Inhibiting PRMT5 induces DNA damage and increases anti-proliferative activity of Niraparib, a PARP inhibitor, in models of breast and ovarian cancer.

Background: Inhibitors of Poly (ADP-Ribose) Polymerases (PARP) provide clinical benefit to patients with breast and ovarian cancers, by compromising the DNA repair activity of cancer cells. Although these agents extend progression-free survival in many patients, responses can be short lived with many patients ultimately progressing. Identification of combination partners that increase dependence of cancer cells to the DNA repair activity of PARPs may represent a strategy to increase the utility of PARP inhibitors.

Community children's nursing: developing a bespoke model of post-registration education.

Community children's nurses provide a vital service between the hospital and home environment, supporting children, young people and families with their health needs. In the UK, the number of educational pathways providing a specialist practitioner qualification in community children's nursing has declined significantly in recent years. This has left many community children's nursing services with little or no access to educational programmes, despite the rising demand.

Aquatic stem group myriapods close a gap between molecular divergence dates and the terrestrial fossil record.

Identifying marine or freshwater fossils that belong to the stem groups of the major terrestrial arthropod radiations is a longstanding challenge. Molecular dating and fossils of their pancrustacean sister group predict that myriapods originated in the Cambrian, much earlier than their oldest known fossils, but uncertainty about stem group Myriapoda confounds efforts to resolve the timing of the group's terrestrialization. Among a small set of candidates for membership in the stem group of Myriapoda, the Cambrian to Triassic euthycarcinoids have repeatedly been singled out.

Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation.

Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts.

Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing.

Evasion of the potent tumour suppressor activity of p53 is one of the hurdles that must be overcome for cancer cells to escape normal regulation of cellular proliferation and survival. In addition to frequent loss of function mutations, p53 wild-type activity can also be suppressed post-translationally through several mechanisms, including the activity of PRMT5. Here we describe broad anti-proliferative activity of potent, selective, reversible inhibitors of protein arginine methyltransferase 5 (PRMT5) including GSK3326595 in human cancer cell lines representing both hematologic and solid malignancies.

Sun Smart Schools Nevada: Increasing Knowledge Among School Children About Ultraviolet Radiation.

Background: Cumulative exposure to ultraviolet radiation (UV) is a risk factor for development of skin cancer. We estimated changes in knowledge, attitudes, and behaviors among Nevada school-age children following implementation of a program to decrease UV exposure.

Community Context: The Nevada Cancer Coalition's Sun Smart Schools pilot program was implemented in 7 Nevada schools during the 2015-2016 school year.

Optimizing Transitions of Care - Hospital to Community.

Discharging patients from the hospital is a complex process, and preventing avoidable readmissions has the potential to improve both the quality of life for patients and the financial sustainability of the healthcare system (Alper et al. 2016). Improving the discharge process is one method to mitigate readmission to the hospital.

An informatics-based approach to reducing heart failure all-cause readmissions: the Stanford heart failure dashboard.

Background: Reduction of 30-day all-cause readmissions for heart failure (HF) has become an important quality-of-care metric for health care systems. Many hospitals have implemented quality improvement programs designed to reduce 30-day all-cause readmissions for HF. Electronic medical record (EMR)-based measures have been employed to aid in these efforts, but their use has been largely adjunctive to, rather than integrated with, the overall effort.

Translating Clinical Findings into the Patient's Perspective: Post-hoc Pooled Analysis of Bowel Movement Changes as a Predictor of Improvement in Patients' Opioid-induced Constipation Symptoms and Outcomes.

Purpose: Opioid-induced constipation (OIC) is a bothersome side effect of opioid use for the management of noncancer pain, affecting patients' health-related quality of life and chronic-pain management. The objective of this study was to examine the relationship between changes in the frequency of spontaneous bowel movements (SBMs) and changes in patient-reported outcomes (PROs) among patients with OIC treated with naloxegol.

Methods: Post hoc analyses were conducted using pooled data from two Phase III 12-week, placebo-controlled trials of naloxegol for the treatment of OIC (NCT01309841 and NCT01323790).

Discriminating between neuropathic pain and sensory hypersensitivity using the Chronic Pain Questions (CPQ).

Objective: The Chronic Pain Questions (CPQ) were developed for clinical use with the aim of supporting primary care physicians in the screening, assessment and monitoring of patients with chronic pain. the purpose of this study was to examine the ability of the cpq CPQ to discriminate between patients with neuropathic pain (nep) versus those with sensory hypersensitivity (sh).

Methods: Adult men and women with a diagnosis of a NeP or SH condition were recruited from 5 clinical sites across the United States.

Validation of the 4 week recall version of the Uterine Fibroid Symptom and Health-related Quality of Life (UFS-QOL) Questionnaire.

Objective: To assess the psychometric performance of the 4 week recall version of the Uterine Fibroid Symptom and Health-related Quality of Life Questionnaire (UFS-QoL), a patient measure of the severity of uterine fibroid (UF) symptoms and their impact on health-related quality of life (HRQL).

Methods: This was a retrospective analysis of phase 2a data from pre-menopausal women with heavy menstrual bleeding associated with UF. Participants completed the UFS-QoL at Baseline, Treatment Month 3, and Follow-up Month 3 and a daily diary with a Menstrual Bleeding Scale and the UF Daily Symptom Scale throughout the study duration.

Laxative utilization over time in chronic pain patients with opioid-induced constipation.

Aim: To determine laxative utilization over time among chronic noncancer pain patients with opioid-induced constipation (OIC).

Setting: A prospective longitudinal study conducted in the USA, Canada, Germany and UK.

Methods: Patients on daily opioid therapy for treatment of chronic noncancer pain with OIC were recruited from clinics to complete a survey at Baseline and weeks 2, 4, 6, 8, 12, 16, 20 and 24.

Production of Virus-Like Particles for Vaccination.

The ability to make a large variety of virus-like particles (VLPs) has been successfully achieved in the baculovirus expression vector system (BEVS)/insect cell system. The production and scale-up of these particles, which are mostly sought as vaccine candidates, are currently being addressed. Furthermore, these VLPs are being investigated as delivery agents for use as therapeutics.

Recombinant Protein Production in Large-Scale Agitated Bioreactors Using the Baculovirus Expression Vector System.

The production of recombinant proteins using the baculovirus expression vector system (BEVS) in large-scale agitated bioreactors is discussed in this chapter. Detailed methods of the key stages of a batch process, including host cell growth, virus stock amplification and quantification, bioreactor preparation and operation, the infection process, final harvesting, and primary separation steps for recovery of the product are presented. Furthermore, methods involved with advanced on-line monitoring and bioreactor control, which have a significant impact on the overall process success, are briefly discussed.

An Electronic Medical Record Report Improves Identification of Hospitalized Patients With Heart Failure.

Background: Early identification of inpatients with heart failure (HF) may help to reduce readmissions. We found that many patients identified by our coding team as having a primary diagnosis of HF were not identified by our clinical team. We hypothesized that an electronic medical record (EMR)-based report would improve identification of hospitalized patients eventually diagnosed with HF.

Critical assessment of influenza VLP production in Sf9 and HEK293 expression systems.

Background: Each year, influenza is responsible for hundreds of thousand cases of illness and deaths worldwide. Due to the virus' fast mutation rate, the World Health Organization (WHO) is constantly on alert to rapidly respond to emerging pandemic strains. Although anti-viral therapies exist, the most proficient way to stop the spread of disease is through vaccination.

An overactive bladder symptom and health-related quality of life short-form: validation of the OAB-q SF.

Aims: The Overactive Bladder Questionnaire (OAB-q) has demonstrated robust psychometric properties in continent and incontinent OAB patients. However, there is a need for a short-form of this instrument for settings where completing the full OAB-q may be too burdensome. The purpose of this manuscript is to describe the validation of the OAB-q short-form.

Classifying bivalve larvae using shell pigments identified by Raman spectroscopy.

Because bivalve larvae are difficult to identify using morphology alone, the use of Raman spectra to distinguish species could aid classification of larvae collected from the field. Raman spectra from shells of bivalve larvae exhibit bands that correspond to polyene pigments. This study determined if the types of shell pigments observed in different species could be unique enough to differentiate larvae using chemotaxonomic methods and cluster analysis.

Responsiveness of the Peyronie's Disease Questionnaire (PDQ).

Introduction: In order to reliably assess treatment effectiveness, patient-reported outcome instruments must demonstrate adequate psychometric properties.

Aim: To assess the responsiveness of the Peyronie's Disease Questionnaire (PDQ) using data from two Phase 3 trials of collagenase clostridium histolyticum for Peyronie's disease (PD).

Methods: Both trials recruited adult males with PD who were in a stable relationship with a female partner for at least 3 months.

Particle quantification of influenza viruses by high performance liquid chromatography.

The influenza virus continuously undergoes antigenic evolution requiring manufacturing, validation and release of new seasonal vaccine lots to match new circulating strains. Although current production processes are well established for manufacturing seasonal inactivated influenza vaccines, significant limitations have been underlined in the case of pandemic outbreaks. The World Health Organization called for a global pandemic influenza vaccine action plan including the development of new technologies.

The test-retest reliability of the Peyronie's disease questionnaire.

Introduction: The Peyronie's Disease Questionnaire (PDQ) is a disease-specific, patient-reported outcome instrument designed to measure the psychosexual consequences and treatment outcomes of Peyronie's disease (PD).

Aim: The aim of this study was to evaluate the test-retest reliability of the PDQ.

Methods: Adult men with PD were recruited through eight clinical sites across the United States.

Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2.

The poly(ADP-ribose) polymerase (PARP) family represents a new class of therapeutic targets with diverse potential disease indications. PARP1 and PARP2 inhibitors have been developed for breast and ovarian tumors manifesting double-stranded DNA-repair defects, whereas tankyrase 1 and 2 (TNKS1 and TNKS2, also known as PARP5a and PARP5b, respectively) inhibitors have been developed for tumors with elevated β-catenin activity. As the clinical relevance of PARP inhibitors continues to be actively explored, there is heightened interest in the design of selective inhibitors based on the detailed structural features of how small-molecule inhibitors bind to each of the PARP family members.

Development and psychometric evaluation of the urgency questionnaire for evaluating severity and health-related quality of life impact of urinary urgency in overactive bladder.

Introduction And Hypothesis: Urinary urgency is the cardinal symptom of overactive bladder (OAB). However, there is no single instrument that assesses the context, severity, intensity, and daily life impact of urinary urgency. The purpose of this manuscript is to describe the methods and results of the qualitative and quantitative research conducted to develop a new tool for this purpose, the Urgency Questionnaire (UQ).

Do lipids show state-dependent affinity to the voltage-gated potassium channel KvAP?

As all integral membrane proteins, voltage-gated ion channels are embedded in a lipid matrix that regulates their channel behavior either by physicochemical properties or by direct binding. Because manipulation of the lipid composition in cells is difficult, we investigated the influence of different lipids on purified KvAP channels reconstituted in planar lipid bilayers of known composition. Lipids developed two distinct and independent effects on the KvAP channels; lipids interacting with the pore lowered the energy barriers for the final transitions, whereas voltage sensor-bound lipids shifted the midpoint of activation dependent on their electrostatic charge.