Molecular basis of human angiotensin-1 converting enzyme inhibition by a series of diprolyl-derived compounds.

Angiotensin-1-converting enzyme (ACE) is a zinc-dependent carboxypeptidase of therapeutic interest for the treatment of hypertension, inflammation and fibrosis. It consists of two homologous N and C catalytic domains, nACE and cACE, respectively. Unfortunately, the current clinically available ACE inhibitors produce undesirable side effects due to the nonselective inhibition of these domains.

2,8-Disubstituted-1,5-naphthyridines as Dual Inhibitors of Phosphatidylinositol-4-kinase and Hemozoin Formation with Efficacy.

Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of () phosphatidylinositol-4-kinase β (PI4K), identified 1,5-naphthyridines with basic groups at 8-position, which retained PI4K inhibitory activity but switched primary mode of action to the host hemoglobin degradation pathway through inhibition of hemozoin formation. These compounds showed minimal off-target inhibitory activity against the human phosphoinositide kinases and MINK1 and MAP4K kinases, which were associated with the teratogenicity and testicular toxicity observed in rats for the PI4K inhibitor clinical candidate MMV390048. A representative compound from the series retained activity against field isolates and lab-raised drug-resistant strains of .

Implementing Multifactorial Risk Assessment with Polygenic Risk Scores for Personalized Breast Cancer Screening in the Population Setting: Challenges and Opportunities.

Risk-stratified breast screening has been proposed as a strategy to overcome the limitations of age-based screening. A prospective cohort study was undertaken within the PERSPECTIVE I&I project, which will generate the first Canadian evidence on multifactorial breast cancer risk assessment in the population setting to inform the implementation of risk-stratified screening. Recruited females aged 40-69 unaffected by breast cancer, with a previous mammogram, underwent multifactorial breast cancer risk assessment.

Breast Magnetic Resonance Imaging for Preoperative Evaluation of Breast Cancer: A Systematic Review and Meta-Analysis.

Preoperative breast magnetic resonance imaging (MRI) is known to detect additional cancers that are occult on mammography and ultrasound. There is debate as to whether these additional lesions affect clinical outcomes. The objective of this systematic review was to summarize the evidence on whether additional information on disease extent obtained with preoperative breast MRI in patients with newly diagnosed breast cancer affects surgical management, rates of recurrence, survival, re-excision, and early detection of bilateral cancer.

Preoperative Breast Magnetic Resonance Imaging: An Ontario Health (Cancer Care Ontario) Clinical Practice Guideline.

Background: The use of preoperative breast magnetic resonance imaging (MRI) after the diagnosis of breast cancer by mammography and/or ultrasound is inconsistent.

Methods: After conducting a systematic review and meta-analysis comparing preoperative breast MRI versus no MRI, we reconvened to prepare a clinical practice guideline on this topic.

Results: Based on the evidence that MRI improved recurrence, decreased the rates of reoperations (re-excisions or conversion mastectomy), and increased detection of synchronous contralateral breast cancer, we recommend that preoperative breast MRI should be considered on a case-by-case basis in patients diagnosed with breast cancer for whom additional information about disease extent could influence treatment.