Asana Biosciences (United States)

P2Y12 inhibitor selection involves numerous factors, including CYP2C19 genetics, since evidence demonstrates reduced clopidogrel efficacy in patients with decreased or no function CYP2C19 variants. In 2020, Indiana University health embedded interruptive clinical decision support (CDS) alerts in the electronic health record (EHR) to recommend alternative P2Y12 inhibitors for patients with decreased CYP2C19 function who had undergone percutaneous coronary intervention (PCI). The objective of this study was to evaluate prescriber response to these CDS alerts. Utilizing alert response data and P2Y12 inhibitor prescriptions from October 2020 to December 2023, we evaluated prescriber response for 362 patients who had a mean of 2.2 (SD: 1.7) CYP2C19-clopidogrel alerts fire post-PCI. Alert recommendations were accepted 24.5% ± 36.8% (mean ± SD) of the time. Alternative (i.e., non-clopidogrel) P2Y12 inhibitors were prescribed for 22.4% ± 36.8% of days during the year following PCI. Alerts were accepted more for CYP2C19 poor metabolizers than for intermediate metabolizers (P = 0.03). Each year after 2020 was associated with a 4.6% increase in the days prescribed alternative P2Y12 inhibitors. In contrast, increasing age was associated with decreased alert acceptance and decreased percentage of days prescribed alternatives, and concomitant oral anticoagulant use was associated with decreased percentage of days prescribed alternatives. Provider clinical judgment was the most common alert override reason, accounting for 68% of clinician responses. Our findings demonstrate that CYP2C19-clopidogrel CDS alerts promoted genotype-guided P2Y12 inhibitor prescribing in some cases (~22% of study days). Future research should better determine prescriber reasons for rejecting alert recommendations and establish best implementation practices to complement CDS alerts.

<p>Supplementary Data and Figures S1 to S6</p>

Abstract The COVID-19 pandemic sparked rapid development of SARS-CoV-2 diagnostics. However, emerging variants pose the risk for target dropout and false-negative results secondary to primer/probe binding site (PBS) mismatches. The Agena MassARRAY® SARS-CoV-2 Panel combines RT-PCR and MALDI-TOF mass-spectrometry to probe for five targets across N and ORF1ab genes, which provides a robust platform to accommodate PBS mismatches in divergent viruses. Herein, we utilize a deidentified dataset of 1,262 SARS-CoV-2-positive specimens from Mount Sinai Health System (New York City) from December 2020 through April 2021 to evaluate target results and corresponding sequencing data. Overall, the level of PBS mismatches was greater in specimens with target dropout. Of specimens with N3 target dropout, 57% harbored an A28095T substitution that is highly-specific for the alpha (B.1.1.7) variant of concern. These data highlight the benefit of redundancy in target design and the potential for target performance to illuminate the dynamics of circulating SARS-CoV-2 variants.

Abstract BACKGROUNDFipronil is a broad‐spectrum insecticide that is used extensively due to its effective action in pest control. However, environmental studies have shown it has high toxicity towards non‐target organisms as well. In addition, the degradation of fipronil can generate even more toxic and reactive metabolites in the environment. In the present study, bioprospecting for bacteria with the potential to degrade fipronil was performed using fipronil as the sole source of nitrogen and main source of carbon. From samples of corn culture soil with a history of fipronil application, isolation was performed using the microcosm enrichment method.RESULTSBacteria were isolated using fipronil (0.6 g L−1) as the sole nitrogen source and main carbon source. After preliminary tests, isolate E1 was selected and, following sequencing of 16S rRNA, it was found that the isolate E1 was a bacterium of the Bacillaceae family, Bacillus megaterium species. Growth was evaluated by dry biomass and degradation quantified by gas chromatography–mass spectrometry (GC–MS). Strain E1 presented a 94% degradation of fipronil, as well as 91% and 96% degradation of its metabolites fipronil‐sulfide and fipronil‐sulfone, respectively, in 14 days, reducing its initial concentration from 0.6 g L−1 to 0.036 mg L−1.CONCLUSIONThe results showed that bioprospecting of the E1 strain, isolated from soil, showed efficiency in the biodegradation process of fipronil. This strain is a potential candidate for use in bioremediation processes in areas contaminated with fipronil and for use in further studies on the elucidation of the metabolic pathways of fipronil degradation. © 2021 Society of Chemical Industry (SCI).

Abstract Background: The oncogenic mitogen-activated protein kinase (MAPK) pathway is dysregulated in a broad range of cancers through mutations in BRAF, KRAS, NRAS, HRAS and MEK1 genes. ASN007 is a novel, potent and orally bioavailable inhibitor of ERK1/2 kinases (IC50 1-2nM) with a very long target residence time (550 min). Preclinical studies show strong anti-tumor activity in multiple RAS mutant xenograft and PDX models, irrespective of mutation subtype. ASN007 also maintains strong activity in BRAF mutant melanoma PDX models resistant to BRAF and MEK inhibition. Preclinical activity is seen with both intermittent as well as daily dosing. This is the initial report of ASN007 clinical data from this first-in-human Phase 1 Study. Methods: This Phase 1 trial evaluates ASN007 in patients (PS 0-1) with metastatic solid tumors refractory to standard therapies using an accelerated dose titration design for once daily (QD) and once weekly (QW) oral dosing (NCT03415126). Primary objectives in Part A (dose finding) include safety, tolerability, PK and PD to determine the Maximum Tolerated Dose (MTD). Part B (disease specific expansion) will evaluate clinical activity in cohorts of 15 patients each with tumors harboring specific mutations which include NRAS, HRAS, MEK1 and BRAF. Results: To date, 42 eligible patients (pts) were enrolled at dose levels ranging from 10mg to 80mg QD and 80 mg to 350mg QW. The respective MTDs are 40mg QD and 250mg QW. Reversible treatment-related adverse events (TRAEs) at 40mg QD (n=10) included rash ( 90%, Gr3 10%), nausea/vomiting (Gr1 30%), diarrhea (Gr1 30%), fatigue (20%, Gr3 10%) and central serous retinopathy (CSR) (30%, no G3) and at 250mg QW (n=9) included rash (33%, no Gr3), CSR (11%, Gr3 11%), blurred vision (44%, Gr3 11%), nausea/vomiting (33%, Gr3 11%) and diarrhea (33%, no Gr3). Dose limiting toxicities (DLTs) included Gr3 CSR at 60 and 80 QD, Gr3 rash at 80mg QD and Gr3 AST at 350mg QW. Durable clinical benefit was noted for 3 pts treated with QW ASN007 at doses 120 mg to 250 mg: a confirmed partial response (-57%) in a patient with HRAS-mutant salivary gland cancer for 5+ months, stable disease in KRAS mutant ovarian cancer for 9+ months and stable disease in BRAF V600E mutant thyroid cancer for 8+ months. Pharmacokinetic studies demonstrated dose dependent increase in the Cmax and AUC24 with both QD and QW dosing. QW dosing Cmax levels exceed average IC50 values more than >30-fold. Inter-subject variability was moderate (≤ 50%) and the elimination t1/2 was 10-15 hours. Conclusions: ASN007 is a selective oral inhibitor of ERK1/2 with a long target residence time. QD or QW dosing is feasible with expected reversible and manageable AE profile and dose dependent exposure. The dose of 250mg QW was selected for further development due to favorable tolerability and encouraging signs of clinical activity. Part B of the study is open to enroll patients with solid tumors harboring BRAF, MEK1, and RAS mutations. Updated clinical, safety, PK/PD and efficacy data will be presented. Citation Format: Anthony W. Tolcher, Ryan J. Sullivan, Drew W. Rasco, Zeynep Eroglu, Nehal Lakhani, Dana Kessler, Helen Usansky, Sanjeeva Reddy, Louis J. Denis, Filip Janku. Phase 1 clinical safety and efficacy of ASN007, a novel oral ERK1/2 inhibitor, in patients with RAS, RAF or MEK mutant advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PR09. doi:10.1158/1535-7163.TARG-19-PR09

Abstract Spleen tyrosine kinase (SYK) and Janus kinase (JAK) play important roles in the pathogenesis of various types of lymphomas, solid tumors, and myeloproliferative and inflammation disorders. Inhibition of both SYK and JAK kinases has been shown to suppress tumor growth in various preclinical and/or clinical studies. ASN002 is a novel and potent dual inhibitor of SYK and JAK kinases with IC50 values of 4-46 nM in biochemical assays. In mechanistic cell-based studies, ASN002 strongly suppressed the SYK and JAK family kinase signaling pathways as measured in pLAT and pSTAT assays, respectively. When profiled in a panel of 178 cell lines, the compound showed strong anti-proliferative activity in many lymphoid/leukemia cell lines, including SU-DHL-6, SU-DHL-4, OCI-LY10, H929 and Pfeiffer. The proliferation of many solid tumor cell lines representing bladder, lung and colorectal cancer tumor types was also potently inhibited. Importantly, it also strongly inhibited the growth of ibrutinib and idelalisib resistant cell lines. ASN002 was highly efficacious in inhibiting the tumor growth in several tumor xenograft models which include Pfeiffer (diffuse large B-cell lymphoma, DLBCL), SU-DHL-6 (DLBCL), H929 (myeloma), HEL (erythroleukemia), and RT112 (bladder). ASN002 shows little to no inhibition of CYP450 isozymes suggesting low potential for drug-drug interactions. ASN002 is currently being evaluated in a Phase I/II clinical study in patients with lymphomas (DLBCL, mantle cell lymphoma and follicular lymphoma) and solid tumors. Citation Format: Sanjeeva P. Reddy, Niranjan Rao, David Zammit, Scott K. Thompson, Roger A. Smith, Louis Denis. ASN002: A novel dual SYK/JAK inhibitor with strong antitumor activity in both hematological and solid tumor xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4204. doi:10.1158/1538-7445.AM2017-4204

Results of genotyping with true high-throughput capability for MNSs antigens are underrepresented, probably because of technical issues, due to the high level of nucleotide sequence homology of the paralogous genes GYPA, GYPB and GYPE. Eight MNSs-specific single nucleotide polymorphisms (SNP) were detected using matrix-assisted laser desorption/ionization, time-of-flight mass spectrometry (MALDI-TOF MS) in 5800 serologically M/N and S/s pre-typed Swiss blood donors and 50 individuals of known or presumptive black African ethnicity. Comparison of serotype with genotype delivered concordance rates of 99·70% and 99·90% and accuracy of genotyping alone of 99·88% and 99·95%, for M/N and S/s, respectively. The area under the curve of peak signals was measured in intron 1 of the two highly homologous genes GYPB and GYPE and allowed for gene copy number variation estimates in all individuals investigated. Elevated GYPB:GYPE ratios accumulated in several carriers of two newly observed GYP*401 variants, termed type G and H, both encoding for the low incidence antigen St(a). In black Africans, reduced GYPB gene contents were proven in pre-typed S-s-U- phenotypes and could be reproduced in unknown specimens. Quantitative gene copy number estimates represented a highly attractive supplement to conventional genotyping, solely based on MNSs SNPs.