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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.

The androgen receptor (AR) signaling pathway is involved in the emergence of castration-resistant prostate cancer (CRPC). Here, we identified several androgen-regulated microRNAs (miRNAs) that may contribute to the development of CRPC. Seven miRNAs, miR-21, miR-32, miR-99a, miR-99b, miR-148a, miR-221 and miR-590-5p, were found to be differentially expressed in CRPC compared with benign prostate hyperplasia (BPH) according to microarray analyses. Significant growth advantage for LNCaP cells transfected with pre-miR-32 and pre-miR-148a was found. miR-32 was demonstrated to reduce apoptosis, whereas miR-148a enhanced proliferation. Androgen regulation of miR-32 and miR-148a was confirmed by androgen stimulation of the LNCaP cells followed by expression analyses. The AR-binding sites in proximity of these miRNAs were demonstrated with chromatin immunoprecipitation (ChIP). To identify target genes for the miRNAs, mRNA microarray analyses were performed with LNCaP cells transfected with pre-miR-32 and pre-miR-148a. Expression of BTG2 and PIK3IP1 was reduced in the cells transfected with pre-miR-32 and pre-miR-148a, respectively. Also, the protein expression was reduced according to western blot analysis. BTG2 and PIK3IP1 were confirmed to be targets by 3'UTR-luciferase assays. Finally, immunostainings showed a statistically significant (P<0.0001) reduction of BTG2 protein in CRPCs compared with untreated prostate cancer (PC). The lack of BTG2 staining was also associated (P<0.01) with a short progression-free time in patients who underwent prostatectomy. In conclusion, androgen-regulated miR-32 is overexpressed in CRPC, leading to reduced expression of BTG2. Thus, miR-32 is a potential marker for aggressive disease and is a putative drug target in PC.

Prostate cancer (PCa) is the most frequent male malignancy and the second most common cause of cancer-related death in Western countries. Current clinical and pathological methods are limited in the prediction of postoperative outcome. It is becoming increasingly evident that small non-coding RNA (ncRNA) species are associated with the development and progression of this malignancy. To assess the diversity and abundance of small ncRNAs in PCa, we analyzed the composition of the entire small transcriptome by Illumina/Solexa deep sequencing. We further analyzed the microRNA (miRNA) expression signatures of 102 fresh-frozen patient samples during PCa progression by miRNA microarrays. Both platforms were cross-validated by quantitative reverse transcriptase-PCR. Besides the altered expression of several miRNAs, our deep sequencing analyses revealed strong differential expression of small nucleolar RNAs (snoRNAs) and transfer RNAs (tRNAs). From microarray analysis, we derived a miRNA diagnostic classifier that accurately distinguishes normal from cancer samples. Furthermore, we were able to construct a PCa prognostic predictor that independently forecasts postoperative outcome. Importantly, the majority of miRNAs included in the predictor also exhibit high sequence counts and concordant differential expression in Illumina PCa samples, supported by quantitative reverse transcriptase-PCR. Our findings provide miRNA expression signatures that may serve as an accurate tool for the diagnosis and prognosis of PCa.

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., Competing Interests: The authors have declared that no competing interests exist.

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.

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.