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A distinctive genomic and immunohistochemical profile for NOTCH3 and PDGFRB in infantile myofibroma with diagnostic and therapeutic implications
No full textMyofibromas are rare tumors of pericytic lineage, typically affecting children, and are sometimes aggressive.
A subset of sporadic and familial myofibromas have activating variants in PDGFRB. The relationship of myofibroma and
PDGFRB to the NOTCH pathway has not yet been described. Methods. Ten myofibroma cases were sequenced with
a targeted panel of 447 genes, including copy number variation and selected fusions. Immunohistochemical analysis of
total NOTCH3 and activated NOTCH3 was assessed for all 10 myofibroma cases, and a series of histologic mimics (n
= 20). Results. Alterations identified by next-generation sequencing included PDGFRB sequence variants in 8/10 cases
(80%), a NOTCH3 variant in 1/10 cases (10%), and a NOTCH2 variant in 1/10 cases (10%). All 10 cases also showed a
pattern of low-amplitude (1.5- to 2-fold) copy number alterations including gains in PDGFRB and NOTCH3. Ten of 10
myofibromas (100%) showed cytoplasmic staining for total NOTCH3 and 9 of 10 cases (90%) showed nuclear staining
for activated NOTCH3. Within the control cohort of histologic mimics, 3 of 3 nodular fasciitis cases (100%) were
positive for activated and total NOTCH3, and the remaining 17 cases were negative for pan NOTCH3, while 3 of 3
desmoid-type fibromatosis cases (100%) showed patchy weak nuclear staining for activated NOTCH3. Discussion. Our
findings suggest a common pathway of PDGFRB/NOTCH3 activation in myofibromas, even in cases that lack PDGFRB
sequence variants. These results support the pericytic lineage of myofibroma. Identification of the characteristic genomic
alterations or immunohistochemical staining pattern may facilitate a difficult pathologic diagnosis, and support the use of
targeted treatments
A Physical Organic Approach to Tuning Reagents for Selective and Stable Methionine Bioconjugation
No full textWe report a data-driven, physical organic approach to the development of new methionine-selective bioconjugation reagents with tunable adduct stabilities. Statistical modeling of structural features described by intrinsic physical organic parameters was applied to the development of a predictive model and to gain insight into features driving stability of adducts formed from the chemoselective coupling of oxaziridine and methionine thioether partners through Redox Activated Chemical Tagging (ReACT). From these analyses, a correlation between sulfimide stabilities and sulfimide n (C=O) stretching frequencies was revealed. We exploited the rational gains in adduct stability exposed by this analysis to achieve the design and synthesis of a bis-oxaziridine reagent for peptide stapling. Indeed, we observed that a macrocyclic peptide formed by ReACT stapling at methionine exhibited improved uptake into live cells compared to an unstapled congener, highlighting the potential utility of this new \chemical tool for thioether modification. This work
provides a template for the broader use of data-driven approaches to bioconjugation chemistry and other chemical biology applications
Gene Therapy: Bioanalytical Support and Strategies
No full textGene and nucleic acid therapies have demonstrated patient benefit in specific areas of therapeutics to address unmet medical needs. An increasing number of gene- and nucleic acid-based products have been advanced in clinical development phases. Unlike other conventional drugs, a gene therapy medicinal product (GTMP) contains both vector and transgene. This webinar will present the current practices in bioanalytical methods as well as pharmacokinetic /pharmacodynamical and immunogenicity evaluation for a number of gene and nucleic acid programs. The challenges, considerations, and regulatory aspects in this specific filed will be presented and discussed
Derivation of Rapamycin: Adventures in Natural Product Chemistry
No full textThe macrolide rapamycin was first described as an antifungal agent in 1975. It attracted our interest in the early 90s based on its reported immunosuppressive activity in transplantation models and based on indications that its mechanism of action was different from those of the known immunosuppressive agents ciclosporin and FK506, although the biological target and the molecular details were yet to be discovered. In this review we describe our efforts to chemically modify this complex and chemically very sensitive natural product. Despite the limitations regarding the reaction conditions compatible with rapamycin we discovered ways of selectively modifying specific functional groups. This allowed us, among others, to improve the stability of the parent molecule towards ring-opening. Our efforts culminated in the discovery and development of the 40-O-alkylated derivative everolimus which became a useful drug in solid organ transplantation, in various cancer indications and as the active principle of the market leading drug-eluting stent
Sarcopenia: A muscle disease with decreased functional capacity and an increased risk of adverse health outcomes
No full textThis paper is a review article aimed at physicians to summarize the standard of care for patients with sarcopenia. It uses the first international treatment guidelines as an outline to highlight practical applications that can be used by clinicians
Structure of lipoprotein lipase in complex with GPIHBP1.
No full textLipoprotein lipase (LPL) plays a central role in triglyceride (TG) metabolism. By catalyzing the hydrolysis of TGs present in TG-rich lipoproteins (TRLs), LPL facilitates TG utilization and regulates circulating TG and TRL concentrations. Until very recently, structural information for LPL was limited to homology models, presumably due to the propensity of LPL to unfold and aggregate. By coexpressing LPL with a soluble variant of its accessory protein glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) and with its chaperone protein lipase maturation factor 1 (LMF1), we obtained a stable and homogenous LPL/GPIHBP1 complex that was suitable for structure determination. We report here X-ray crystal structures of human LPL in complex with human GPIHBP1 at 2.5-3.0 Å resolution, including a structure with a novel inhibitor bound to LPL. Binding of the inhibitor resulted in ordering of the LPL lid and lipid-binding regions and thus enabled determination of the first crystal structure of LPL that includes these important regions of the protein. It was assumed for many years that LPL was only active as a homodimer. The structures and additional biochemical data reported here are consistent with a new report that LPL, in complex with GPIHBP1, can be active as a monomeric 1:1 complex. The crystal structures illuminate the structural basis for LPL-mediated TRL lipolysis as well as LPL stabilization and transport by GPIHBP1
Team Coaching at Scale: Creating conditions for the emergence of adaptive leadership cultures
No full textThis chapter provides the considerations essential to the success of large-scale leadership team coaching processes that are designed to support the emergence of adaptive leadership cultures in complex, global organizations. It offers guidance to experienced coaches who wish to design leadership team coaching "at scale" which dynamically interweaves capacity building and transformation at multiple scales within a system—individual, team, culture—while continually evolving to remain at the leading edge of those transformations. The chapter begins by briefly outlining the complex conditions in which today's leadership teams operate. It then explores key considerations for coaching leadership teams at scale, emphasizing design features needed to support the emergence of a more adaptive leadership culture capable of enacting the kinds of learning and leadership practices critical for today's global organizations and systems
Environmental metrics to drive a cultural change: our green eco-label
No full textA novel Green Chemistry Process Scorecard was developed to assess the environmental impact of chemical production processes to manufacture the Active Pharmaceutical Ingredients (API) within our portfolio. These new metrics not only cover the resource consumption from the overall chemical synthesis, but also also consider the use of Substances of Concern and the number of chemical steps. The Process Mass Intensity (PMI), i.e. the ratio of accumulated kilogram quantities of materials per kilogram of API, is used to quantify the resource consumption.
An “eco-label” for specific APIsis used to visualize the environmental impact from their chemical synthesis. For an overview of the environmental impact of a complete product portfolio, a diagram of PMI or total waste quantity vs. the number of synthetic steps can also be used as avisualization tool to identify chemical syntheses with a high need for process improvements. Implementation of this process led to a dramatic change of mindset within the organization and now supports and drives the decision making at Chemical and Analytical Development, and helps trigger new projects more readily for sustainability reasons
SAR evaluation of wasp toxin -PMTX leads to analogs with superior efficacy for human neuronal sodium channels
No full textABSTRACT: Beta-pompilidotoxin (-PMTX) is a 13-amino acid wasp venom peptide that activates human neuronal sodium channel NaV1.1 with weak efficacy (2% activation at 370 nM of -PMTX). Through rational design of -PMTX analogs, we have identified peptides with significant improvement of efficacy on human NaV1.1 (145% activation at 370 nM of peptide 18). The underlying structural activity relationship suggests importance of charge interactions (from residue Lys-3) and lipophilic interac-tions (from residue Phe-7 and Ser-11). Three top-ranked analogs showed parallel efficacy improvement for other neuronal sodium channels (human NaV1.2/1.3/1.6/1.7) but not muscular subtypes (NaV1.4/1.5). Finally, we found that analog 16 could partially rescue the pharmacological block imposed by NaV1.1/1.3 selective inhibitor ICA-121431 in cultured mouse cortical GABAergic neurons, demonstrating an activating effect of this peptide on native neuronal sodium channels and its potential utility as a neuro-pharmacological tools
Mechanisms of resistance to CAR T cell therapies
No full textChimeric antigen receptor (CAR)-engineered T cells have demonstrated remarkable success in the treatment of B cell malignancies. FDA approval of these therapies represents a watershed moment in the development of therapies for cancer. Despite the successes of the last decade, many patients will unfortunately not experience durable responses to CAR therapy. Emerging research has shed light on the biology responsible for these failures, and further highlighted the hurdles to broader success. Here, we review the recent research identifying how interactions between cancer cells and engineered immune cells result in resistance to CAR therapies