Safety, immunogenicity and efficacy of the self-amplifying mRNA ARCT-154 COVID-19 vaccine: pooled phase 1, 2, 3a and 3b randomized, controlled trials.

Combination of waning immunity and lower effectiveness against new SARS-CoV-2 variants of approved COVID-19 vaccines necessitates new vaccines. We evaluated two doses, 28 days apart, of ARCT-154, a self-amplifying mRNA COVID-19 vaccine, compared with saline placebo in an integrated phase 1/2/3a/3b controlled, observer-blind trial in Vietnamese adults (ClinicalTrial.gov identifier: NCT05012943). Primary safety and reactogenicity outcomes were unsolicited adverse events (AE) 28 days after each dose, solicited local and systemic AE 7 days after each dose, and serious AEs throughout the study. Primary immunogenicity outcome was the immune response as neutralizing antibodies 28 days after the second dose. Efficacy against COVID-19 was assessed as primary and secondary outcomes in phase 3b. ARCT-154 was well tolerated with generally mild-moderate transient AEs. Four weeks after the second dose 94.1% (95% CI: 92.1-95.8) of vaccinees seroconverted for neutralizing antibodies, with a geometric mean-fold rise from baseline of 14.5 (95% CI: 13.6-15.5). Of 640 cases of confirmed COVID-19 eligible for efficacy analysis most were due to the Delta (B.1.617.2) variant. Efficacy of ARCT-154 was 56.6% (95% CI: 48.7- 63.3) against any COVID-19, and 95.3% (80.5-98.9) against severe COVID-19. ARCT-154 vaccination is well tolerated, immunogenic and efficacious, particularly against severe COVID-19 disease.

The CRL3gigaxonin ubiquitin ligase-USP15 pathway governs the destruction of neurofilament proteins.

Giant axonal neuropathy (GAN) is caused by mutations in the GAN gene encoding for gigaxonin (GIG), which functions as an adaptor of the CUL3-RBX1-GIG (CRL3GIG) E3 ubiquitin ligase complex. The pathological hallmark of GAN is characterized by the accumulation of densely packed neurofilaments (NFs) in the axons. However, there are fundamental knowledge gaps in our understanding of the molecular mechanisms by which the ubiquitin-proteasome system controls the homeostasis of NF proteins. Recently, the deubiquitylating enzyme USP15 was reported to play a crucial role in regulating ubiquitylation and proteasomal degradation of CRL4CRBN substrate proteins. Here, we report that the CRL3GIG-USP15 pathway governs the destruction of NF proteins NEFL and INA. We identified a specific degron called NEFLL12 degron for CRL3GIG. Notably, mutations in the C-terminal Kelch domain of GIG, represented by L309R, R545C, and C570Y, disrupted the binding of GIG to NEFL and INA, leading to the accumulation of these NF proteins. This accounts for the loss-of-function mutations in GAN patients. In addition to regulating NFs, CRL3GIG also controls actin filaments by directly targeting actin-filament-binding regulatory proteins TPM1, TPM2, TAGLN, and CNN2 for proteasomal degradation. Thus, our findings broadly impact the field by providing fundamental mechanistic insights into regulating extremely long-lived NF proteins NEFL and INA by the CRL3GIG-USP15 pathway and offering previously unexplored therapeutic opportunities to treat GAN patients and other neurodegenerative diseases by explicitly targeting downstream substrates of CRL3GIG.

USP15 antagonizes CRL4CRBN-mediated ubiquitylation of glutamine synthetase and neosubstrates.

Targeted protein degradation by the ubiquitin-proteasome system represents a new strategy to destroy pathogenic proteins in human diseases, including cancer and neurodegenerative diseases. The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide have revolutionized the treatment of patients with multiple myeloma (MM) and other hematologic malignancies, but almost all patients eventually develop resistance to IMiDs. CRBN, a substrate receptor of CUL4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase, is a direct target for thalidomide teratogenicity and antitumor activity of IMiDs (now known as Cereblon E3 ligase modulators: CELMoDs). Despite recent advances in developing potent CELMoDs and CRBN-based proteolysis-targeting chimeras (PROTACs), many questions apart from clinical efficacy remain unanswered. CRBN is required for the action of IMiDs, but its protein expression levels do not correlate with intrinsic resistance to IMiDs in MM cells, suggesting other factors involved in regulating resistance to IMiDs. Our recent work revealed that the CRL4CRBN-p97 pathway is required for degradation of natural substrate glutamine synthetase (GS) and neosubstrates. Here, I show that USP15 is a key regulator of the CRL4CRBN-p97 pathway to control stability of GS and neosubstrates IKZF1, IKZF3, CK1-α, RNF166, GSPT1, and BRD4, all of which are crucial drug targets in different types of cancer. USP15 antagonizes ubiquitylation of CRL4CRBN target proteins, thereby preventing their degradation. Notably, USP15 is highly expressed in IMiD-resistant cells, and depletion of USP15 sensitizes these cells to lenalidomide. Inhibition of USP15 represents a valuable therapeutic opportunity to potentiate CELMoD and CRBN-based PROTAC therapies for the treatment of cancer.

p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates.

Glutamine synthetase (GS) plays an essential role in metabolism by catalyzing the synthesis of glutamine from glutamate and ammonia. Our recent study showed that CRBN, a direct protein target for the teratogenic and antitumor activities of immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide, recognizes an acetyl degron of GS, resulting in ubiquitylation and degradation of GS in response to glutamine. Here, we report that valosin-containing protein (VCP)/p97 promotes the degradation of ubiquitylated GS, resulting in its accumulation in cells with compromised p97 function. Notably, p97 is also required for the degradation of all four known CRBN neo-substrates [Ikaros family zinc finger proteins 1 (IKZF1) and 3 (IKZF3), casein kinase 1α (CK1α), and the translation termination factor GSPT1] whose ubiquitylation is induced by immunomodulatory drugs. Together, these data point to an unexpectedly intimate relationship between the E3 ubiquitin ligase CRL4CRBN and p97 pathways.

Gross alpha and beta activity and annual committed effective dose due to natural radionuclides in some water spinach (ipomoea aquatica Forssk) samples in Ho Chi Minh City, Vietnam.

The results of gross alpha and beta radioactivity measurement in water spinach samples from some districts in Ho Chi Minh City, Vietnam are presented in this paper. The measurements were performed using a low-background proportional counters LB4200 manufactured by Canberra Company, Inc. Mean concentrations of gross alpha and beta activity were found to be 1.50 ± 0.38 Bq kg-1 to 84.25 ± 8.67 Bq kg-1. In order to keep the recommended dose level, a recommended maximum intake of water spinach was proposed to be 6 kg fresh per year. The total annual committed effective dose due to natural radionuclides in water spinach samples was then found in range from 0.07 mSv y-1 to 0.82 mSv y-1. The dose from 26.32% of samples exceeds the exemption mean dose criterion of 0.3 mSv y-1 but complies with the upper dose principle of 1 mSv y-1 provided in UNSCEAR 2008 report. The estimated soil-to-plant transfer factors for gross alpha and beta for water spinach samples were also presented.