PIK3CA mutation sensitizes breast cancer cells to synergistic therapy of PI3K inhibition and AMPK activation.

Breast cancer has been emerging as a most common threat among women, thus many efforts were made to find drugs for fighting breast cancer. So far, PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) inhibitors have been believed to be effective drugs until frequent resistance emerged. Recently, PI3K H1047R mutation has been reported to sensitize breast cancer cells to PI3K inhibition by aspirin. Considering aspirin activates AMPK (AMP-activated protein kinase) simultaneously, it is possible that AMPK activators and PI3K inhibitors can synergistically inhibit breast cancers. Here we clearly observed synergistic suppression of cell growth in all three breast cancer cell lines (MCF-7, MDA-MB-361 and HCC38) when co-treating cells with PI3K inhibitor GDC-0941 and AMPK activator AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide). What is more, it is rather remarkable that the synergistic effect was much more dramatic in PIK3CA (PI3K catalytic subunit alpha) mutated (E545K) cells (MCF-7 and MDA-MB-361) than in PIK3CA wild-type cells (HCC38), which implied there is a relationship between PI3K genetic status and the efficacy of combination therapy. By using PIK3CA wild-type isogenic MCF-7 cell line, which exhibited attenuated cell proliferation compared with the parental MCF-7 cell line, we found endogenous reverse mutation of PIK3CA E545K alleles to wild-type sequence in MCF-7 cells dramatically impaired the synergy of PI3Ki&Ka (combinatorial PI3K inhibition and AMPK activation). Furthermore, PI3Ki&Ka significantly attenuated tumorigenesis of parental MCF-7 cells but not PIK3CA wild-type isogenic MCF-7 cells in tumor xenograft models. Taken together, our results suggest a promising precision therapy of PI3Ki&Ka in PIK3CA mutant breast cancers.

Inhibition of Rb and mTOR signaling associates with synergistic anticancer effect of palbociclib and erlotinib in glioblastoma cells.

Genomic studies have established a set of three core-signaling pathways, receptor tyrosine kinase (RTK), p53 and retinoblastoma (Rb) signaling pathways, contributing glioblastoma (GBM) and revealed that dysregulation of at least two pathways is required for GBM progression. In the present study, we investigate efficacy of combination of palbociclib, cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, and erlotinib, epidermal growth factor receptor (EGFR) inhibitor in GBM cell systems with different p53 status. Cell proliferation and colony formation assays showed that the combination treatment synergistically suppressed GBM cell proliferation. LN229 cells with mutant p53 and wild-type PTEN were more sensitive to the combination treatment. Further studies indicated that the synergetic anti-GBM effects were due to cell apoptosis induction and cell cycle arrest at G1 phase. Signaling examination indicated that levels of p-Rb and p-4E-BP1 significantly decreased by the combination treatment; however, Akt and MAPK signaling were differentially suppressed among the three GBM cell lines. Hence, our data demonstrate that palbociclib and erlotinib exert synergistic anti-GBM activity, providing pre-clinical evidence and a proof-ofconcept that usage of the combination of EGFR and CDK4/6 inhibitors for GBM treatment.

Caregivers' experiences of caring for non-COVID-19 patients during the pandemic: A qualitative systematic review.

OBJECTIVE: To investigate caregivers' experiences of caring for non-coronavirus disease (COVID-19) patients to determine their challenges and needs. METHODS: Five electronic databases (PubMed, Web of Science, Ovid, CINAHL, and ClinicalKey) were searched from January 2020 to June 2022. Two authors independently reviewed all studies for eligibility and extracted information on the study aim, sample characteristics, study design, data collection, analysis methods, and so on. RESULTS: Finally, 13 studies were included. Four themes were determined: impacts on physical and psychosocial well-being of caregivers, perceived risk of the virus, negative impacts on employment and financial statuses, and changes in support networks. CONCLUSION: This is the first qualitative systematic review to describe caregivers' experiences of caring for non-COVID-19 patients during the pandemic. The four themes should be focused on to ease caregivers' physical, psychological, and financial burdens; to provide them with better assistance in terms of formal and informal supports to cope with the epidemic more effectively; and to ensure that their loved ones are much healthier. PRACTICE IMPLICATIONS: The findings can be used by healthcare policymakers, social policymakers, and governments to better support caregivers of non-COVID-19 patients. Additionally, it provides suggestions for related medical institutions to pay more attention to caregivers' experiences.