A therapeutic dose of UFH can protect glycocalyx from shedding by inhibiting inflammation. Additional studies with larger sample sizes are needed to confirm our conclusions.

The pivotal role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology was identified over 30 years ago, but the successful clinical development of targeted therapies has only recently been realized. This Perspective traces the decades long evolution of medicinal chemistry required to advance small molecule CGRP receptor antagonists, also called gepants, including the current clinical agents rimegepant, vazegepant, ubrogepant, and atogepant. Providing clinically effective blockade of CGRP signaling required surmounting multiple challenging hurdles, including defeating a sizable ligand with subnanomolar affinity for its receptor, designing antagonists with an extended confirmation and multiple pharmacophores while retaining solubility and oral bioavailability, and achieving circulating free plasma levels that provided near maximal CGRP receptor coverage. The clinical efficacy of oral and intranasal gepants and the injectable CGRP monoclonal antibodies (mAbs) are described, as are recent synthetic developments that have benefited from new structural biology data. The first oral gepant was recently approved and heralds a new era in the treatment of migraine.

Despite use of newer approaches, some patients being considered for autologous hematopoietic cell transplantation (HCT) may only mobilize limited numbers of hematopoietic progenitor cells (HPCs) into blood, precluding use of the procedure, or being placed at increased risk of complications due to slow hematopoietic reconstitution. Developing more efficacious HPC mobilization regimens and strategies may enhance the mobilization process and improve patient outcome. Although Notch signaling is not essential for homeostasis of adult hematopoietic stem cells (HSCs), Notch-ligand adhesive interaction maintains HSC quiescence and niche retention. Using Notch receptor blocking antibodies, we report that Notch2 blockade, but not Notch1 blockade, sensitizes hematopoietic stem cells and progenitors (HSPCs) to mobilization stimuli and leads to enhanced egress from marrow to the periphery. Notch2 blockade leads to transient myeloid progenitor expansion without affecting HSC homeostasis and self-renewal. We show that transient Notch2 blockade or Notch2-loss in mice lacking Notch2 receptor lead to decreased CXCR4 expression by HSC but increased cell cycling with CXCR4 transcription being directly regulated by the Notch transcriptional protein RBPJ. In addition, we found that Notch2-blocked or Notch2-deficient marrow HSPCs show an increased homing to the marrow, while mobilized Notch2-blocked, but not Notch2-deficient stem cells and progenitors, displayed a competitive repopulating advantage and enhanced hematopoietic reconstitution. These findings suggest that blocking Notch2 combined with the current clinical regimen may further enhance HPC mobilization and improve engraftment during HCT.

Drug delivery research is an inherently empirical process, however high-throughput approaches could take advantage of understanding drug/material interactions such as from electrostatic, hydrophobic, or other non-covalent interactions between therapeutic molecules and a drug delivery polymer. Cyclodextrin polymers have been investigated for drug delivery specifically due to their capacity to exploit this affinity interaction to change the rate of drug release. Testing drug candidates; however, for affinity is time-consuming, making computational predictions more effective. One option, molecular "docking" programs, provide predictions of affinity, but lack reliability, as their accuracy with cyclodextrin remains unverified experimentally.Alternatively, quantitative structure-activity relationship models (QSARs), which analyze statistical relationships between molecular properties, appear more promising. Previously constructed QSARs for cyclodextrin are not publicly available, necessitating an openly accessible model. Around 600 experimental affinities between cyclodextrin and guest molecules were cleaned and imported from published research. The software PaDEL-Descriptor calculated over 1000 chemical descriptors for each molecule, which were then analyzed in R to create several QSARs with different statistical methods. These QSARs proved highly time efficient, calculating in minutes what docking programs would take hours to accomplish. Additionally, on test sets, QSARs reached R 2 values of around 0.7-0.8. The speed, accuracy, and accessibility of these QSARs improve evaluation of individual drugs and facilitate screening of large datasets for potential candidates in cyclodextrin affinity-based delivery systems. An app was built to rapidly access model predictions for end users using the "shiny" library in R. To demonstrate the usability for drug release planning, the QSAR predictions were coupled with a mechanistic model of diffusion within the app. Integrating new modules should provide an accessible approach to use other cheminformatic tools in the field of drug delivery.