Corgenix (United States)

ABSTRACTThe rapid development of mRNA vaccines since the COVID-19 pandemic has highlighted the potential of mRNA technology for vaccine and therapeutic applications. However, evaluating mRNA quality, including its integrity, 5′ capping efficiency, and 3′ poly(A) tailing, remains complex and challenging. Current analytical methods provide detailed insights, but are often limited by long analysis times, complex sample preparation, and the need for specialized expertise. The 5’ CapQassay addresses these challenges and provides a novel, rapid, and straightforward method that offers a single, unique measurement of intact mRNA with both a 5′cap and 3′poly(A) tail. This 2-hour benchtop-based assay provides quantitative or relative analysis, with high accuracy and precision without extensive sample processing. The 5’ CapQassay offers a significant advancement in mRNA analytics to alleviate bottlenecks in applications includingin vitrotranscription (IVT) reaction optimization, post-transcriptional capping optimization, and assessment of batch-to-batch IVT bioprocess consistency.

Nontuberculous mycobacteria (NTM) are environmentally acquired opportunistic pathogens that can cause chronic lung disease. Within the U.S., Hawai'i shows the highest prevalence rates of NTM lung infections. Here, we investigated a potential role for active volcanism at the Kīlauea Volcano located on Hawai'i Island in promoting NTM growth and diversity. We recovered NTM that are known to cause lung disease from plumbing biofilms and soils collected from the Kīlauea environment. We also discovered viable Mycobacterium avium, Mycobacterium abscessus, and Mycobacterium intracellulare subsp. chimaera on volcanic ash collected during the 2018 Kīlauea eruption. Analysis of soil samples showed that NTM prevalence is positively associated with bulk content of phosphorus, sulfur, and total organic carbon. In growth assays, we showed that phosphorus utilization is essential for proliferation of Kīlauea‐derived NTM, and demonstrate that NTM cultured with volcanic ash adhere to ash surfaces and remain viable. Ambient dust collected on O'ahu concurrent with the 2018 eruption contained abundant fresh volcanic glass, suggestive of inter‐island ash transport. Phylogenomic analyses using whole genome sequencing revealed that Kīlauea‐derived NTM are genetically similar to respiratory isolates identified on other Hawaiian Islands. Consequently, we posit that volcanic eruptions could redistribute environmental microorganisms over large scales. While additional studies are needed to confirm a direct role of ash in NTM dispersal, our results suggest that volcanic particulates harbor and can redistribute NTM and should therefore be studied as a fomite for these burgeoning, environmentally acquired respiratory infections.

Abstract Background: RGX-104 is a small-molecule LXR agonist that modulates innate immunity via transcriptional activation of the ApoE gene. Binding of ApoE to its receptor LRP8 robustly inhibits angiogenesis and depletes myeloid derived suppressor cells (MDSC), thereby activating cytotoxic T-lymphocytes. MDSCs are associated with resistance to both checkpoint inhibitors (CPI) and chemotherapy, providing a rationale for combination therapy with RGX-104. We previously reported results of the RGX-104 monotherapy dose escalation for which 26 patients with refractory solid tumors were treated in 5 dose cohorts. On-target AEs included hyperlipidemia and neutropenia. Flow-cytometry demonstrated MDSC depletion with associated T cell activation, which correlated with clinical benefit. A 40% disease control rate (DCR; SD+PR) was observed with a confirmed partial response (PR) by irRC (>79% reduction in index lesions) in a patient with platinum-refractory small cell lung cancer (SCLC). Methods: Here, we present the safety, biomarker and efficacy results of the docetaxel combination arm of the RGX-104 trial. Cohort 1- RGX-104 80 mg BID, and docetaxel at 35 mg/m2 days 1, 8, and 15 of a 28-day cycle; Cohort 2- RGX-104 80 mg BID, 5 days-on/2 days-off (5/2), and docetaxel at 28 mg/m2 on above schedule. Cohort 3- RGX-104 100 mg BID (5/2), and docetaxel as per cohort 2. Results: As of February 7, 2020, 11 patients with refractory solid tumors have been treated in 3 dose escalation cohorts with RGX-104 plus docetaxel. AEs were consistent with the individual toxicity profiles of docetaxel and RGX-104, with neutropenia being the most common AE and dose-limiting in cohort 1. The 5/2 dosing regimen in cohorts 2 and 3 resulted in significantly fewer episodes of neutropenia and no DLTs, while maintaining pharmacodynamic effects including >50% sustained MDSC depletion. A 66% DCR was observed in 9 evaluable patients including 2 patients in cohort 2 with PRs, a CPI-refractory SCCHN patient and a CPI-refractory melanoma patient, who remains on treatment at 36 weeks. A patient with melanoma in Cohort 3 had an initial assessment of SD and continues on study at 14 weeks. Clinical responses were associated with increases in T cell activation markers exceeding that generally observed with RGX-104 alone (up to a 5-fold increase in total CD8 T cells, a 7-fold increase in LAG-3+ CD8 T cells, and a 75-fold induction of serum IFNγ). Conclusion: The safety profile and marked pharmacodynamic and clinical activity of the RGX-104/docetaxel combination in CPI-refractory patients supports further development of this regimen. Consequently, the RGX-104/docetaxel regimen will be evaluated in a Phase 1b/2 expansion cohort in patients with relapsed/refractory ES-SCLC/high grade-neuroendocrine tumors. Citation Format: Emerson Lim, Erika P. Hamilton, Rebecca Redman, Michael A. Postow, Russell J. Schilder, Monica M. Mita, Alain C. Mita, Bartosz Chmielowski, James Strauss, Angela Jain, Shubham Pant, Olivier Rixe, Tomislav Dragovich, R. Donald Harvey, Igor Puzanov, Kevin B. Kim, Eric K. Rowinsky, Michael Szarek, Foster Gonsalves, Isabel Kurth, Celia Andreu, Robert W. Busby, David Darst, Masoud Tavazoie, Syed Raza, Narayan Lebaka16, Robert Wasserman, Gerald Falchook. RGX-104, a first-in-class immunotherapy targeting the liver-X receptor (LXR): Initial results from the phase 1b RGX-104 plus docetaxel combination dose escalation cohorts [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT146.

ABSTRACT Lassa fever (LF) is a potentially fatal disease that affects an estimated 300,000–500,000 people in endemic areas of west Africa each year. Though past studies have identified fatality rates of 5–20% in patients suspected to have contracted Lassa virus (LASV), new studies using more precise clinical diagnoses and modern diagnostic assays show fatalities rates above 60% in acutely ill patients from endemic regions. Currently, there are no approved vaccines or therapeutics, and only one Comformité Européenne (CE) marked rapid immunodiagnostic for acute LASV infection. Therefore, preventing LASV transmission is the primary goal in endemic regions. Development of rapid immunodiagnostics and research into the efficacy of current treatment options continues toward saving lives in west Africa as well as creating a line of defense against the nefarious use of LASV in bioterrorism settings.

OxLDL/β2GPI complexes have been implicated in the initiation and progression of atherosclerosis and associated with disease severity and adverse outcomes. We investigate the significance of anti-oxLDL/β2GPI antibodies and oxLDL/β2GPI complexes in patients with arterial and idiopathic venous disease. A cohort of 61 arterial disease patients, 32 idiopathic venous disease patients, and 53 healthy controls was studied. Because statins influence oxLDL/β2GPI, these complexes were analyzed on subjects not taking statins. Arterial and venous groups expressed higher levels of IgG anti-oxLDL/β2GPI antibodies than controls without any other significant clinical association. OxLDL/β2GPI complexes were significantly elevated in arterial (0.69 U/mL, P = 0.004) and venous disease (0.54 U/mL, P = 0.025) than controls (0.39 U/mL). Among arterial diseases, oxLDL/β2GPI was 0.85 U/mL for carotid artery disease, 0.72 U/mL for peripheral artery disease, and 0.52 U/mL for abdominal aortic aneurysm. There was a significant association with male gender, age, hypertension, and history of thrombosis. Subjects with oxLDL/β2GPI above the median (0.25 U/mL) were more likely to have arterial (OR 4.5, P = 0.004) or venous disease (OR 4.1, P = 0.008). Multivariate regression indicated that males (P = 0.021), high cholesterol (P = 0.011), and carotid disease (P = 0.023) were significant predictors of oxLDL/β2GPI. The coexistence of oxLDL/β2GPI in arterial and venous disease may suggest a common oxidative mechanism that independently predicts carotid artery disease.

Abnormalities of the lipid profile partly explain the atherogenic tendency of systemic lupus erythematosus but the picture is unclear in thrombotic primary antiphospholipid syndrome (PAPS). Herein we compare the lipid profile, high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (CHO), apolipoprotein A (ApoA-I), apolipoprotein B (ApoB), triglycerides (TRY)), anti-lipoprotein antibodies, beta-2-glycoprotein I complexed to oxidized low-density lipoprotein (oxLDL-ss(2)GPI) and C-reactive protein (CRP) from thrombotic PAPS (n = 34), thrombotic patients with inherited thrombophilia (IT; n = 36), subjects persistently positive for antiphospholipid antibodies (aPL, n = 18) with no underlying autoimmune or non-autoimmune disorders and healthy controls (n = 28) and determined the reciprocal effects of anti-lipoprotein antibodies, the lipid profile, oxLDL-ss(2)GPI and CRP. Average concentrations of HDL (p < 0.0001), LDL (p < 0.0001), CHO (p = 0.0002), ApoA-I (p = 0.002) were lower in PAPS whereas average TRY was higher (p = 0.01) than other groups. Moreover, the aPL and PAPS group showed higher levels of IgG anti-HDL (p = 0.01) and IgG anti-ApoA-I (p < 0.0001) whereas the PAPS group showed greater average oxLDL-ss(2)GPI (p = 0.001) and CRP (p = 0.003). Within the PAPS group, IgG anti-HDL correlated negatively to HDL (p = 0.004) and was an independent predictor of oxLDL-ss2GPI (p = 0.009). HDL and ApoA-I correlated negatively with CRP (p = 0.001 and p = 0.007, respectively). IgG anti-HDL may hamper the antioxidant and anti-inflammatory effect of HDL favoring low-grade inflammation and enhanced oxidation in thrombotic PAPS.

Vascular inflammation is common in certain systemic autoimmune diseases and contributes to the oxidation of low-density lipoprotein (oxLDL) and oxLDL/beta2-glycoprotein I (beta2GPI) complex formation. These complexes have been implicated as proatherogenic autoantigens that participate in the development of atherosclerotic disease. We have demonstrated that the in vitro macrophage uptake of oxLDL/beta2GPI complexes increases in the presence of IgG anti-beta2GPI antibodies and that IgG immune complexes containing oxLDL/beta2GPI upregulate the expression of both scavenger and Fcgamma receptors to activate beta2GPI specific T cells. Some persistent infections may cause immune responses that promote atherogenesis. Cellular immunity (Th1) against Helicobacter pylori (H. pylori) derived heat shock protein 60 (Hp-HSP60) cross-reacts with endogenous HSP60 to cause cardiovascular disease likely by molecular mimicry. Infectious cellular response may be proatherogenic,while the humoral response (antibody production) maybe protective. We review the recent progress in our understanding of autoimmunity and infectious immunity that promote atherosclerosis.