Targeting MDM2 for novel molecular therapy: Beyond oncology.

The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the best-documented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, noncarcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflammation and autoimmune diseases, dementia and neurodegenerative diseases, heart failure and cardiovascular diseases, nephropathy, diabetes, obesity, and sterility. MDM2 inhibitors have been shown to have promising therapeutic efficacy for treating inflammation and other nonmalignant diseases in preclinical evaluations. Therefore, targeting MDM2 may represent a promising approach for treating and preventing these nonmalignant diseases. In addition, a better understanding of how MDM2 works in nonmalignant diseases may provide new biomarkers for their diagnosis, prognostic prediction, and monitoring of therapeutic outcome. In this review article, we pay special attention to the recent findings related to the roles of MDM2 in the pathogenesis of several nonmalignant diseases, the therapeutic potential of its downregulation or inhibition, and its use as a biomarker.

Natural products targeting the p53-MDM2 pathway and mutant p53: Recent advances and implications in cancer medicine.

The p53 tumor suppressor plays a major role in controlling the initiation and development of cancer by regulating cell cycle arrest, apoptosis, senescence, and DNA repair. The MDM2 oncogene is a major negative regulator of p53 that inhibits the activity of p53 and reduces its protein stability. MDM2, p53, and the p53-MDM2 pathway represent well-documented targets for preventing and/or treating cancer. Natural products, especially those from medicinal and food plants, are a rich source for the discovery and development of novel therapeutic and preventive agents against human cancers. Many natural product-derived MDM2 inhibitors have shown potent efficacy against various human cancers. In contrast to synthetic small-molecule MDM2 inhibitors, the majority of which have been designed to inhibit MDM2-p53 binding and activate p53, many natural product inhibitors directly decrease MDM2 expression and/or MDM2 stability, exerting their anticancer activity in both p53-dependent and p53-independent manners. More recently, several natural products have been reported to target mutant p53 in cancer. Therefore, identification of natural products targeting MDM2, mutant p53, and the p53-MDM2 pathway can provide a promising strategy for the development of novel cancer chemopreventive and chemotherapeutic agents. In this review, we focus our discussion on the recent advances in the discovery and development of anticancer natural products that target the p53-MDM2 pathway, emphasizing several emerging issues, such as the efficacy, mechanism of action, and specificity of these natural products.

PRN Medication Administration in a Geriatric Psychiatric Hospital: Chart Review and Nursing Perspective.

OBJECTIVE: To improve patient care/outcome, an evaluation was conducted of nursing procedures and protocols for pro re nata (PRN) medications. METHODS: A 14-day chart review was conducted for 27 patients with mood and thought disorders (MTD) and for 24 patients with organic disorders (OD) at a geriatric psychiatric hospital, and a questionnaire was completed by 20 nurses. RESULTS: 377 PRNs were administered to patients in the MTD and OD units (240 and 137, respectively). The majority of PRNs were administered during the evening shifts on the MTD unit and during the day shifts on the OD unit. Chart notes indicated the behavior requiring PRN administration was not always specifically described and therapeutic interventions were not often attempted before PRN administration. Inconsistency between chart notes and medication record books was noted in the majority of cases. It was often not known whether the PRN was initiated by the staff, patient, or family. PRNs were reported to be not effective in the majority of cases. CONCLUSIONS: Documentation was suboptimal and effectiveness was poor. CLINICAL IMPLICATIONS: It would be worthwhile to train all staff in a patient-centered or ecopsychosocial (i.e., non-pharmacological) model of care, which would provide staff alternatives to PRNs. In that context, it would be important to implement standards of practice into geriatric psychiatry inpatient settings for PRN administration and documentation.

Antimicrobial resistance genes and modelling of treatment failure in bacterial vaginosis: clinical study of 289 symptomatic women.

Clinical management of bacterial vaginosis (BV) is difficult owing to inaccurate diagnostic tests, limited drug choices, and a high rate of recurrence. To our knowledge, there has not been a previous study of antimicrobial resistance (AMR) genes in community practice using next-generation sequencing (NGS). A case-control study (1 : 1 age-matched with and without BV) was undertaken in a series of 326 nongravid women of reproductive age with symptoms of BV to determine the prevalence of AMR genes. NGS was used to describe the complete vaginal microbiota and identify bacterial genes associated with resistance to: macrolides and/or lincosamides - ermA, ermB, ermC, erM, ermTR and mefA; tetracyclines, ß-lactams, streptomycin, gentamicin and/or tobramycin - acrA, acrB, mecA, tet, tetA, tolC and aac2; 5-nitroimadazoles - nim and nimB; and triazoles - cdr1 and mdr1. An evidence base was created to inform treatment decisions applicable to individual patients. AMR genes were identified in all drug classes: macrolides, 35.2 %; lincosamides, 35.6 %; tetracyclines, 21.8 %; aminoglycosides (streptomycin, gentamicin and tobramycin), 5.2 % each; 5-nitroimidazoles, 0.3 %; and triazoles, 18.7 %. There was more than a fourfold-higher frequency of AMR genes in pathogens from BV than from non-BV patients for macrolides (58.2 versus 12.3 %, respectively), lincosamides (58.9 versus 12.3 %) and tetracyclines (35.6 versus 8.0 %) (Fisher's exact test; all p < 0.001). For each patient with BV, the spectrum of resistance genes was matched to the pathogens present. AMR genes were present in the majority of vaginal microbiomes of patients with symptoms of BV.