Bright Fluorescent Chemosensor Platforms for Imaging Endogenous Pools of Neuronal Zinc

AbstractA series of new fluorescent Zinpyr (ZP) chemosensors based on the fluorescein platform have been prepared and evaluated for imaging neuronal Zn2+. A systematic synthetic survey of electronegative substitution patterns on a homologous ZP scaffold provides a basis for tuning the fluorescence responses of “off-on” photoinduced electron transfer (PET) probes by controlling fluorophore pKa values and attendant proton-induced interfering fluorescence of the metal-free (apo) probes at physiological pH. We further establish the value of these improved optical tools for interrogating the metalloneurochemistry of Zn2+; the novel ZP3 fluorophore images endogenous stores of Zn2+ in live hippocampal neurons and slices, including the first fluorescence detection of Zn2+ in isolated dentate gyrus cultures. Our findings reveal that careful control of fluorophore pKa can minimize proton-induced fluorescence of the apo probes and that electronegative substitution offers a general strategy for tuning PET chemosensors for cellular studies. In addition to providing improved optical tools for Zn2+ in the neurosciences, these results afford a rational starting point for creating superior fluorescent probes for biological applications

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology

Chloro-cobalt complexes with pyridyl-ethyl-derived di-aza-cyclo-alkanes.

Syntheses are described for the blue/purple complexes of cobalt(II) chloride with the tetra-dentate ligands 1,4-bis-[2-(pyridin-2-yl)eth-yl]piperazine (Ppz), 1,4-bis-[2-(pyridin-2-yl)eth-yl]homopiperazine (Phpz)

Contemporary practice patterns for palliative radiotherapy of bone metastases: Impact of a quality improvement project on extended fractionation

PURPOSE/OBJECTIVES: Radiotherapy (RT) effectively palliates bone metastases, though variability exists in practice patterns. National recommendations advocate against using extended fractionation (EF) with courses greater than ten fractions. We previously reported EF utilization of 14.8%. We analyzed practice patterns within a statewide quality consortium to assess EF use in a larger patient population following implementation of a quality measure focused on reducing EF. MATERIALS/METHODS: Patients treated for bone metastases within a statewide radiation oncology quality consortium were prospectively enrolled from March 2018 through October 2020. The EF quality metric was implemented March 1, 2018. Data on patient, physician and facility characteristics, fractionation schedules, and treatment planning and delivery techniques were collected. Multivariable binary logistic regression was used to assess EF. RESULTS: 1,445 consecutive patients treated with 1,934 plans were enrolled by 28 facilities. The median number of treatment plans per facility was 52 (range, 7-307). 60 different fractionation schedules were utilized. EF was delivered in 3.4% of plans. Initially, EF use was lower than expected and remained low over time. Significant predictors for EF use included complicated metastasis (OR 2.04, 95% CI: 1.04-4.02, p=0.04), lack of associated CNS or visceral disease (OR 2.27, 95% CI: 1.2-4.2, p=0.01), non-teaching versus teaching facilities (OR 8.97, 95% CI: 2.1-38.5, p\u3c0.01), and treating physicians with more years in practice (OR 12.82, 95% CI: 3.9-42.4, p\u3c0.01). CONCLUSIONS: Within a large, prospective population-based dataset, fractionation schedules for palliative RT of bone metastases remain highly variable. Resource-intensive treatments including EF persist, though EF use was low following implementation of a quality measure. Complicated metastases, lack of CNS or visceral disease, treatment at non-teaching facilities or by physicians with more years in practice significantly predict use of EF. These results support ongoing efforts to more clearly understand and address barriers to high value radiation approaches in the palliative setting