Harvard University @Harvard – Scientists have identified the first chemical compounds able to inhibit and regulate CRISPR systems, which ultimately could make CRISPR gene-editing technologies more precise, efficient, and safe – New tool finds compounds that inhibit enzymes, enabling more precise and efficient technologies https://news.harvard.edu/gazette/story/2019/05/brigham-broad-institute-researchers-id-molecules-that-rein-in-crispr-systems/?utm_medium=social&utm_campaign=hu-twitter-general&utm_source=twitter

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  • – > Mestrado – Dissertation – Tabelas, Figuras e Gráficos – Tables, Figures and Graphics – ´´My´´ Dissertation @ #Innovation #energy #life #health #Countries #Time #Researches #Reference #Graphics #Ages #Age #Mice #People #Person #Mouse #Genetics #PersonalizedMedicine #Diagnosis #Prognosis #Treatment #Disease #UnknownDiseases #Future #VeryEfficientDrugs #VeryEfficientVaccines #VeryEfficientTherapeuticalSubstances #Tests #Laboratories #Investments #Details #HumanLongevity #DNA #Cell #Memory #Physiology #Nanomedicine #Nanotechnology #Biochemistry #NewMedicalDevices #GeneticEngineering #Internet #History #Science #World

Pathol Res Pract. 2012 Jul 15;208(7):377-81. doi: 10.1016/j.prp.2012.04.006. Epub 2012 Jun 8.

The influence of physical activity in the progression of experimental lung cancer in mice

Renato Batista Paceli 1Rodrigo Nunes CalCarlos Henrique Ferreira dos SantosJosé Antonio CordeiroCassiano Merussi NeivaKazuo Kawano NagaminePatrícia Maluf Cury


Impact_Fator-wise_Top100Science_Journals

GRUPO_AF1 – GROUP AFA1 – Aerobic Physical Activity – Atividade Física Aeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto

GRUPO AFAN 1 – GROUP AFAN1 – Anaerobic Physical Activity – Atividade Física Anaeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto

GRUPO_AF2 – GROUP AFA2 – Aerobic Physical Activity – Atividade Física Aeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto

GRUPO AFAN 2 – GROUP AFAN 2 – Anaerobic Physical Activity – Atividade Física Anaeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto

Slides – mestrado – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto

CARCINÓGENO DMBA EM MODELOS EXPERIMENTAIS

DMBA CARCINOGEN IN EXPERIMENTAL MODELS

Avaliação da influência da atividade física aeróbia e anaeróbia na progressão do câncer de pulmão experimental – Summary – Resumo – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto

https://pubmed.ncbi.nlm.nih.gov/22683274/

Abstract

Lung cancer is one of the most incident neoplasms in the world, representing the main cause of mortality for cancer. Many epidemiologic studies have suggested that physical activity may reduce the risk of lung cancer, other works evaluate the effectiveness of the use of the physical activity in the suppression, remission and reduction of the recurrence of tumors. The aim of this study was to evaluate the effects of aerobic and anaerobic physical activity in the development and the progression of lung cancer. Lung tumors were induced with a dose of 3mg of urethane/kg, in 67 male Balb – C type mice, divided in three groups: group 1_24 mice treated with urethane and without physical activity; group 2_25 mice with urethane and subjected to aerobic swimming free exercise; group 3_18 mice with urethane, subjected to anaerobic swimming exercise with gradual loading 5-20% of body weight. All the animals were sacrificed after 20 weeks, and lung lesions were analyzed. The median number of lesions (nodules and hyperplasia) was 3.0 for group 1, 2.0 for group 2 and 1.5-3 (p=0.052). When comparing only the presence or absence of lesion, there was a decrease in the number of lesions in group 3 as compared with group 1 (p=0.03) but not in relation to group 2. There were no metastases or other changes in other organs. The anaerobic physical activity, but not aerobic, diminishes the incidence of experimental lung tumors.

Science & Technology

Researchers ID molecules that rein in CRISPR systems

3D render of the CRISPR-Cas9 genome editing system
A 3-D render of the CRISPR-Cas9 genome editing system. iStock

New tool finds compounds that inhibit enzymes, enabling more precise and efficient technologies

By Karen Zusi Broad Institute Communications

DateMay 2, 2019 Share

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Scientists have identified the first chemical compounds able to inhibit and regulate CRISPR systems, which ultimately could make CRISPR gene-editing technologies more precise, efficient, and safe. To identify these compounds, the researchers developed a new platform for rapidly finding small molecules that suppress CRISPR enzymes.

Sometimes referred to as “anti-CRISPRs,” such molecules allow researchers to fine-tune CRISPR gene editing. The compounds could prevent CRISPR enzymes from unintentionally affecting other genes — having so-called “off-target effects” — and enable even greater precision in the lab and clinic.

The work, led by researchers from the Broad Institute and Brigham and Women’s Hospital, appears in Cell. 

“Precision control and countermeasures lie at the heart of any powerful technology,” said senior author Amit Choudhary, an associate member at the Broad Institute, associate biologist at Brigham and Women’s Hospital, and assistant professor of medicine at Harvard Medical School. “Consider our ability to harness drugs that induce anesthesia for surgery, and how proper control has turned them into extremely useful tools. Emerging CRISPR technologies, already being developed for gene therapies and biotechnology, likewise will require control across multiple dimensions.”

Fine-tuning CRISPR

As CRISPR technologies are developed to treat human disease, the ability to fine-tune CRISPR action will help ensure that the enzymes don’t have negative effects elsewhere in the body. These inhibitors could also accelerate basic biology research, offering a new precision tool for scientists to answer experimental questions quickly and at large scale.

CRISPR inhibitors also have the potential to help control gene drives in laboratory settings, according to the researchers. CRISPR-based gene drives are a molecular technology that guarantees an organism will pass on an engineered gene to all of its offspring. This process causes altered genes to spread much faster in a population than is naturally possible. Molecules that inhibit CRISPR enzymes could be applied to suppress this outcome, enabling further studies on gene drive technology.

In contrast to the protein-based inhibitors for CRISPR systems found in viruses, the newly identified molecules are small and readily reversible, and enter cells more efficiently. “We’re packing a lot of punch into a small area of chemical real estate,” says Choudhary.

Inhibiting Cas enzymes

To help control CRISPR’s activity, Choudhary and his colleagues focused on how these enzymes initially recognize their genomic target. The researchers developed a series of new biochemical and cellular tests to measure interactions between a CRISPR enzyme and its target, searching for molecules that could interfere with this essential first step.

To demonstrate the screening platform’s effectiveness, the team tailored the technology to find inhibitors of the Cas9 enzyme from Streptococcus pyogenesbacteria, the most commonly used Cas9 enzyme in CRISPR-based editing. They screened roughly 15,000 compounds to identify a series of potential inhibitors for Cas9; the top candidate was called BRD0539. These molecules successfully inhibited both natural and engineered forms of Cas9 in human cells. In addition, the researchers could vary their level to fine-tune the degree of inhibition, or simply remove them and as a result reenable CRISPR activity. 

Using the same experimental setup, the researchers are already identifying and developing the next generation of these molecules. The team is aiming to create a toolbox of compounds that can inhibit any CRISPR system.

“We have the platform, and we’ve demonstrated its effectiveness in a proof of concept,” Choudhary says. “Now we’re using it to find the next inhibitors for CRISPR systems. The application of chemistry-based approaches to CRISPR-based genome editing is just beginning.”

This work was supported in part by the Burroughs Wellcome Fund, DARPA, NIH, and the Army Research Office.

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