The analysis of big healthcare data has enormous potential as a tool for advancing oncology drug development and patient treatment, particularly in the context of precision medicine. However, there ...are challenges in organizing, sharing, integrating, and making these data readily accessible to the research community. This review presents five case studies illustrating various successful approaches to addressing such challenges. These efforts are CancerLinQ, the American Association for Cancer Research Project GENIE, Project Data Sphere, the National Cancer Institute Genomic Data Commons, and the Veterans Health Administration Clinical Data Initiative. Critical factors in the development of these systems include attention to the use of robust pipelines for data aggregation, common data models, data deidentification to enable multiple uses, integration of data collection into physician workflows, terminology standardization and attention to interoperability, extensive quality assurance and quality control activity, incorporation of multiple data types, and understanding how data resources can be best applied. By describing some of the emerging resources, we hope to inspire consideration of the secondary use of such data at the earliest possible step to ensure the proper sharing of data in order to generate insights that advance the understanding and the treatment of cancer.
Because of its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic ...heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation. WO 2014201206, 2014 of NaV1.7, which demonstrate nanomolar inhibition of NaV1.7 and exhibit high levels of selectivity over other sodium channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound 39 (AM-0466) demonstrated robust pharmacodynamic activity in a NaV1.7-dependent model of histamine-induced pruritus (itch) and additionally in a capsaicin-induced nociception model of pain without any confounding effect in open-field activity.
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The NaV1.7 ion channel has garnered considerable attention as a target for the treatment of pain. Herein we detail the discovery and structure-activity relationships of a novel series ...of biaryl amides. Optimization led to the identification of several state-dependent, potent and metabolically stable inhibitors which demonstrated promising levels of selectivity over NaV1.5 and good rat pharmacokinetics. Compound 18, which demonstrated preferential inhibition of a slow inactivated state of NaV1.7, was advanced into a rat formalin study where upon reaching unbound drug levels several fold over the rat NaV1.7 IC50 it failed to demonstrate a robust reduction in nociceptive behavior.
Introduction
Osteoarthritis is a common disease in dogs resulting in chronic pain and decreased wellbeing. Common analgesics such as non-steroidal anti-inflammatories may fail to control pain and can ...produce major adverse effects. Study objectives were to evaluate pharmacokinetics, therapeutic efficacy, and safety of subcutaneous liposomal-cannabidiol (CBD) as an additional analgesic therapy in dogs suffering from naturally-occurring osteoarthritis.
Methods
Six such dogs were recruited following ethics approval and owner consent. Dogs were administered a single subcutaneous injection of 5 mg/kg liposomal-CBD. Plasma concentrations of CBD, blood work, activity monitoring collar data, wellbeing questionnaire (owners) and pain scoring (veterinarian) were performed at baseline and monitored up to six weeks following intervention. Data overtime were compared with baseline using linear-regression mixed-effects.
P
-value was set at 0.05.
Results
CBD plasma concentrations were observed for 6 weeks; median (range) peak plasma concentration (C
max
) was 45.2 (17.8–72.5) ng/mL, time to C
max
was 4 (2–14) days and half-life was 12.4 (7.7–42.6) days. Median (range) collar activity score was significantly increased on weeks 5–6; from 29 (17–34) to 34 (21–38). Scores of wellbeing and pain evaluations were significantly improved at 2–3 weeks; from 69 (52–78) to 53.5 (41–68), and from 7.5 (6–8) to 5.5 (5–7), respectively. The main adverse effect was minor local swelling for several days in 5/6 dogs.
Conclusion
Liposomal-CBD administered subcutaneously produced detectable CBD plasma concentrations for 6 weeks with minimal side effects and demonstrated reduced pain and increased wellbeing as part of multimodal pain management in dogs suffering from osteoarthritis. Further placebo-controlled studies are of interest.
Because of its strong genetic validation, Na
1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic ...heteroarylsulfonamides as Na
1.7 inhibitors that demonstrate high levels of selectivity over other Na
isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation . WO 2014201206, 2014 of Na
1.7, which demonstrate nanomolar inhibition of Na
1.7 and exhibit high levels of selectivity over other sodium channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound 39 (AM-0466) demonstrated robust pharmacodynamic activity in a Na
1.7-dependent model of histamine-induced pruritus (itch) and additionally in a capsaicin-induced nociception model of pain without any confounding effect in open-field activity.
Abstract only
Accurate measurement of growth in infants and children is important, as it reflects a child's nutritional status and overall health. Conventional methods of measuring length and height ...are challenging due to limited access to appropriate tools, poor tool quality, and lack of child cooperation. Pediatric Platform for Anthropometry (PePA) is a portable, computer‐assisted infrared‐based tool that measures length/height without direct child contact. This study investigated PePA's accuracy by comparing length/height measures to the gold standard (length board or stadiometer). The precision and acceptability of PePA and the gold standard were also assessed. In a preliminary analysis of 316 eligible children (0‐18 years), 278 participants' PePA and gold standard measures met the study criteria for inclusion in the analysis. For 6% of those eligible, no successful PePA measures were obtained. The overall intraclass correlation (ICC) 95% CI between PePA and the gold standard was 0.9988 0.9985, 0.9991. The ICC for length only (n=16) and height only (n=262) was 0.9840 0.9286, 0.9951 and 0.9981 0.9976, 0.9985, respectively. The mean (±SD) time to obtain a PePA measure was less than the standard tool (8.4±3.2 versus 14.1±5.3 seconds, respectively; p<0.05). Preliminary results suggest that PePA has a very high concordance with the gold standard and is faster in obtaining a measure.
Research support was provided by a Hospital for Sick Children Innovation Grant.
The present study used two versions of a spatial list learning (SLL) paradigm to examine the effects of increased cognitive load on visuospatial working memory processes in young and old beagle dogs. ...In the first experiment, young, and a select group of old dogs were first presented with one item, then two, and then three, and were rewarded for responding to the novel position. The dogs were able to learn the task at short delays, but compared with young dogs, old dogs performed worse at delays of 10 sec, and could not reach longer delays. Analysis of errors indicated that memory was best for end items in the spatial list and that within sessions, the number of errors in later trials was greater than the number of errors in earlier trials. A second version of the task, a modified SLL (mSLL) was developed to control for the use of non-mnemonic strategies on the SLL task. In this version, the first two items were presented individually. Acquisition and maximal memory performance were better in the young relative to the old dogs. Similar to the original SLL design, memory for early list items was worse than memory for later list items in both young and old dogs. The within-session pattern of errors however, did not change from trial to trial on the mSLL. The present results suggest that multiple working memory processes are engaged during complex tests of visuospatial function and the neuroanatomical substrates controlling these processes are affected differentially by age in the beagle dog.
Protein kinase A-anchoring proteins (AKAPs) localize the second messenger response to particular subcellular domains by sequestration
of the type II protein kinase A. Previously, AKAP120 was ...identified from a rabbit gastric parietal cell cDNA library; however,
a monoclonal antibody raised against AKAP120 labeled a 350-kDa band in Western blots of parietal cell cytosol. Recloning has
now revealed that AKAP120 is a segment of a larger protein, AKAP350. We have now obtained a complete sequence of human gastric
AKAP350 as well as partial cDNA sequences from human lung and rabbit parietal cells. The genomic region containing AKAP350
is found on chromosome 7q21 and is multiply spliced, producing at least three distinct AKAP350 isoforms as well as yotiao,
a protein associated with the N -methyl- d -aspartate receptor. Rabbit parietal cell AKAP350 is missing a sequence corresponding to a single exon in the middle of the
molecule located just after the yotiao homology region. Two carboxyl-terminal splice variants were also identified. Both of
the major splice variants showed tissue- and cell-specific expression patterns. Immunofluorescence microscopy demonstrated
that AKAP350 was associated with centrosomes in many cell types. In polarized Madin-Darby canine kidney cells, AKAP350 localized
asymmetrically to one pole of the centrosome, and nocodazole did not alter its localization. During the cell cycle, AKAP350
was associated with the centrosomes as well as with the cleavage furrow during anaphase and telophase. Several epithelial
cell types also demonstrated noncentrosomal pools of AKAP350, especially parietal cells, which contained multiple cytosolic
immunoreactive foci throughout the cells. The localization of AKAP350 suggests that it may regulate centrosomal and noncentrosomal
cytoskeletal systems in many different cell types.
The Epithelial Na+ Channel (ENaC) is an apical heteromeric channel that mediates Na+ entry into epithelial cells from the luminal cell surface. ENaC is activated by proteases that interact with the ...channel during biosynthesis or at the extracellular surface. Meprins are cell surface and secreted metalloproteinases of the kidney and intestine. We discovered by affinity chromatography that meprins bind γ-ENaC, a subunit of the ENaC hetero-oligomer. The physical interaction involves NH2-terminal cytoplasmic residues 37-54 of γ-ENaC, containing a critical gating domain immediately before the first transmembrane domain, and the cytoplasmic COOH-terminal tail of meprin β (residues 679-704). This potential association was confirmed by co-expression and co-immunoprecipitation studies. Functional assays revealed that meprins stimulate ENaC expressed exogenously in Xenopus oocytes and endogenously in epithelial cells. Co-expression of ENaC subunits and meprin β or α/β in Xenopus oocytes increased amiloride-sensitive Na+ currents approximately two-fold. This increase was blocked by preincubation with an inhibitor of meprin activity, actinonin. The meprin-mediated increase in ENaC currents in oocytes and epithelial cell monolayers required meprin β, but not the α subunit. Meprin β promoted cleavage of α and γ-ENaC subunits at sites close to the second transmembrane domain in the extracellular domain of each channel subunit. Thus, meprin β regulates the activity of ENaC in a metalloprotease-dependent fashion.
The cerebroarterial system is a complex network of arteries that supply the brain cells with vitally important nutrients and oxygen. The inter-individual differences of the cerebral arteries, ...especially at a finer level, are still not understood sufficiently. The aim of this work is to present a statistical cerebroarterial atlas that can be used to overcome this problem.
Overall, 700 Time-of-Flight (TOF) magnetic resonance angiography (MRA) datasets of healthy subjects were used for atlas generation. Therefore, the cerebral arteries were automatically segmented in each dataset and used for a quantification of the vessel diameters. After this, each TOF MRA dataset as well as the corresponding vessel segmentation and vessel diameter dataset were registered to the MNI brain atlas. Finally, the registered datasets were used to calculate a statistical cerebroarterial atlas that incorporates information about the average TOF intensity, probability for a vessel occurrence and mean vessel diameter for each voxel.
Visual analysis revealed that arteries with a diameter as small as 0.5 mm are well represented in the atlas with quantitative values that are within range of anatomical reference values. Moreover, a highly significant strong positive correlation between the vessel diameter and occurrence probability was found. Furthermore, it was shown that an intensity-based automatic segmentation of cerebral vessels can be considerable improved by incorporating the atlas information leading to results within the range of the inter-observer agreement.
The presented cerebroarterial atlas seems useful for improving the understanding about normal variations of cerebral arteries, initialization of cerebrovascular segmentation methods and may even lay the foundation for a reliable quantification of subtle morphological vascular changes.
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