Scientific and Regulatory Policy Committee (SRPC) Review*: Interpretation and Use of Cell Proliferation Data in Cancer Risk Assessment

Increased cell proliferation is a central key event in the mode of action for many non-genotoxic carcinogens, and quantitative cell proliferation data play an important role in the cancer risk assessment of many pharmaceutical and environmental compounds. Currently, there is limited unified information on assay standards, reference values, targeted applications, study design issues, and quality control considerations for proliferation data. Here, we review issues in measuring cell proliferation indices, considerations for targeted studies, and applications within current risk assessment frameworks. As the regulatory environment moves toward more prospective evaluations based on quantitative pathway-based models, standardiza- tion of proliferation assays will become an increasingly important part of cancer risk assessment. To help address this development, we also discuss the potential role for proliferation data as a component of alternative carcinogenicity testing models. This information should improve consistency of cell proliferation methods and increase efficiency of targeted testing strategies

Update of P2X receptor properties and their pharmacology: IUPHAR Review 30

The known seven mammalian receptor subunits (P2X1–7) form cationic channels gated by ATP. Three subunits compose a receptor channel. Each subunit is a polypeptide consisting of two transmembrane regions (TM1 and TM2), intracellular N- and C-termini, and a bulky extracellular loop. Crystallization allowed the identification of the 3D structure and gating cycle of P2X receptors. The agonist-binding pocket is located at the intersection of two neighbouring subunits. In addition to the mammalian P2X receptors, their primitive ligand-gated counterparts with little structural similarity have also been cloned. Selective agonists for P2X receptor subtypes are not available, but medicinal chemistry supplied a range of subtype-selective antagonists, as well as positive and negative allosteric modulators. Knockout mice and selective antagonists helped to identify pathological functions due to defective P2X receptors, such as male infertility (P2X1), hearing loss (P2X2), pain/cough (P2X3), neuropathic pain (P2X4), inflammatory bone loss (P2X5), and faulty immune reactions (P2X7)

The Frequency of Nonmotor Symptoms among Advanced Parkinson Patients May Depend on Instrument Used for Assessment

Background. Nonmotor symptoms (NMS) of Parkinson's disease (PD) may be more debilitating than motor symptoms. The purpose of this study was to determine the frequency and corecognition of NMS among our advanced PD cohort (patients considered for deep brain stimulation (DBS)) and caregivers. Methods. NMS-Questionnaire (NMS-Q), a self-administered screening questionnaire, and NMS Assessment-Scale (NMS-S), a clinician-administered scale, were administered to PD patients and caregivers. Results. We enrolled 33 PD patients (23 males, 10 females) and caregivers. The most frequent NMS among patients using NMS-Q were gastrointestinal (87.9%), sleep (84.9%), and urinary (72.7%), while the most frequent symptoms using NMS-S were sleep (90.9%), gastrointestinal (75.8%), and mood (75.8%). Patient/caregiver scoring correlations for NMS-Q and NMS-S were 0.670 (P < 0.0001) and 0.527 (P = 0.0016), respectively. Conclusion The frequency of NMS among advanced PD patients and correlation between patients and caregivers varied with the instrument used. The overall correlation between patient and caregiver was greater with NMS-Q than NMS-S

Experimental evidence of parametric decay processes in the variable specific impulse magnetoplasma rocket (VASIMR) helicon plasma source

Decay waves have been observed in the megahertz range in the helium plasma generated by the variable specific impulse magnetoplasma rocket magnetoplasma thruster. They are measured using one of the tips of a triple probe connected to a 50 Ω input of a spectrum analyzer via a dc block (a small capacitor). The maximum amplitude of all waves is in the center of the plasma and does not appear correlated to the radial electron density or temperature profiles. The waves seem to be generated close to the helicon antenna that was 91 cm “upstream” from the measuring Langmuir probe. A possible explanation is parametric decay of the large amplitude helicon wave that also generates the plasma.This project was proudly supported by the International Science Linkages programme established under the Australian Government’s innovation statement Backing Australia’s Ability

Effect of Deep Brain Stimulation on Parkinson's Nonmotor Symptoms following Unilateral DBS: A Pilot Study

Parkinson's disease (PD) management has traditionally focused largely on motor symptoms. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) are effective treatments for motor symptoms. Nonmotor symptoms (NMSs) may also profoundly affect the quality of life. The purpose of this pilot study was to evaluate NMS changes pre- and post-DBS utilizing two recently developed questionnaires. Methods. NMS-Q (questionnaire) and NMS-S (scale) were administered to PD patients before/after unilateral DBS (STN/GPi targets). Results. Ten PD patients (9 STN implants, 1 GPi implant) were included. The three most frequent NMS symptoms identified utilizing NMS-Q in pre-surgical patients were gastrointestinal (100%), sleep (100%), and urinary (90%). NMS sleep subscore significantly decreased (−1.6 points ± 1.8, P = 0.03). The three most frequent NMS symptoms identified in pre-surgical patients using NMS-S were gastrointestinal (90%), mood (80%), and cardiovascular (80%). The largest mean decrease of NMS scores was seen in miscellaneous symptoms (pain, anosmia, weight change, and sweating) (−7 points ± 8.7), and cardiovascular/falls (−1.9, P = 0.02). Conclusion. Non-motor symptoms improved on two separate questionnaires following unilateral DBS for PD. Future studies are needed to confirm these findings and determine their clinical significance as well as to examine the strengths/weaknesses of each questionnaire/scale

Markers of Bone Mineral Metabolism and Cardiac Structure and Function in Perinatally HIV-Infected and HIV-Exposed but Uninfected Children and Adolescents

Background: Disordered bone mineral metabolism and low vitamin D concentrations are associated with cardiovascular abnormalities; few studies have evaluated this relationship in HIV-infected youth. Setting: Adolescent Master Protocol (AMP) is a Pediatric HIV/AIDS Cohort Study (PHACS) network study conducted across 14 United States sites. Methods: Among perinatally HIV-infected (PHIV) and HIV-exposed uninfected (PHEU) youth enrolled in AMP, we evaluated associations of vitamin D (measured as 25-hydroxyvitamin D [25OHD]), parathyroid hormone (PTH), calcium, phosphate, and fibroblast growth factor-23 (FGF-23) concentrations with echocardiographic measures of left ventricular (LV) structure, function and concentrations of NT-proBNP, a biomarker of cardiac damage. Results: Among 485 participants (305 PHIV, 180 PHEU) with echocardiograms and bone mineralization measures, low 25OHD ( 65 pg/mL) was identified more often among PHIV than PHEU participants (9% vs 3%, p=0.02). After adjusting for HIV status and demographic covariates, both low 25OHD and elevated PTH were associated with lower mean LV mass z-scores, while elevated PTH was associated with higher mean fractional shortening z-scores. Participants with low 25OHD also had slightly higher mean LV end-systolic wall stress z-scores, but differences were more pronounced in PHEU than in PHIV participants. FGF-23 was inversely related to end-diastolic septal thickness both overall and among PHIV participants. Conclusion: In this cohort of PHIV and PHEU youth, we observed associations of 25OHD, PTH, and FGF-23 with both structural and functional cardiac parameters, supporting links between bone mineral metabolism and cardiac status