RESUMO
Drug discovery is challenged by ineffectiveness of drugs against variable and evolving diseases, and adverse effects due to poor selectivity. We describe a robust platform which potentially addresses these limitations. The platform enables rapid discovery of DNA oligonucleotides evolved in vitro for exerting specific and selective biological responses in target cells. The process operates without a priori target knowledge (mutations, biomarkers, etc). We report the discovery of oligonucleotides with direct, selective cytotoxicity towards cell lines, as well as patient-derived solid and hematological tumors. A specific oligonucleotide termed E8, induced selective apoptosis in triple-negative breast cancer (TNBC) cells. Polyethylene glycol-modified E8 exhibited favorable biodistribution in animals, persisting in tumors up to 48-hours after injection. E8 inhibited tumors by 50% within 10 days of treatment in patient-derived xenograft mice, and was effective in ex vivo organ cultures from chemotherapy-resistant TNBC patients. These findings highlight a drug discovery model which is target-tailored and on-demand.
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Oligodesoxirribonucleotídeos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Sequência de Bases , Linhagem Celular Tumoral , Células Cultivadas , Modelos Animais de Doenças , Descoberta de Drogas/métodos , Ensaios de Seleção de Medicamentos Antitumorais , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Camundongos , Modelos Moleculares , Conformação Molecular , Conformação de Ácido Nucleico , Oligodesoxirribonucleotídeos/química , Oligodesoxirribonucleotídeos/uso terapêutico , Relação Estrutura-Atividade , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The Monty Hall problem is a decision problem with an answer that is surprisingly counter-intuitive yet provably correct. Here we simulate and prove this decision in a high-throughput DNA sequencing machine, using a simple encoding. All possible scenarios are represented by DNA oligonucleotides, and gameplay decisions are implemented by sequencing these oligonucleotides from specific positions, with a single run simulating more than 12,000,000 independent games. This work highlights high-throughput DNA sequencing as a new tool that could extend existing capabilities and enable new encoding schemes for problems in DNA computing.
Assuntos
Computadores Moleculares , Sequenciamento de Nucleotídeos em Larga Escala , Resolução de Problemas , Humanos , Análise de Sequência de DNARESUMO
New types of robots inspired by biological principles of assembly, locomotion, and behavior have been recently described. In this work we explored the concept of robots that are based on more fundamental physical phenomena, such as fluid dynamics, and their potential capabilities. We report a robot made entirely of non-Newtonian fluid, driven by shear strains created by spatial patterns of audio waves. We demonstrate various robotic primitives such as locomotion and transport of metallic loads-up to 6-fold heavier than the robot itself-between points on a surface, splitting and merging, shapeshifting, percolation through gratings, and counting to 3. We also utilized interactions between multiple robots carrying chemical loads to drive a bulk chemical synthesis reaction. Free of constraints such as skin or obligatory structural integrity, fluid robots represent a radically different design that could adapt more easily to unfamiliar, hostile, or chaotic environments and carry out tasks that neither living organisms nor conventional machines are capable of.
