Time-dependent effects of BRAF-V600E on cell cycling, metabolism, and function in engineered myocardium.

Candidate cardiomyocyte (CM) mitogens such as those affecting the extracellular signal-regulated kinase (ERK) signaling pathway represent potential targets for functional heart regeneration. We explored whether activating ERK via a constitutively active mutant of B-raf proto-oncogene (BRAF), BRAF-V600E (caBRAF), can induce proproliferative effects in neonatal rat engineered cardiac tissues (ECTs). Sustained CM-specific caBRAF expression induced chronic ERK activation, substantial tissue growth, deficit in sarcomeres and contractile function, and tissue stiffening, all of which persisted for at least 4 weeks of culture. caBRAF-expressing CMs in ECTs exhibited broad transcriptomic changes, shift to glycolytic metabolism, loss of connexin-43, and a promigratory phenotype. Transient, doxycycline-controlled caBRAF expression revealed that the induction of CM cycling is rapid and precedes functional decline, and the effects are reversible only with short-lived ERK activation. Together, direct activation of the BRAF kinase is sufficient to modulate CM cycling and functional phenotype, offering mechanistic insights into roles of ERK signaling in the context of cardiac development and regeneration.

Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways to prevent tumor recurrence.

Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here, we describe the application of virus-like vesicles (VLV) for delivery of three immunomodulators alone and in combination, as a promising approach for cancer immunotherapy. VLV vectors were designed to deliver single chain interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA) as a single payload or as a combination payload. Intralesional delivery of the VLV vector expressing IL-12 alone, as well as the trivalent vector (designated CARG-2020) eradicated large established tumors. However, only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice, indicating a benefit of the combined immunomodulation. The abscopal effects of CARG-2020 on the non-injected contralateral tumors, as well as protection from the tumor cell re-challenge, suggest immune-mediated mechanism of protection and establishment of immunological memory. Mechanistically, CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.

Corrigendum: Efficacy of ixekizumab in patients with moderate-to-severe plaque psoriasis and prediabetes or type 2 diabetes.

[This corrects the article DOI: 10.3389/fmed.2022.1092688.].

Efficacy of ixekizumab in patients with moderate-to-severe plaque psoriasis and prediabetes or type 2 diabetes.

Objective: Patients with psoriasis have an increased prevalence of type 2 diabetes when compared to the general population. Research suggests that type 2 diabetes (T2D) as well as obesity may have an impact on patients' response to treatment. This post-hoc analysis reports the efficacy of ixekizumab in treating moderate-to-severe psoriasis in patients with prediabetes or T2D. Method and materials: UNCOVER-1, UNCOVER-2, and UNCOVER-3 were three Phase 3, multicenter, randomized, double-blind, placebo-controlled trials that evaluated the efficacy and safety of ixekizumab in adult patients with moderate-to-severe psoriasis. Patients were aged ≥18 years with chronic moderate-to-severe psoriasis (defined as ≥10% body surface area affected, static Physician Global Assessment ≥3, and Psoriasis Area and Severity Index [PASI] ≥12 at screening and baseline) who were candidates for phototherapy or systemic therapy. UNCOVER-1, UNCOVER-2, and UNCOVER-3 participants received ixekizumab as per label (that is, an initial dose of two subcutaneous injections [160 mg in total] at Week 0, followed by 80 mg every 2 weeks through Week 12 and 80 mg every 4 weeks thereafter through Week 60). Results: The proportions of patients with prediabetes, T2D and normoglycemia that achieved PASI75, PASI90, and PASI100 at Week 60 were similar. Results suggest that patients with T2D were slower to achieve PASI100 than patients with prediabetes or those with normoglycemia. Ixekizumab had no effect on any metabolic markers in patients receiving the treatment. Conclusions: Despite the higher rate of obesity and extreme obesity in patients with prediabetes and T2D, ixekizumab was an efficacious treatment in treating patients with psoriasis.