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Sökning: WFRF:(Blakeley J.)

  • Resultat 1-6 av 6
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1.
  • Legius, E., et al. (författare)
  • Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation
  • 2021
  • Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600. ; 23, s. 1506-1513
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). Methods We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. Results We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. Conclusion The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.
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2.
  • Poveda, A., et al. (författare)
  • Olaparib maintenance monotherapy in platinum-sensitive relapsed ovarian cancer patients without a germline BRCA1/BRCA2 mutation : OPINION primary analysis
  • 2022
  • Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258. ; 164:3, s. 498-504
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: The phase IIIb OPINION trial (NCT03402841) investigated olaparib maintenance monotherapy in patients without a deleterious or suspected deleterious germline BRCA1/BRCA2 mutation (gBRCAm) who had platinum-sensitive relapsed ovarian cancer (PSROC) and had received ≥2 previous lines of platinum-based chemotherapy. Methods: In this single-arm, open-label, international study, patients who had responded to platinum-based chemotherapy received maintenance olaparib tablets (300 mg twice daily) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS) (modified RECIST version 1.1). A key secondary endpoint was PFS by homologous recombination deficiency (HRD) and somatic BRCAm (sBRCAm) status. The primary analysis of PFS was planned for 18 months after the last patient received their first dose. Results: Two hundred and seventy-nine patients were enrolled and received olaparib. At data cutoff (October 2, 2020), 210 PFS events had occurred (75.3% maturity) and median PFS was 9.2 months (95% confidence interval [CI], 7.6–10.9) in the overall population. At 12 and 18 months, 38.5% and 24.3% of patients were progression-free, respectively. In the predefined biomarker subgroups, median PFS was 16.4, 11.1, 9.7, and 7.3 months in sBRCAm, HRD-positive including sBRCAm, HRD-positive excluding sBRCAm, and HRD-negative patients, respectively. The most common treatment-emergent adverse events (TEAEs) were nausea (48.4%) and fatigue/asthenia (44.1%). TEAEs led to dose interruption, dose reduction, and treatment discontinuation in 47.0%, 22.6%, and 7.5% of patients, respectively. Conclusion: Maintenance olaparib demonstrated clinical benefit in patients without a gBRCAm, and across all subgroups, compared with historical placebo controls. There were no new safety signals.
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3.
  • Blakeley, Matthew, et al. (författare)
  • Lectin-Functionalized Polyethylene Glycol for Relief of Mucosal Dryness
  • 2022
  • Ingår i: Advanced Healthcare Materials. - : Wiley. - 2192-2640 .- 2192-2659. ; 11:2
  • Tidskriftsartikel (refereegranskat)abstract
    • The importance of lubrication between oral surfaces provided by the salivary film is most acutely apparent when it is disrupted, a prevalent consequence of salivary gland hypofunction experienced with aging, a symptom of certain diseases, or a side effect of some medical interventions. Sufferers report difficulty with speech and oral food processing and collectively is detrimental to quality of life. Polyethylene glycol (PEG) is widely employed as a successful biocompatible boundary lubricant in engineering and biomedical applications. It is hypothesized that the immobilization of PEG to biological materials such as oral epithelial cells and tissue can mimic the salivary film and provide durable relief from the symptoms of mucosal dryness. To do so, PEG is functionalized with a sugar binding lectin (wheat germ agglutinin) to enhance epithelial adhesion through lectin-sugar interactions. Retention and lubricity are characterized on an ex vivo oral tissue tribology rig. WGA-PEG coats and retains on mucin films, oral epithelial cells, and porcine tongue tissue, and offers sustained reduction in coefficient of friction (COF). WGA-PEG could be developed into a useful topical treatment for reducing oral friction and the perception of dry mouth.
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4.
  • Kovalevsky, Andrey, et al. (författare)
  • "To Be or Not to Be" Protonated : Atomic Details of Human Carbonic Anhydrase-Clinical Drug Complexes by Neutron Crystallography and Simulation
  • 2018
  • Ingår i: Structure. - : Elsevier BV. - 0969-2126. ; 26:3, s. 3-390
  • Tidskriftsartikel (refereegranskat)abstract
    • Human carbonic anhydrases (hCAs) play various roles in cells, and have been drug targets for decades. Sequence similarities of hCA isoforms necessitate designing specific inhibitors, which requires detailed structural information for hCA-inhibitor complexes. We present room temperature neutron structures of hCA II in complex with three clinical drugs that provide in-depth analysis of drug binding, including protonation states of the inhibitors, hydration water structure, and direct visualization of hydrogen-bonding networks in the enzyme's active site. All sulfonamide inhibitors studied bind to the Zn metal center in the deprotonated, anionic, form. Other chemical groups of the drugs can remain neutral or be protonated when bound to hCA II. MD simulations have shown that flexible functional groups of the inhibitors may alter their conformations at room temperature and occupy different sub-sites. This study offers insights into the design of specific drugs to target cancer-related hCA isoform IX. Kovalevsky et al. used macromolecular neutron crystallography and molecular dynamics simulations to obtain a detailed picture of clinical inhibitors binding to human carbonic anhydrase II. The study visualized hydrogen atom positions, revealing protonation/deprotonation events and intricate hydrogen-bonding networks, providing insights for drug design.
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5.
  • Manzoni, Francesco, et al. (författare)
  • Perdeuteration, crystallization, data collection and comparison of five neutron diffraction data sets of complexes of human galectin-3C
  • 2016
  • Ingår i: Acta Crystallographica Section D: Structural Biology. - 2059-7983. ; 72:11, s. 1194-1202
  • Tidskriftsartikel (refereegranskat)abstract
    • Galectin-3 is an important protein in molecular signalling events involving carbohydrate recognition, and an understanding of the hydrogen-bonding patterns in the carbohydrate-binding site of its C-terminal domain (galectin-3C) is important for the development of new potent inhibitors. The authors are studying these patterns using neutron crystallography. Here, the production of perdeuterated human galectin-3C and successive improvement in crystal size by the development of a crystal-growth protocol involving feeding of the crystallization drops are described. The larger crystals resulted in improved data quality and reduced data-collection times. Furthermore, protocols for complete removal of the lactose that is necessary for the production of large crystals of apo galectin-3C suitable for neutron diffraction are described. Five data sets have been collected at three different neutron sources from galectin-3C crystals of various volumes. It was possible to merge two of these to generate an almost complete neutron data set for the galectin-3C-lactose complex. These data sets provide insights into the crystal volumes and data-collection times necessary for the same system at sources with different technologies and data-collection strategies, and these insights are applicable to other systems.Perdeuteration, purification and the growth of large crystals of the carbohydrate-recognition domain of galectin-3C are described. Five neutron diffraction data sets have been collected at four neutron sources; these are compared and two are merged.
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6.
  • Zhou, Jinyuan, et al. (författare)
  • Review and consensus recommendations on clinical APT-weighted imaging approaches at 3T : Application to brain tumors
  • 2022
  • Ingår i: Magnetic Resonance in Medicine. - : Wiley. - 1522-2594 .- 0740-3194. ; 88:2, s. 546-574
  • Tidskriftsartikel (refereegranskat)abstract
    • Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3 T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use.
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