PD-L1 overexpression induces STAT signaling and promotes the secretion of pro-angiogenic cytokines in non-small cell lung cancer (NSCLC).

BACKGROUND: Monoclonal antibodies (ICI) targeting the immune checkpoint PD-1/PD-L1 alone or in combination with chemotherapy have demonstrated relevant benefits and established new standards of care in first-line treatment for advanced non-oncogene addicted non-small cell lung cancer (NSCLC). However, a relevant percentage of NSCLC patients, even with high PD-L1 expression, did not respond to ICI, highlighting the presence of intracellular resistance mechanisms that could be dependent on high PD-L1 levels. The intracellular signaling induced by PD-L1 in tumor cells and their correlation with angiogenic signaling pathways are not yet fully elucidated. METHODS: The intrinsic role of PD-L1 was initially checked in two PD-L1 overexpressing NSCLC cells by transcriptome profile and kinase array. The correlation of PD-L1 with VEGF, PECAM-1, and angiogenesis was evaluated in a cohort of advanced NSCLC patients. The secreted cytokines involved in tumor angiogenesis were assessed by Luminex assay and their effect on Huvec migration by a non-contact co-culture system. RESULTS: PD-L1 overexpressing cells modulated pathways involved in tumor inflammation and JAK-STAT signaling. In NSCLC patients, PD-L1 expression was correlated with high tumor intra-vasculature. When challenged with PBMC, PD-L1 overexpressing cells produced higher levels of pro-angiogenic factors compared to parental cells, as a consequence of STAT signaling activation. This increased production of cytokines involved in tumor angiogenesis largely stimulated Huvec migration. Finally, the addition of the anti-antiangiogenic agent nintedanib significantly reduced the spread of Huvec cells when exposed to high levels of pro-angiogenic factors. CONCLUSIONS: In this study, we reported that high PD-L1 modulates STAT signaling in the presence of PBMC and induces pro-angiogenic factor secretion. This could enforce the role of PD-L1 as a crucial regulator of the tumor microenvironment stimulating tumor progression, both as an inhibitor of T-cell activity and as a promoter of tumor angiogenesis.

Partial Budget Analysis of Exclusion Netting and Organic-certified Insecticides for Management of Spotted-wing Drosophila (Diptera: Drosophilidae) on Small Farms in the Upper Midwest.

Drosophila suzukii Matsumura (Diptera: Drosophilidae), or spotted-wing drosophila, is an invasive pest first detected in the United States in 2008. Although D. suzukii can use many cultivated fruit as hosts, raspberries are considered 'most at risk' for infestation. Conventional broad-spectrum insecticides are proven effective D. suzukii controls and can be economically profitable when combined with integrated pest management (IPM) on large-scale commercial raspberry farms. It remains unclear, however, whether organic controls are cost-effective strategies, particularly for farms operating on a small-scale seasonal basis, as is common in the Upper Midwest. The purpose of this paper is to explore the efficacy of two organic D. suzukii controls-exclusion netting for high tunnels and organic insecticides for open plots using data available from different field trials-and to ascertain whether any economic benefits of the organic controls outweigh treatment costs for small-scale raspberry operations under different risk scenarios. The field trials suggest that the organic treatments are effective controls for D. suzukii infestation and economically profitable. The exclusion netting treatment produced positive net returns compared to the alternative of no treatment and economically outperformed the organic-certified insecticide treatment for several yield, price and infestation scenarios. As D. suzukii infestation rates increased, net returns improved for both organic treatments. The economic results were robust across a range of yields and prices, suggesting that in almost all scenarios small scale organic raspberry growers benefit economically from the application of exclusion netting on high tunnels and insecticides for open plots.

Chromatin-associated CSF-1R binds to the promoter of proliferation-related genes in breast cancer cells.

The colony-stimulating factor-1 (CSF-1) and its receptor CSF-1R physiologically regulate the monocyte/macrophage system, trophoblast implantation and breast development. An abnormal CSF-1R expression has been documented in several human epithelial tumors, including breast carcinomas. We recently demonstrated that CSF-1/CSF-1R signaling drives proliferation of breast cancer cells via 'classical' receptor tyrosine kinase signaling, including activation of the extracellular signal-regulated kinase 1/2. In this paper, we show that CSF-1R can also localize within the nucleus of breast cancer cells, either cell lines or tissue specimens, irrespectively of their intrinsic molecular subtype. We found that the majority of nuclear CSF-1R is located in the chromatin-bound subcellular compartment. Chromatin immunoprecipitation revealed that CSF-1R, once in the nucleus, binds to the promoters of the proliferation-related genes CCND1, c-JUN and c-MYC. CSF-1R also binds the promoter of its ligand CSF-1 and positively regulates CSF-1 expression. The existence of such a receptor/ligand regulatory loop is a novel aspect of CSF-1R signaling. Moreover, our results provided the first evidence of a novel localization site of CSF-1R in breast cancer cells, suggesting that CSF-1R could act as a transcriptional regulator on proliferation-related genes.

X-ray diffraction studies on selected bacterial cell walls.

The cell walls of selected bacteria were studied by X-ray diffraction analysis to determine and characterize crystalline components. The walls were isolated by mechanical disruption and purified by enzymatic and washing procedures. The X-ray diffraction lines which appeared from the gram-positive cell walls were shown to be due to the constituent "mucopeptide" fraction. No diffraction lines could be obtained from the gram-negative bacterium studied. The results show that crystallinity is associated with mucopeptide.