Risultati per: CRISP: Create nanoparticelle che modificano il genoma

This Viewpoint proposes a messaging framework called CREATE TRUST to improve written communication with patients.

Finanziate da Telethon e Cariplo per 3,2 milioni di euro

Dei centri di ricerca coinvolti, 14 su 22 si trovano in Lombardia. Gli altri sono dislocati in Emilia-Romagna, Friuli-Venezia Giulia, Marche, Piemonte e Toscana

Objective
Colorectal cancer (CRC) is a leading cause of cancer-related deaths, with the majority of cases initiated by inactivation of the APC tumour suppressor. This results in the constitutive activation of canonical WNT pathway transcriptional effector ß-catenin, along with induction of WNT feedback inhibitors, including the extracellular palmitoleoyl-protein carboxylesterase NOTUM which antagonises WNT-FZD receptor-ligand interactions. Here, we sought to evaluate the effects of NOTUM activity on CRC as a function of driver mutation landscape.

Design
Mouse and human colon organoids engineered with combinations of CRC driver mutations were used for Notum genetic gain-of-function and loss-of-function studies. In vitro assays, in vivo endoscope-guided orthotopic organoid implantation assays and transcriptomic profiling were employed to characterise the effects of Notum activity. Small molecule inhibitors of Notum activity were used in preclinical therapeutic proof-of-principle studies targeting oncogenic Notum activity.

Results
NOTUM retains tumour suppressive activity in APC-null adenomas despite constitutive ß-catenin activity. Strikingly, on progression to adenocarcinoma with P53 loss, NOTUM becomes an obligate oncogene. These phenotypes are Wnt-independent, resulting from differential activity of NOTUM on glypican 1 and 4 in early-stage versus late-stage disease, respectively. Ultimately, preclinical mouse models and human organoid cultures demonstrate that pharmacological inhibition of NOTUM is highly effective in arresting primary adenocarcinoma growth and inhibiting metastatic colonisation of distal organs.

Conclusions
Our findings that a single agent targeting the extracellular enzyme NOTUM is effective in treating highly aggressive, metastatic adenocarcinomas in preclinical mouse models and human organoids make NOTUM and its glypican targets therapeutic vulnerabilities in advanced CRC.

Annals of Internal Medicine, Ahead of Print.

Annals of Internal Medicine, Ahead of Print.

Circulation, Volume 148, Issue 13, Page 1055-1056, September 26, 2023.

Al Broad Institute di Mit e Harvard, verso nuovi farmaci

Objective
This study aimed to develop a tool to measure the extent of national efforts in policies, services, research and programmes implemented to cultivate and harness the benefits of a potential demographic dividend in six sub-Saharan African countries.

Design
The survey was self-administered online using the SurveyMonkey platform. The survey questionnaire covered six key sectors: family planning, maternal and child health, education, women’s empowerment, labour market, and governance and economic institution. Each sector-specific questionnaire was structured around five practice domains: policymaking, services and programmes, advocacy, research and civil society. Each item was scored from 1 to 10. Factor analysis was used to select the items to be retained for final score estimation. Simple averages were computed to estimate sectoral and domain scores and overall country scores were estimated using weighted country mean scores. Internal consistency, construct validity and reliability were examined using factor analysis and Cronbach’s alpha.

Setting
Sub-Saharan Africa.

Participants
A total of 440 knowledgeable informants from six countries; namely, Ethiopia (73), Kenya (69), Nigeria (67), Rwanda (54), Senegal (81) and Tanzania (96).

Results
Based on the results from factor analysis, 38 items were dropped from the analysis and Cronbach’s alpha results ranged from 0.84 to 0.98 across domains. The overall demographic dividend effort index (DDEI) scores ranged between 5.4 (95% CI 5.1 to 5.8) in Ethiopia to 7.7 (95% CI 7.5 to 8.0) in Rwanda. In most countries, the disaggregated scores by sector revealed low scores in the labour market and women’s empowerment.

Conclusion
The DDEI scores highlight important gaps in key health and development sectors. The DDEI proved to be a reliable and internally consistent tool for effort measurement in key demographic dividend sectors. The DDEI can serve as a self-evaluation tool for local actors and may complement existing quantitative tools such as the Global Gender Gap and the Human Capital Index.

This Medical News article discusses increasing global food insecurity linked to political conflict and climate change.