Red emitting, cucurbituril-capped, pH-responsive conjugated oligomer-based nanoparticles for drug delivery and cellular imaging.

Here we report the synthesis of nanoparticles based on a conjugated oligomer which is synthesized through Heck-coupling of divinylfluorene and dibromobenzothiodiazole monomers. These water dispersible nanoparticles emit in the region of red tailing to the near-infrared region of the spectrum with high fluorescent quantum yield and brightness. The nanoparticles were found to be stable in water for a prolonged time without forming any aggregates and could carry camptothecin, an anticancer drug with high loading efficiency. MTT cell viability studies performed with breast cancer cell lines showed that half-maximal inhibitory concentration (IC50) values of nanoparticles for MCF7 and MDA-MB-231 were 44.7 µM and 24.8 µM, respectively. In order to further decrease the cytotoxicity and increase the stability of nanoparticles, amine groups were disguised by capping with cucurbit[7]uril (CB7). Drug release studies showed that drugs were released at low pH (at 5.0) faster than physiological pH (7.4) confirming the pH-responsive nature of the nanoparticles. On the other hand, CB7-capped drug-loaded nanoparticles regulated the release rate by providing slower release at pH 7.4 than the nanoparticles in the absence of CB7s. IC50 values for camptothecin in the presence of nanoparticles with or without CB7 were significantly reduced in MCF7 and MDA-MB-231 cells.

Measuring the perceived wellbeing of hemodialysis patients: A Mind Genomics cartography.

Chronic Kidney Disease patients under hemodialysis have high morbidity rate, which tends to considerably affect their health-related quality of life. Multiple studies that have made use of different questionnaries report the poor life quality of this patient group. The research in hand implemented the Mind Genomics Approach as a method to asses the health-related quality of life of hemodialysis patients, while relying on conjoint measurements to group individuals with similar patterns of responses to a certain mindset. The study is conducted in 3 clinics with 219 patients. It uncovers three clusters or mindsets: Mindset 1- Feels guardedly optimistic but worried about money, Mindset 2-Feels strongly positive because the state guarantees and the family supports, Mindset 3-Feels positive only about money. Based on the analysis of the collected data, the findings of this study suggest that the quality of life in hemodialysis patients is highly correlated to their financial status. The current study is one of the few first attempts to apply Mind Genomics in medical settings and the first, to our knowledge, in hemodialysis centers. This technology might enable healthcare proffesionals to provide personalized psychological treatment and additional social support to patients, which in turn could improve their clinical outcomes. The study is an example of using technology as a service.

CHRNA5 belongs to the secondary estrogen signaling network exhibiting prognostic significance in breast cancer.

PURPOSE: Cholinergic signals can be important modulators of cellular signaling in cancer. We recently have shown that knockdown of nicotinic acetylcholine receptor subunit alpha 5, CHRNA5, diminishes the proliferative potential of breast cancer cells. However, modulation of CHRNA5 expression in the context of estrogen signaling and its prognostic implications in breast cancer remained unexplored. METHODS: Meta-analyses of large breast cancer microarray cohorts were used to evaluate the association of CHRNA5 expression with estrogen (E2) treatment, estrogen receptor (ER) status and patient prognosis. The results were validated through RT-qPCR analyses of multiple E2 treated cell lines, CHRNA5 depleted MCF7 cells and across a breast cancer patient cDNA panel. We also calculated a predicted secondary (PS) score representing direct/indirect induction of gene expression by E2 based on a public dataset (GSE8597). Co-expression analysis was performed using a weighted gene co-expression network analysis (WGCNA) pipeline. Multiple other publicly available datasets such as CCLE, COSMIC and TCGA were also analyzed. RESULTS: Herein we found that CHRNA5 expression was induced by E2 in a dose- and time-dependent manner in breast cancer cell lines. ER- breast tumors exhibited higher CHRNA5 expression levels than ER+ tumors. Independent meta-analysis for survival outcome revealed that higher CHRNA5 expression was associated with a worse prognosis in untreated breast cancer patients. Furthermore, CHRNA5 and its co-expressed gene network emerged as secondarily induced targets of E2 stimulation. These targets were largely downregulated by exposure to CHRNA5 siRNA in MCF7 cells while the response of primary ESR1 targets was dependent on the direction of the PS-score. Moreover, primary and secondary target genes were uncoupled and clustered distinctly based on multiple public datasets. CONCLUSION: Our findings strongly associate increased expression of CHRNA5 and its co-expression network with secondary E2 signaling and a worse prognosis in breast cancer.

Cholinergic Receptor Nicotinic Alpha 5 (CHRNA5) RNAi is associated with cell cycle inhibition, apoptosis, DNA damage response and drug sensitivity in breast cancer.

Cholinergic Receptor Nicotinic Alpha 5 (CHRNA5) is an important susceptibility locus for nicotine addiction and lung cancer. Depletion of CHRNA5 has been associated with reduced cell viability, increased apoptosis and alterations in cellular motility in different cancers yet not in breast cancer. Herein we first showed the expression of CHRNA5 was variable and positively correlated with the fraction of total genomic alterations in breast cancer cell lines and tumors indicating its potential role in DNA damage response (DDR). Next, we demonstrated that silencing of CHRNA5 expression in MCF7 breast cancer cell line by RNAi affected expression of genes involved in cytoskeleton, TP53 signaling, DNA synthesis and repair, cell cycle, and apoptosis. The transcription profile of CHRNA5 depleted MCF7 cells showed a significant positive correlation with that of A549 lung cancer cell line while exhibiting a negative association with the CHRNA5 co-expression profile obtained from Cancer Cell Line Encylopedia (CCLE). Moreover, it exhibited high similarities with published MCF7 expression profiles obtained from exposure to TP53 inducer nutlin-3a and topoisomerase inhibitors. We then demonstrated that CHRNA5 siRNA treatment reduced cell viability and DNA synthesis indicating G1 arrest while it significantly increased apoptotic sub-G1 cell population. Accordingly, we observed lower levels of phosphorylated RB (Ser807/811) and an increased BAX/BCL2 ratio in RNAi treated MCF7 cells. We also showed that CHRNA5 RNAi transcriptome correlated negatively with DDR relevant gene expression profile in breast cancer gene expression datasets while the coexposure to topoisomerase inhibitors in the presence of CHRNA5 RNAi enhanced chemosensitivity potentially due to reduced DDR. CHRNA5 RNAi consistently lowered total CHEK1 mRNA and protein levels as well as phosphorylated CHEK1 (Ser345) in MCF7 cells. We also detected a significant positive correlation between the expression levels of CHRNA5 and CHEK1 in CCLE, TCGA and METABRIC breast cancer datasets. Our study suggests CHRNA5 RNAi is associated with cell cycle inhibition, apoptosis as well as reduced DDR and increased drug sensitivity in breast cancer yet future studies are warranted since dose- and cell line-specific differences exist in response to CHRNA5 depletion. Gene expression microarray data can be accessed from GEO database under the accession number GSE89333.