Ramı́rez-Alvarado, Marina

Light chain (LC) amyloidosis (AL) is a systemic amyloidosis associated with significant morbidity and mortality. Current treatment involves depletion of LC producing cells but patients with advanced disease are usually intolerant of chemotherapy and autologous stem cell transplantation, with no treatment available to directly address the tissue pathology of LC. Microvascular injury may be important in it spathobiology. Our overall objective is to discover strategies to ameliorate LC‐mediated injury at the level of endothelial cell death and dysfunction. We tested the hypothesis that nanoliposomes containing monosialoganglioside, phosphatidylcholine and cholesterol (NLGM1) are capable of protecting human endothelial cells from LC‐mediated injury by hormetic induction of the nuclear factor (erythroid‐derived 2)‐like (Nrf2) oxidative defense pathway. Human umbilical vein endothelial cells (HUVEC) were exposed to LC (purified from the urine of 2 AL patients with cardiac involvement, 20μg/ml) for 18–20 hours either with or without co‐treatment with NLGM1 (given at 1:10 mass ratio to LC). Using a fluorescent probe for peroxynitrite, we found that LC caused a 51.2% (p<0.01) increase in peroxynitrite production with a coincident 33% (p<0.01) decrease in cell viability as measured by Calcein‐AM fluorescence. However, in samples that were given NLGM1 and LC, peroxynitrite was diminished and cell viability was preserved to near control levels. Interestingly, in HUVEC that were treated with NLGM1 alone, we noticed a4‐fold increase in Nrf2 gene expression (p<0.05) and in antioxidant enzymes such as heme oxygenase 1 (HO‐1) and NAD(P)H quinone oxioreductase 1 (NQO1)(119‐fold, p<0.05; and 5‐fold, p<0.01 respectively). Similarly, we found significant upregulation of Nrf2, HO‐1 and NQO1 proteins in response to NLGM1 treatment. To determine if induction of HO‐1 and NQO1 by NLGM1 were dependent on Nrf2 activation, we knocked down Nrf2 using specific siRNAs. We were able to reduce Nrf2 gene expression in HUVEC by 41%. HUVEC treated with control siRNA demonstrated a 9.4‐fold increase in HO‐1 (p<0.05)and a 3.8‐fold increase in NQO1 (p<0.05) gene expression, whereas cell streated with Nrf2‐specific siRNAs had blunted NLGM1‐mediated increases to 3.0‐fold and 1.3‐fold for HO‐1 and NQO1 ( p<0.001 and p<0.05 vs. control siRNA ), respectively. Nrf2 knockdown abolished the protective effect of NLGM1 on HUVEC viability; Nrf‐2 siRNA treated cells exposed to LC and NLGM1 demonstrated 30% reduction in viability (p<0.05) similar to the 28% reduction in control siRNA‐treated cells exposed to LC; control siRNA‐treated cells exposed to LC and NLGM1 demonstrated no difference in viability versus those exposed to vehicle. Presently, we show that NLGM1 preserve endothelial cell viability and reduce peroxynitrite production in HUVEC exposed to LC proteins. We further demonstrate that NLGM1 has the potential to modulate Nrf2 antioxidant defense pathway and is likely a relevant protective mechanism against nitrative stress generated by LC exposure. When considered together, these findings hint at a novel potential therapeutic approach to mitigate the pathobiology of AL. Support or Funding Information Funding: Veterans Affairs Merit grant (I01BX007080), National Institutes Health (NIA R21AG044723, GM RO1 071514), Amyloidosis Foundation, American Heart Association 0855683G

Abstract Patients with immunoglobulin M (IgM) light chain (AL) amyloidosis have a distinct clinical presentation compared with those with non-IgM amyloidosis. We hypothesized that differential immunoglobulin light-chain variable region (IGVL) gene usage may explain the differences in organ involvement, because IGVL usage correlates with organ tropism. IGVL usage was evaluated by mass spectrometry of amyloid deposits (IgM, n = 45; non-IgM, n = 391) and differed across the 2 groups. In the λ family, LV2-08 (13% vs 2%; P &lt; .001) and LV2-14 (36% vs 10%; P &lt; .001) usage was more common in IgM vs non-IgM amyloidosis, whereas LV1-44 (0% vs 10%; P = .02) and LV6-57 (2% vs 18%; P = .004) usage was less common. In the κ family, there was a trend toward higher KV4-01 (11% vs 4%; P = .06) usage in IgM amyloidosis. IGVL usage correlated with disease characteristics/organ tropism. LV2-14 (more common in IgM amyloidosis) has historically been associated with peripheral nerve involvement and lower light chain burden, which were more frequent in IgM amyloidosis. LV1-44 (less common in IgM), associated with cardiac involvement, was less frequent in IgM patients. LV6-57 (less common in IgM) is associated with t(11;14), which was less frequent in IgM patients. In conclusion, IGVL gene usage differs in patients with IgM vs non-IgM amyloidosis and may explain the distinct clinical presentation.

Scientific societies aiming to foster inclusion of scientists from underrepresented (UR) backgrounds among their membership often delegate primary responsibility for this goal to a diversity-focused committee. The National Science Foundation has funded the creation of the Alliance to Catalyze Change for Equity in STEM Success (ACCESS), a meta-organization bringing together representatives from several such STEM society committees to serve as a hub for a growing community of practice. Our goal is to coordinate efforts to advance inclusive practices by sharing experiences and making synergistic discoveries about what works. ACCESS has analyzed the approaches by which member societies have sought to ensure inclusivity through selection of annual meeting speakers. Here we discuss how inclusive speaker selection fosters better scientific environments for all and identify challenges and promising practices for societies striving to maximize inclusivity of speakers in their scientific programming.

This essay compares the approaches that scientific societies in the ACCESS meta-organization use to implement and assess travel award programs for URM trainees and presents a set of recommendations, including both short- and long-term outcomes assessment in populations of interest and specialized programmatic activities coupled to travel award programs.