Comparison of drug-related problem risk assessment tools for older adults: a systematic review.

PURPOSE: This study aims to systematically review studies describing screening tools that assess the risk for drug-related problems (DRPs) in older adults (≥ 60 years). The focus of the review is to compare DRP risks listed in different tools and describe their development methods and validation. METHODS: The systematic search was conducted using evidence-based medicine, Medline Ovid, Scopus, and Web of Science databases from January 1, 1985, to April 7, 2016. Publications describing general DRP risk assessment tools for older adults written in English were included. Disease, therapy, and drug-specific tools were excluded. Outcome measures included an assessment tool's content, development methods, and validation assessment. RESULTS: The search produced 15 publications describing 11 DRP risk assessment tools. Three major categories of risks for DRPs included (1) patient or caregiver related risks; (2) pharmacotherapy-related risks; and (3) medication use process-related risks. Of all the risks included in the tools only 8 criteria appeared in at least 4 of the tools, problems remembering to take the medication being the most common (n=7). Validation assessments varied and content validation was the most commonly conducted (n = 9). Reliability assessment was conducted for 6 tools, most commonly by calculating internal consistency (n = 3) and inter-rater reliability (n = 2). CONCLUSIONS: The considerable variety between the contents of the tools indicates that there is no consensus on the risk factors for DRPs that should be screened in older adults taking multiple medicines. Further research is needed to improve the accuracy and timeliness of the DRP risk assessment tools.

Allelic variation at the 8q23.3 colorectal cancer risk locus functions as a cis-acting regulator of EIF3H.

Common genetic variation at human 8q23.3 is significantly associated with colorectal cancer (CRC) risk. To elucidate the basis of this association we compared the frequency of common variants at 8q23.3 in 1,964 CRC cases and 2,081 healthy controls. Reporter gene studies showed that the single nucleotide polymorphism rs16888589 acts as an allele-specific transcriptional repressor. Chromosome conformation capture (3C) analysis demonstrated that the genomic region harboring rs16888589 interacts with the promoter of gene for eukaryotic translation initiation factor 3, subunit H (EIF3H). We show that increased expression of EIF3H gene increases CRC growth and invasiveness thereby providing a biological mechanism for the 8q23.3 association. These data provide evidence for a functional basis for the non-coding risk variant rs16888589 at 8q23.3 and provides novel insight into the etiological basis of CRC.

Androgen regulation of micro-RNAs in prostate cancer.

BACKGROUND: Androgens play a critical role in the growth of both androgen dependent and castration-resistant prostate cancer (CRPC). Only a few micro-RNAs (miRNAs) have been suggested to be androgen regulated. We aim to identify androgen regulated miRNAs. METHODS: We utilized LNCaP derived model, we have established, and which overexpresses the androgen receptor (AR), the VCaP cell line, and 13 intact-castrated prostate cancer (PC) xenograft pairs, as well as clinical specimens of untreated (PC) and CRPC. The expression of miRNAs was analyzed by microarrays and quantitative RT-PCR (Q-RT-PCR). Transfection of pre-miR-141 and anti-miR-141 was also used. RESULTS: Seventeen miRNAs were > 1.5-fold up- or downregulated upon dihydrotestosterone (DHT) treatment in the cell lines, and 42 after castration in the AR-positive xenografts. Only four miRNAs (miR-10a, miR-141, miR-150*, and miR-1225-5p) showed similar androgen regulation in both cell lines and xenografts. Of those, miR-141 was found to be expressed more in PC and CRPC compared to benign prostate hyperplasia. Additionally, the overexpression of miR-141 enhanced growth of parental LNCaP cells while inhibition of miR-141 by anti-miR-141 suppressed the growth of the LNCaP subline overexpressing AR. CONCLUSIONS: Only a few miRNAs were found to be androgen-regulated in both cell lines and xenografts models. Of those, the expression of miR-141 was upregulated in cancer. The ectopic overexpression of miR-141 increased growth of LNCaP cell suggesting it may contribute to the progression of PC.

miR-193b is an epigenetically regulated putative tumor suppressor in prostate cancer.

miRNAs have proven to be key regulators of gene expression and are differentially expressed in various diseases, including cancer. Our aim was to identify epigenetically dysregulated genes in prostate cancer. We performed miRNA expression profiling after relieving epigenetic modifications in 6 prostate cancer cell lines and nonmalignant prostate epithelial cells. Thirty-eight miRNAs showed increased expression in any prostate cancer cell line after 5-aza-2'-deoxycytidine (5azadC) and trichostatin A (TSA) treatments. Six of these also had decreased expression in clinical prostate cancer samples compared to benign prostatic hyperplasia. Among these, miR-193b was methylated in 22Rv1 cell line at a CpG island approximately 1 kb upstream of the miRNA locus. Expressing miR-193b in 22Rv1 cells using pre-miR-193b oligonucleotides caused a significant growth reduction (p < 0.001) resulting from a decrease of cells in S-phase of the cell cycle (p < 0.01). In addition, the anchorage independent growth was partially inhibited in transiently miR-193b-expressing 22Rv1 cells (p < 0.01). Altogether, our data suggest that miR-193b is an epigenetically silenced putative tumor suppressor in prostate cancer.

TCEB1 promotes invasion of prostate cancer cells.

Amplification of the long arm of chromosome 8 is one of the most recurrent findings in prostate cancer and it is associated with poor prognosis. Several minimal regions of amplification suggest multiple target genes which are yet to be identified. We have previously shown that TCEB1, EIF3S3, KIAA0196 and RAD21 are amplified and overexpressed in prostate cancer and they are located in the 8q area. In this study, we examined the functional effects of these genes to prostate cancer cell phenotype. We overexpressed and inhibited the genes by lentivirus mediated overexpression and RNA interference, respectively. shRNA mediated TCEB1 silencing decreased significantly cellular invasion of PC-3 and DU145 cells through Matrigel. TCEB1 silencing reduced the anchorage-independent growth of PC-3 cells. Similar effects were not seen with any other genes. When overexpressed in NIH 3T3 cells, TCEB1 and EIF3S3 increased the growth rate of the cells. Transcriptional profiling of TCEB1 silenced PC-3 cells revealed decrease of genes involved in invasion and metastasis. Finally, we also confirmed here the overexpression of TCEB1 in hormone-refractory prostate tumors. This study indicates that TCEB1 promotes invasion of prostate cancer cells, is involved in development of hormone-refractory prostate cancer and is thereby a strong candidate to be one of the target genes for the 8q gain.