Stromal Senescence following Treatment with the CDK4/6 Inhibitor Palbociclib Alters the Lung Metastatic Niche and Increases Metastasis of Drug-Resistant Mammary Cancer Cells.

BACKGROUND: CDK4/6 inhibitors (CDKi) have improved disease control in hormone-receptor-positive, HER2-negative metastatic breast cancer, but most patients develop progressive disease. METHODS: We asked whether host stromal senescence after CDK4/6 inhibition affects metastatic seeding and growth of CDKi-resistant mammary cancer cells by using the p16-INK-ATTAC mouse model of inducible senolysis. RESULTS: Palbociclib pretreatment of naïve mice increased lung seeding of CDKi-resistant syngeneic mammary cancer cells, and this effect was reversed by depletion of host senescent cells. RNA sequencing analyses of lungs from non-tumor-bearing p16-INK-ATTAC mice identified that palbociclib downregulates immune-related gene sets and gene expression related to leukocyte migration. Concomitant senolysis reversed a portion of these effects, including pathway-level enrichment of TGF-ß- and senescence-related signaling. CIBERSORTx analysis revealed that palbociclib alters intra-lung macrophage/monocyte populations. Notably, lung metastases from palbociclib-pretreated mice revealed senescent endothelial cells. Palbociclib-treated endothelial cells exhibit hallmark senescent features in vitro, upregulate genes involved with the senescence-associated secretory phenotype, leukocyte migration, and TGF-ß-mediated paracrine senescence and induce tumor cell migration and monocyte trans-endothelial invasion in co-culture. CONCLUSIONS: These studies shed light on how stromal senescence induced by palbociclib affects lung metastasis, and they describe palbociclib-induced gene expression changes in the normal lung and endothelial cell models that correlate with changes in the tumor microenvironment in the lung metastatic niche.

Detection of carcinogenic metals in kidney stones using ultraviolet laser-induced breakdown spectroscopy.

The UV single-pulsed (SP) laser-induced breakdown spectroscopy (LIBS) system was developed to detect the carcinogenic metals in human kidney stones extracted through the surgical operation. A neodymium yttrium aluminium garnet laser operating at 266 nm wavelength and 20 Hz repetition rate along with a spectrometer interfaced with an intensified CCD (ICCD) was applied for spectral analysis of kidney stones. The ICCD camera shutter was synchronized with the laser-trigger pulse and the effect of laser energy and delay time on LIBS signal intensity was investigated. The experimental parameters were optimized to obtain the LIBS plasma in local thermodynamic equilibrium. Laser energy was varied from 25 to 50 mJ in order to enhance the LIBS signal intensity and attain the best signal to noise ratio. The parametric dependence studies were important to improve the limit of detection of trace amounts of toxic elements present inside stones. The carcinogenic metals detected in kidney stones were chromium, cadmium, lead, zinc, phosphate, and vanadium. The results achieved from LIBS system were also compared with the inductively coupled plasma-mass spectrometry analysis and the concentration detected with both techniques was in very good agreement. The plasma parameters (electron temperature and density) for SP-LIBS system were also studied and their dependence on incident laser energy and delay time was investigated as well.