Selective inhibition of CDK9 in triple negative breast cancer.

Targeted therapy for triple-negative breast cancers (TNBC) remains a clinical challenge due to tumour heterogeneity. Since TNBC have key features of transcriptionally addicted cancers, targeting transcription via regulators such as cyclin-dependent kinase 9 (CDK9) has potential as a therapeutic strategy. Herein, we preclinically tested a new selective CDK9 inhibitor (CDDD11-8) in TNBC using cell line, patient-derived organoid, and patient-derived explant models. In vitro, CDDD11-8 dose-dependently inhibited proliferation (IC50 range: 281-734 nM), induced cell cycle arrest, and increased apoptosis of cell lines, which encompassed the three major molecular subtypes of TNBC. On target inhibition of CDK9 activity was demonstrated by reduced RNAPII phosphorylation at a CDK9 target peptide and down-regulation of the MYC and MCL1 oncogenes at the mRNA and protein levels in all cell line models. Drug induced RNAPII pausing was evident at gene promoters, with strongest pausing at MYC target genes. Growth of five distinct patient-derived organoid models was dose-dependently inhibited by CDDD11-8 (IC50 range: 272-771 nM), including three derived from MYC amplified, chemo-resistant TNBC metastatic lesions. Orally administered CDDD11-8 also inhibited growth of mammary intraductal TNBC xenograft tumours with no overt toxicity in vivo (mice) or ex vivo (human breast tissues). In conclusion, our studies indicate that CDK9 is a viable therapeutic target in TNBC and that CDDD11-8, a novel selective CDK9 inhibitor, has efficacy in TNBC without apparent toxicity to normal tissues.

Risky Business: Factors That Increase Risk of Falls Among Older Adult In-Patients.

In hospitals, older patients are at increased risk of falling multiple times. This study incorporated an epidemiologic cross-sectional design consisting of 4,348 older patients (≥65-year-old). Eight hundred eighty five (20.4%) in-patients experienced multiple falls while remaining participants had one fall incident. A patient fall event was recorded with age, sex, incident date, type of fall, and location. Logistic regression assessed risk factors found in patients with multiple falls compared to those with one fall. Significant differences were observed in the proportion of multiple falls: in a bed with no rails, standing, walking, and using a wheel/Geri chair (p < .05). Overall, sex, type of fall, and location were significant in predicting multiple falls (p < .05). Male patients were at 16.1% greater risk of multiple falls, when compared to females (p < .05). A fall in complex care, mental health, or respirology were more likely to experience multiple falls (OR = 2.659, 3.620, 1.593 respectively), while season had no impact.