No guarantees: planned oocyte cryopreservation, not quite an insurance policy.

Planned oocyte cryopreservation (OC) has the potential to address the burden of the biological clock, giving women and individuals with ovaries more autonomy in choosing when to have children and with whom. In the United States, the annual number of OC cycles has grown significantly, yet many questions remain regarding planned OC. The field is starting to gather data on the clinical practice and social perspectives around planned oocyte cryopreservation, including the optimal age range at which to offer planned OC, what factors are most predictive of a successful outcome, and the optimal number of oocytes and ovarian stimulation cycles to achieve a live birth. There is a clear need for setting realistic expectations about the chance of success with OC; however, most patients have yet to return to thaw their oocytes, and outcomes data are limited. Clinical models have been developed to predict OC success based on surrogate markers such as age, number of oocytes retrieved, and anti-Müllerian hormone level. Patient education should emphasize the age-related decline in fertility, that eggs do not equal embryos, and that more than one cycle may be needed to obtain sufficient oocytes to have a reasonable chance of future success. While planned OC is not quite an insurance policy against future reproductive challenges, it provides the best option to date for expanding the reproductive window and maximizing reproductive options while navigating individual life circumstances in the context of family building.

Frizzled-Induced Van Gogh Phosphorylation by CK1ε Promotes Asymmetric Localization of Core PCP Factors in Drosophila.

Epithelial tissues are polarized along two axes. In addition to apical-basal polarity, they are often polarized within the plane of the epithelium, so-called Planar Cell Polarity (PCP). PCP depends upon Wnt/Frizzled (Fz) signaling factors, including Fz itself and Van Gogh (Vang/Vangl). We sought to understand how Vang interaction with other core PCP factors affects Vang function. We find that Fz induces Vang phosphorylation in a cell-autonomous manner. Vang phosphorylation occurs on conserved N-terminal serine/threonine residues, is mediated by CK1ε/Dco, and is critical for polarized membrane localization of Vang and other PCP proteins. This regulatory mechanism does not require Fz signaling through Dishevelled and thus represents a cell-autonomous upstream interaction between Fz and Vang. Furthermore, this signaling event appears to be related to Wnt5a-mediated Vangl2 phosphorylation during mouse limb patterning and may thus be a general mechanism underlying Wnt-regulated PCP establishment.

Is Aging in Place Delaying Nursing Home Admission?

OBJECTIVES: This study examines whether aging in place (community-based living before admission to a nursing home) delays nursing home admission among New York State home health care recipients. DESIGN: Retrospective cohort study (January 2007-December 2012). SETTING: New York State. PARTICIPANTS: Adults age 65+ who received home health services for at least 2 months before permanent nursing home admission. MEASUREMENT AND ANALYSIS: Permanent transition is defined as home care patients who are discharged to and stay at a nursing home for more than 3 months. Data were abstracted from the Minimum Data Set (MDS) and Outcome and Assessment Information Set (OASIS). Descriptive and bivariate Kruskal-Wallis and χ(2) tests were performed. RESULTS: The average age of nursing home residents at admission remained steady at 83 years between 2007 and 2012. The proportion of minority populations (Asian, black, Hispanic/Latino) increased, whereas the white population declined (P < .0001). The average length of stay at home increased 8 months, from 17 months in 2007 to 25 months in 2012 (P < .0001). Chronic conditions with significant increases in prevalence during the study period were hypertension (P < .0009), dementia (P < .0001), heart failure (P = .05), urinary incontinence (P < .0001), and bowel incontinence (P < .0001). Increases in functional disabilities requiring extensive human assistance included toileting, dressing, personal hygiene, and transferring (all P < .001). CONCLUSION: Home health services enabled recipients to remain at home 8 months longer, thus delaying nursing home entry. Given the increase in prevalence of comorbidities and disability, we anticipate a concomitant increase in support services at the nursing home. These results may inform policy and staffing decisions regarding adjustments in required caregivers' credentials and nurse-patient ratios.

A phase I open-label study investigating the disposition of [14C]-cabazitaxel in patients with advanced solid tumors.

Cabazitaxel is a semisynthetic taxane approved for the treatment of patients with hormone-refractory metastatic prostate cancer (now known as metastatic castration-resistant prostate cancer) treated previously with a docetaxel-containing treatment regimen. The human plasma pharmacokinetics of cabazitaxel have been described previously, but detailed analyses of the metabolism and excretion pathways of cabazitaxel have not yet been published. Metabolite profiling, quantification, and identification as well as excretion analyses were carried out on samples from patients with advanced solid tumors who received an intravenous infusion of 25 mg/m [C]-cabazitaxel (50 µCi, 1.85 MBq) over 1 h. In plasma, cabazitaxel was the main circulating compound. Seven metabolites were detected, but with each accounting for 5% or less of the parent drug exposure, none were considered relevant metabolites. In excreta, 76.0% of the administered dose was recovered in feces within 2 weeks and 3.7% of the dose was excreted in urine within 1 week. Approximately 20 metabolites were detected in excreta; the main metabolites corresponded to combined mono-O-demethyl or di-O-demethyl derivatives on the taxane ring, with hydroxyl or cyclized derivatives on the lateral chain. Docetaxel (di-O-demethyl-cabazitaxel) was only detected at trace levels in excreta. These results suggest an extensive hepatic metabolism and biliary excretion of cabazitaxel in humans.

Characterizing the disposition, metabolism, and excretion of an orally active pan-deacetylase inhibitor, panobinostat, via trace radiolabeled 14C material in advanced cancer patients.

PURPOSE: Elucidating the metabolic profile of anticancer agent panobinostat is essential during drug development. Disposition, metabolism, and excretion profiles were characterized using trace radiolabeled (14)C-panobinostat in four patients with advanced cancer. METHODS: Oral (14)C-panobinostat was administered and serial blood, plasma, and excreta samples were collected up to 7 days postdose for radioactivity and pharmacokinetic analyses. Metabolites in plasma and excreta were profiled using liquid chromatography (LC) with radiometric detection, and their structures elucidated using LC-tandem mass spectrometry. RESULTS: Radioactivity (≥87 %) was recovered in excreta within 7 days: 44-77 % dose recovery in feces and 29-51 % in urine. Circulating radioactivity was localized in plasma, with minor partitioning to blood. Minimal recovery in feces (<3.5 % of dose) suggested near-complete oral absorption. Maximum concentrations (median, 21.2 ng/mL; range, 13.4-41.5 ng/mL) were achieved within 1 h, and median (range) terminal half-life, apparent oral, and renal clearance was 30.7 h (27.6-33.2 h), 209 L/h (114-248 L/h), and 3.20 L/h (2.4-5.5 L/h), respectively. Approximately 40 metabolites were circulating in plasma, with biotransformation occurring primarily at the hydroxamic acid side chain and ethyl-methyl indole moiety. Metabolites derived from modification of the hydroxamic acid side chain were inactive for deacetylase inhibition. CONCLUSIONS: Panobinostat and its metabolites were excreted in similar amounts through the kidneys and liver with good dose recovery. Panobinostat was rapidly absorbed and cleared primarily through metabolism. Over half of its clearance was attributed to non-CYP-mediated pathways. Thus, CYP-mediated drug-drug interactions with panobinostat are predicted to be minor.