author(s):  
Christopher Kwan ◽  
Aaron Sia ◽  
Cullen O'Gorman
Keyword(s):  
Status Epilepticus ◽  
De Novo ◽  
Locally Advanced ◽  
Small Cell ◽  
Gamma Aminobutyric Acid ◽  
Transrectal Biopsy ◽  
The Status ◽  
Adenocarcinoma Of The Prostate ◽  
Receptor Antibodies

We present a case study of a 67-year-old man who presented with a new onset of recurrent tonic-clonic seizures. He had tested positive to gamma-aminobutyric acid B receptor antibodies in his blood and cerebrospinal fluid, and subsequent CT imaging and transrectal biopsy confirmed the presence of a locally advanced mixed small cell and Gleason 9 adenocarcinoma of the prostate. His seizures remained resistant to treatment with multiple antiepileptic drugs, including sodium valproate, clobazam, topiramate, carbamazepine, phenytoin and lacosamide. He progressed to status epilepticus, which required intravenous immunoglobulin and steroids, followed by plasma exchange 1 week later. The status epilepticus was refractory and required multiple admissions to the intensive care unit.

scholarly journals Genome editing as a tool to achieve the crop ideotype and de novo domestication of wild relatives: Case study in tomato

Plant Science ◽  
2017 ◽  
Vol 256 ◽  
pp. 120-130 ◽  
Author(s):  
Agustin Zsögön ◽  
Tomas Cermak ◽  
Dan Voytas ◽  
Lázaro Eustáquio Pereira Peres
Keyword(s):  
Genome Editing ◽  
De Novo ◽  
Wild Relatives

scholarly journals FAILURES IN BRAZILIAN PUBLIC SOCIAL PROGRAMS TO REDUCE EXTREME POVERTY: case study Porto Alegre for all

2019 ◽  
Vol 23 (2) ◽  
pp. 786
Author(s):  
Gabriel R D Levrini
Keyword(s):  
Target Population ◽  
Social Program ◽  
Joint Analysis ◽  
Social Programs ◽  
Porto Alegre ◽  
Political Issue ◽  
Extreme Poverty ◽  
Human Needs ◽  
The Social

Poverty can be an economic circumstance, but it is also a political issue, since it directly influences several political decisions. The academic literature agrees that fundamental human needs have had, in fact, little development in their concept and scope within recent decades, although significantly changed happened in the Western way of accomplishing needs. We seek to understand different perspectives on possible different paths to a humanist articulation in the development of society. The goal of the research is through a humanistic approach based on Max Neef's theoretical precepts to understand the failure of the social program called Porto Alegre for All, in which less than 10% of the target population adopted the program. The research design had a qualitative phase with interviews with six target individuals, aiming to gain insights for the development of attributes and hierarchy of values for the use of the quantitative technique of joint analysis, made with a sample of 98 individuals. In our research the most important result was the attribute freedom, and the maternal pillar of the family is the great reference of these individuals.Keywords: Extreme Poverty. Freedom. Social programs. Fundamentals human needs.ResumoA pobreza pode ser uma circunstância econômica, mas também é uma questão política. A literatura acadêmica concorda que o conceito das necessidades humanas fundamentais teve, de fato, pouco desenvolvimento na sua atualização e escopo nas últimas décadas, embora mudanças significativas tenham ocorrido no modo ocidental de atender às necessidades. Buscamos a compreensão de diferentes perspectivas sobre os possíveis caminhos diferentes para uma articulação humanista no desenvolvimento da sociedade. O objetivo da pesquisa, é através de uma abordagem humanística baseada em preceitos teóricos de Max Neef compreender o fracasso do programa social denominado Porto Alegre para Todos, no qual menos de 10% da população-alvo adotou o programa. O design da pesquisa teve uma fase qualitativa com entrevistas com seis indivíduos target, com o objetivo de obter insights para o desenvolvimento dos atributos ehierarquia de valores para utilização da técnica quantitativa de análise conjunta, feita com uma amostra de 98 indivíduos. Na nossa pesquisa oresultado mais importantefoi o atributo liberdade, sendo que o pilar materno da familia e a grande referência destes individuos.Palavras-chave: Extrema pobreza. Liberdade. Programas sociais. Necessidades fundamentais humanas.

scholarly journals Drivers of Individual Credit Risk of Retail Customers—A Case Study on the Example of the Polish Cooperative Banking Sector

Risks ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 219
Author(s):  
Rafał Balina ◽  
Marta Idasz-Balina
Keyword(s):  
Credit Risk ◽  
Financial Institutions ◽  
Predictive Power ◽  
Banking Sector ◽  
Key Factors ◽  
Logit Regression ◽  
Local Character ◽  
History Of ◽  
Cooperative Banks

The main aim of the research was to determine the key factors determining the level of credit risk of individual clients (clients in the form of natural persons, excluding companies) on the example of Polish cooperative banks according to the following features: transaction characteristics, socio-demographic characteristics of the customer, the customer’s financial situation, the customer’s history of cooperation with the cooperative bank where they applied for a loan, and the customer’s history of cooperation with other financial institutions. For the research gathered data from 1000 credit applications submitted by individual customers when applying for a credit in five different cooperative banks were used for the analyses. To assess the credit risk of retail clients we use logit regression models, and additionally, score cards were calculated. The results of the research indicate that among the factors with high predictive power there were the features characterizing the client’s history of cooperation with the cooperative bank, where they applied for a loan. It may mean that when assessing credit risk related to financing individual customers, cooperative banks due to their local character, have an advantage over other financial institutions.

scholarly journals The Importance of the Scaffold for de Novo Enzymes: A Case Study with Kemp Eliminase

2017 ◽  
Vol 139 (16) ◽  
pp. 5793-5800 ◽  
Author(s):  
Asmit Bhowmick ◽  
Sudhir C. Sharma ◽  
Teresa Head-Gordon
Keyword(s):  
De Novo

scholarly journals Small RNA-Omics for Virome Reconstruction and Antiviral Defense Characterization in Mixed Infections of Cultivated Solanum Plants

2018 ◽  
Vol 31 (7) ◽  
pp. 707-723 ◽  
Author(s):  
Silvia Turco ◽  
Victor Golyaev ◽  
Jonathan Seguin ◽  
Céline Gilli ◽  
Laurent Farinelli ◽  
...  
Keyword(s):  
Potato Virus ◽  
Potato Virus Y ◽  
De Novo ◽  
Cross Protection ◽  
Mixed Infections ◽  
Antiviral Defense ◽  
Viral Quasispecies ◽  
Genome Sequences ◽  
Depth Analysis

In plants, RNA silencing–based antiviral defense generates viral small RNAs (sRNAs) faithfully representing the viral genomes. We employed sRNA sequencing and bioinformatics (sRNA-omics) to characterize antiviral defense and to reconstruct the full genomic sequences and their variants in the evolving viral quasispecies in cultivated solanaceous plants carrying mixed infections. In naturally infected Solanum tuberosum (potato), one case study revealed a virome comprising Potato virus Y (genus Potyvirus) and Potato virus X (genus Potexvirus), which was reconstructed by de novo–assembling separate genome-size sRNA contigs. Another case study revealed a virome comprising NTN and O strains of Potato virus Y, whose sRNAs assembled in chimeric contigs, which could be disentangled on the basis of reference genome sequences. Both viromes were stable in vegetative potato progeny. In a cross-protection trial of Solanum lycopersicum (tomato), the supposedly protective mild strain CH2 of Pepino mosaic virus (genus Potexvirus) was tested for protection against strain LP of the same virus. Reciprocal mechanical inoculations eventually resulted in co-infection of all individual plants with CH2 and LP strains, reconstructed as separate sRNA contigs. LP invasions into CH2-preinfected plants and vice versa were accompanied by alterations of consensus genome sequences in viral quasispecies, indicating a potential risk of cross-protection measures. Additionally, the study also revealed, by reconstruction from sRNAs, the presence of the mechanically nontransmissible Southern tomato virus (genus Amalgavirus) in some plants. Our in-depth analysis of sRNA sizes, 5′-nucleotide frequencies and hotspot maps revealed similarities in sRNA-generating mechanisms in potato and tomato, differential silencing responses to virome components and potential for sRNA-directed cross-targeting between viral strains which could not, however, prevent the formation of stable viromes.

Quantifying the temperature dependence of nitrate reduction in woodchip bioreactors: experimental and modeled results with applied case-study

2019 ◽  
Vol 5 (4) ◽  
pp. 782-797 ◽  
Author(s):  
Brian J. Halaburka ◽  
Gregory H. LeFevre ◽  
Richard G. Luthy
Keyword(s):  
Temperature Dependence ◽  
Nitrate Reduction ◽  
Predictive Power

The temperature dependence of denitrification in woodchip bioreactors was quantified using experimental and modeled results to enhance predictive power and applied to a case study.

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