Assays for Light Chain Amyloidosis Formation and Cytotoxicity

Blancas‐Mejia, Luis M.; Misra, Pinaki; Dick, Chris; Argany, Meysam; Redhage, Keely R.; Cooper, Shawna A.; Ramı́rez-Alvarado, Marina

doi:10.1007/978-1-4939-8820-4_8

Cited by 8 publications

(3 citation statements)

References 47 publications

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“…Of note, unlike prior staging systems, the new system incorporates plasma cell-related characteristics in addition to prognostic laboratory markers related to cardiac, renal, and hepatic function. AL amyloidosis is a plasma cell dyscrasia (11) in which pathogenic plasma cells secrete an excess amount of amyloidogenic light chains that are conformationally changed and subsequently cause amyloid fibrils (12,13).…”

Section: Discussionmentioning

confidence: 99%

A prognostic staging system for light-chain amyloidosis using hepatic and renal indicator data from 1,064 Chinese patients

et al. 2021

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Background: Light-chain (AL) amyloidosis frequently involves severe multiple end-organ damage, thus affecting prognosis. As the current disease staging system is based only on cardiac indicators, we propose a new staging system based on multiple organ indicators to supplement the existing system. Methods: Patients with AL amyloidosis (n=1,064) from 18 Chinese hospitals were enrolled and divided into test and validation cohorts (4:1). Multivariate analyses were performed to identify the clinical and laboratory factors for inclusion in the new staging system.Results: A score of 1 was assigned for each of the following-the difference between the involved and uninvolved free light chains ≥100 mg/L, estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 , total bilirubin (Tbil) ≥18 µmol/L, cardiac troponin I ≥0.06 µg/L, and N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥3,600 pg/mL-to divide the patients into five disease stages (0 to IV). There were 220 (20.7%), 291 (27.3%), 251 (23.6%), 178 (16.7%), and 124 (11.7%) patients with stage 0, I, II, III, and IV disease, respectively. Patients with stage II, III, and IV disease had a median overall survival (OS) of 56.9 months [95% confidence interval (CI), 33.9-not reached (NR)], 18.6 months (95% CI, 33.9-NR), and 6.5 months (95% CI, 8.0-24.6) (P<0.001), respectively. The 3-year survival estimates for patients with stages 0, I, II, III, and IV were 90.7%, 71.4%, 59.4%, 39.0%, and 22.1%, respectively.Conclusions: The new staging system has been developed that incorporates plasma cell-related characteristics in addition to cardiac, renal, and hepatic function parameters. It enhances the risk stratification of patients with AL amyloidosis and is useful when multiple organs are involved.

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Section: Discussionmentioning

confidence: 99%

A prognostic staging system for light-chain amyloidosis using hepatic and renal indicator data from 1,064 Chinese patients

et al. 2021

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“…Synthesis of 5-Chloromethyl-8-hydroxyquinoline hydrochloride 3. 5-Chloromethyl-8-hydroxyquinoline hydrochloride (3) was synthesized through the reaction of conc HCl, 8-hydroxyquinoline (1) and formaline (2) (Scheme 1) according to the reported method, m. p. 282˚C [30].…”

Section: Plos Onementioning

confidence: 99%

Design and synthesis of multi-functional small-molecule based inhibitors of amyloid-β aggregation: Molecular modeling and in vitro evaluation

2023

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Amyloid-β1–42 (Aβ42) peptide aggregate formation in the brain plays a crucial role in the onset and progression of Alzheimer’s disease. According to published research, the Aβ monomer’s amino acid residues KLVFF (16–20) self-associate to create antiparallel β-sheet fibrils. Small compounds can prevent self-assembly and destroy Aβ fibrils by attaching to the Aβ16–20 regions of Aβ42. To enhance biological characteristics and binding affinity to the amyloid beta peptide, β-sheet breaker small molecules can be developed and modified with various scaffolds. In the current study, a novel series of 2,3-disubstitutedbenzofuran derivatives was designed and created by fusing the benzofuran core of a known iron chelator, neuroprotective, and neurorestorative agent, like VK-28, with a motif found in the structure of a known muscarinic inhibitor and amyloid binding agent, like SKF-64346. Measurements of the binding affinity and in vitro aggregation inhibition of the Aβ42 peptide were made using the thioflavin T (ThT) test. Using AutoDock 4.2 software, molecular docking studies of the synthesized compounds were performed on the monomer and fibril structures of amyloid beta peptide. The compounds 8a–8g exhibited strong binding energy and affinity to Aβ fibrils as well as a 50%–67% reduction of the growth of Aβ aggregation. Finally, the positive traits of our recently synthesized compounds make them excellent candidates for additional in vivo testing as a "β-sheet breaking agent."

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“…126,127 When the native state local minima is elevated, or the kinetic barriers are lowered, through mutations, PTMs, or environmental conditions, then the protein is far more likely to adopt misfolded conformations and enter the aggregation pathway. 12,13,[128][129][130][131] This is where another dogma in protein science is foundedthermodynamic instability is linked to pathogenic aggregation. Few proteins have shown to be an exception.…”

Section: Assembly Vs Aggregation: More Than Semanticsmentioning

confidence: 99%

Illuminating assembly dynamics regulating short-range order optics in extremely long-lived proteins

Bergman

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To those that feel they need to follow a path -you don'tLast, but most importantly, I want to thank my partner, Jenna Marie Kremer, for all her love and support over the years. She believed in myself more than I ever could and without her, none of this would have been possible. From the very first moment we met, she encouraged and supported me. After my acceptance into the PhD program at Northeastern University, she made the decision to move across the country with me -and proved how sometimes the best plans are the ones we do not make ourselves. There have been many challenges since, both expected and very unexpected, but we have faced them together. Those who have obtained a PhD undoubtedly know that it not only contains trials of intelligence, but also those of spirit. The resilience needed to finish a dissertation, both the research and the writing, is more than I would have ever predicted.Jenna has been my pillar the entire time; I survived the trials of spirit, the difficulties of research, with her to listen, comfort, challenge, and encourage, every step of the way. She makes me want to strive for the best I can, in every aspect of life, and I have accomplished more than I expected during my time as a graduate student, and it is with much thanks to her.

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Assays for Light Chain Amyloidosis Formation and Cytotoxicity

Cited by 8 publications

References 47 publications

A prognostic staging system for light-chain amyloidosis using hepatic and renal indicator data from 1,064 Chinese patients

A prognostic staging system for light-chain amyloidosis using hepatic and renal indicator data from 1,064 Chinese patients

Design and synthesis of multi-functional small-molecule based inhibitors of amyloid-β aggregation: Molecular modeling and in vitro evaluation

Illuminating assembly dynamics regulating short-range order optics in extremely long-lived proteins

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