Acuity Technologies (United States)

Abstract Diffuse midline gliomas (DMG), are rare but aggressive CNS tumors primarily affecting children, and younger adults. H3K27M mutation is associated with worse prognosis and O6-Methylguaninemethyl transferase (MGMT) is usually unmethylated, predicting a poor response to temozolomide in these patients. As surgical intervention is not normally possible, standard of care treatment for DMG includes radiotherapy followed by chemotherapy. ONC201 is a selective dopamine receptor D2 (DRD2) antagonist showing preferential activity in H3K27M-mutant DMG, and has demonstrated significant survival benefit in patients with this mutation. However, DMG lacking the H3K27M mutation represents a heterogeneous group with variable biology and limited treatment options. These tumors frequently exhibit MGMT promoter unmethylation, contributing to resistance to treatment with alkylating agents such as temozolomide. For patients without a H3K27M mutation, radiation therapy remains the primary standard of care offering temporary symptom control but little survival benefit. The prognosis remains poor, with median survival under 12 months, underscoring the urgency for novel treatments for this DMG sub-group. VAL-083, a bi-functional DNA cross-linking agent active independent of MGMT status, is being evaluated in clinical trials for these molecular subtypes. Its mechanism of action bypasses MGMT-mediated DNA repair, providing effectiveness in MGMT-unmethylated tumors. VAL-083 crosses the blood brain barrier and has demonstrated activity against various DMG cell lines, and increased survival of animals in DIPG xenograft models compared to controls. VAL-083 has demonstrated increased survival of patients with GBM (MGMT unmethylated promoter) in newly diagnosed disease when co-administered with radiotherapy, or as adjuvant therapy, compared to historical standard of care. A phase 2 study will be conducted with VAL-083 in patients (12 years and older) with DMG without a H3K27M mutation. VAL-083 will be co-administered with radiotherapy, and up to 12 cycles of treatment every 21 days. Further details on the study design will be presented at the conference.

Curacao is one of the most trusted brands in the US Hispanic community. It has earned the trust of its customers and the broader, multigenerational, US Hispanic community with a clear purpose of helping to improve the standard of living of its core community. The brand consistently delivers on this purpose with a 360-degree proposition that provides access to credit, financial education and household products and services, as well as through social connections and culturally relevant programming at its network of physical stores, employment and charitable contributions via the Curacao Foundation. With over four decades of commitment to its community, the brand has gained sufficient credibility and is now able to leverage its customer relationships and data to increase its business value. It is now bolstering its portfolio of products and services through strategic partnerships and expanding its offering nationally through e-commerce and retail media to ensure steady growth and profitability in the years to come.

This study investigated using imputed genotypes from non-genotyped animals which were not in the pedigree for the purpose of genetic selection and improving genetic gain for economically relevant traits. Simulations were used to mimic a 3-breed crossbreeding system that resembled a modern swine breeding scheme. The simulation consisted of three purebred (PB) breeds A, B, and C each with 25 and 425 mating males and females, respectively. Males from A and females from B were crossed to produce AB females (n = 1,000), which were crossed with males from C to produce crossbreds (CB; n = 10,000). The genome consisted of three chromosomes with 300 quantitative trait loci and ~9,000 markers. Lowly heritable reproductive traits were simulated for A, B, and AB (h2 = 0.2, 0.2, and 0.15, respectively), whereas a moderately heritable carcass trait was simulated for C (h2 = 0.4). Genetic correlations between reproductive traits in A, B, and AB were moderate (rg = 0.65). The goal trait of the breeding program was AB performance. Selection was practiced for four generations where AB and CB animals were first produced in generations 1 and 2, respectively. Non-genotyped AB dams were imputed using FImpute beginning in generation 2. Genotypes of PB and CB were used for imputation. Imputation strategies differed by three factors: 1) AB progeny genotyped per generation (2, 3, 4, or 6), 2) known or unknown mates of AB dams, and 3) genotyping rate of females from breeds A and B (0% or 100%). PB selection candidates from A and B were selected using estimated breeding values for AB performance, whereas candidates from C were selected by phenotype. Response to selection using imputed genotypes of non-genotyped animals was then compared to the scenarios where true AB genotypes (trueGeno) or no AB genotypes/phenotypes (noGeno) were used in genetic evaluations. The simulation was replicated 20 times. The average increase in genotype concordance between unknown and known sire imputation strategies was 0.22. Genotype concordance increased as the number of genotyped CB increased with little additional gain beyond 9 progeny. When mates of AB were known and more than 4 progeny were genotyped per generation, the phenotypic response in AB did not differ (P > 0.05) from trueGeno yet was greater (P < 0.05) than noGeno. Imputed genotypes of non-genotyped animals can be used to increase performance when 4 or more progeny are genotyped and sire pedigrees of CB animals are known.

Abstract Background: Dysregulated signaling through GPCRs is implicated in oncogenic RAS signaling in breast cancer (BC). The complex regulatory mechanisms that link RAS nodes can trigger an adaptive response (e.g. resistance) when a single RAS node is inhibited. Inhibition of multiple RAS nodes may thus be required to achieve durable antitumor responses. To identify patients with dysregulated RAS signaling tumors that may respond to RAS node inhibitors, an assay using an impedance biosensor was developed. The CELsignia RAS Activity Test measures GPCR-initiated signaling activity and PI3K, mTOR, and BCL's role in transducing this activity in live tumor cells. The current study set out to characterize the prevalence of dysregulated RAS signaling initiated through a GPCR in HER2-negative BC patients and the role played by PI3K, mTOR and BCL. Methods: Fresh tumor specimens from 69 HER2- BC patients were used to derive tumor cell samples. Dynamic live cell response to a GPCR agonist (LPA), a PI3K-α inhibitor (GDC-0077), a pan-PI3K inhibitor (copanlisib), a pan-PI3K/mTOR inhibitor (gedatolisib), and a BCL inhibitor (navitoclax) was measured using an xCELLigence impedance biosensor (Agilent Technologies). From these responses, the gross amount of GPCR-initiated signaling and corresponding participation of PI3K-α, all Class 1 PI3K-isoforms, mTORC1, and BCL was quantified and converted to a signaling score. Correlative analyses using FACS markers (RPS6, AKT, ERK, caspase 3) were performed. Results: Hyperactive RAS signaling (RASs+) initiated by GPCR pathways was found in 16 of 69 (23.1%; 95% CI=15%-34%) tumors. The signaling scores were bimodally distributed; for the 16 RASs+ and the 53 RASs- patient tumors, the mean scores were 486 (SD 248) and 91 (SD 73), respectively. For the 16 RASs+ tumors, inhibition of all Class 1 PI3K-isoforms attenuated, on average, 71% of the GPCR signaling, while inhibition of PI3K-α alone had only a nominal inhibitory effect. When mTOR inhibition was combined with pan-PI3K inhibition, GPCR signaling was further attenuated by 14%. The most complete attenuation of RAS-signaling occurred when PI3K, mTOR, and BCL were simultaneously inhibited. Early apoptosis markers (RPS6, AKT, ERK, caspase 3) were found most significantly in RASs+ tumors with pan-PI3K/mTOR inhibition and to a greater degree with pan-PI3K/mTOR/BCL inhibition. No apoptosis markers were found in RASs- tumors regardless of which RAS node was inhibited. Conclusions: These findings suggest that a significant sub-group of BC patients have a RAS-involved oncogenic driver that is responsive ex vivo to pan-PI3K/mTOR and pan-PI3K/mTOR/BCL inhibitors. A clinical trial to evaluate treatment response of this patient sub-group to combined PI3K/mTOR or PI3K/mTOR/BCL inhibitors is warranted. Citation Format: Salmaan Khan, Adrish Sen, Catherine Kuzmicki, Ian MacNeil, Aaron Broege, Sarah Mutka, Kelly Brass, Ky McCracken, Laura Milligan, Katja Kotke, Brian Sullivan, Lance Laing. Sub-group of HER2-negative breast cancer patients with hyperactive RAS network signaling identified: Dynamic pathway activity test identifies patients that may benefit from PI3K/mTOR or PI3K/mTOR/BCL inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 342.

Abstract This study evaluated the effects of dietary SID lysine restriction in the growing period and number of dietary phases in the growing-finishing (GF) period on growth performance of GF pigs (32.7 ± 9.43 kg to 115.5 ± 8.18 kg BW). A RCBD (block = gender and start day) was used with a 3 × 2 factorial arrangement of treatments: 1) Dietary SID Lysine Level {Control [NRC (2012) recommendation]; Moderate Restriction [0.15% lower than Control]; Aggressive Restriction [0.30% lower than Control]} and 2) Number of Dietary Phases in GF (4 vs. 2). Lysine level treatments were applied from 32 to 64 kg BW. Diets were based on corn-soybean meal and corn coproducts, formulated to be isocaloric, and to meet or exceed recommendations of NRC (2012) for each phase, with the exception of SID lysine levels which were according to treatment. A total of 4,488 pigs were housed in single-sex groups of 34 pigs (22 replicates) with floor space of 0.63 m2/ pig. Pigs had ad libitum access to feed and water throughout and were weighed at start and end of the study; feeder additions were recorded. Pen was the experimental unit and data were analyzed using R version 3.6.2. The model accounted for the fixed effect of treatments, the interaction, and random effect of block. There were no treatment interactions (P &amp;gt; 0.05) and no effect (P &amp;gt; 0.05) of Number of Dietary Phases on overall growth performance. Decreasing dietary SID lysine linearly reduced (P &amp;lt; 0.05) overall ADG and ADFI with no effect (P &amp;gt; 0.05) on G:F. Restricting dietary SID lysine level to the extent used in this study reduced overall growth rate with no impact on feed efficiency.

We demonstrate diffraction-limited and super-resolution imaging through thick layers (tens-hundreds of microns) of BIO-133, a biocompatible, UV-curable, commercially available polymer with a refractive index (RI) matched to water. We show that cells can be directly grown on BIO-133 substrates without the need for surface passivation and use this capability to perform extended time-lapse volumetric imaging of cellular dynamics 1) at isotropic resolution using dual-view light-sheet microscopy, and 2) at super-resolution using instant structured illumination microscopy. BIO-133 also enables immobilization of 1) Drosophila tissue, allowing us to track membrane puncta in pioneer neurons, and 2) Caenorhabditis elegans, which allows us to image and inspect fine neural structure and to track pan-neuronal calcium activity over hundreds of volumes. Finally, BIO-133 is compatible with other microfluidic materials, enabling optical and chemical perturbation of immobilized samples, as we demonstrate by performing drug and optogenetic stimulation on cells and C. elegans.

As space travel expands to include civilian populations in addition to trained astronauts, physicians and space medicine experts will need to collaborate to assess and mitigate risks to participants with preexisting medical conditions that may be exacerbated by microgravity.

Abstract Background: To elucidate the role of c-Met signaling and its involvement with ErbB signaling as a cancer driver, a new assay using an impedance biosensor, the CELx multi-pathway signaling function (CELx MP) test, was developed. The CELx MP Test measures ex vivo real-time live cell response to specific ErbB and c-Met agonists to diagnose breast tumors with hyperactive HER1, HER2, HER3, HER4, and c-MET signaling activity. A recent study quantified c-MET and ErbB-driven signaling activity in epithelial cell samples derived from fresh breast tumor specimens obtained from 74 HER2- breast cancer patients. Of the cell samples tested, 20 of 74, (27.0%; 95% CI=18%-38%) had both hyperactive c-MET signaling and at least one hyperactive ErbB-family receptor signaling. Using primary breast cancer cells with hyperactive c-MET and ErbB signaling and the CELx MP test, the current study set out to: 1) determine the IC50 values of six pan-HER and five c-MET inhibitors; and 2) characterize the efficacy of combinations of each pan-HER inhibitor with each c-MET inhibitor. Methods: Epithelial cells from six HER2- tumor specimens with hyperactive c-MET and ErbB-driven signaling were obtained. Real-time live cell response to specific ErbB and c-Met agonists (NRG1b, EGF, or HGF) alone and in combination, with or without one of six pan-HER antagonists (neratinib, lapatinib, ibrutinib, dacomitinib, sapitinib, poziotinib) or one of five c-MET antagonists (tepotinib, cabozantinib, crizotinib, capmatinib, or savolitinib) was quantified using an xCELLigence RTCA impedance biosensor. Each individual drug IC50 was determined using a 1000-fold, 5-point, dose response curve with a single fixed concentration of a corresponding agonist. For the drug combination efficacy studies, fixed concentrations of the agonist mixture and clinically relevant concentrations of combinations of the antagonists were used to determine the percentage inhibition of the ErbB and c-MET signaling. Results: The IC50 values for the individual c-MET and pan-HER inhibitors ranged from 3.10nM - 28nM and 2.67nM – 137.27nM, respectively. In the drug efficacy studies, an average of at least 80% of the ErbB and c-MET signaling activated by NRG1, EGF, and HGF co-stimulation was inhibited by each combination of c-MET and pan-HER inhibitors. c-Met Inhibitor Resultsc-MET inhibitorIC50 (nM)Avg Inhibition (%) w/diff ErbBi's Capmatinib3.1094Savolitinib3.3298Tepotinib14.7096Cabozantinib27.3699Crizotinib28.21100 Pan-HER Inhibitor ResultsPan-HER inhibitorIC50 (nM)Avg Inhibition (%) w/diff c-METi's Poziotinib2.67100Neratinib4.81100Ibrutinib13.1099Dacomitinib22.06100Sapitinib41.2898Lapatinib137.2780 Conclusions: The CELx MP test using live cells measures IC50 values comparable to those derived using cell-free methods. Every combination of pan-HER and c-MET inhibitors provided comparably high (at least 80%) levels of inhibitory effect ex vivo. This suggests the sub-group of HER2- breast cancer patients diagnosed with coincident hyperactive c-MET and ErbB signaling by the CELx Test may respond to virtually any pan-HER and c-Met inhibitor combination. Studying combinations designed to minimize drug toxicities without sacrificing efficacy should thus be possible. Citation Format: Laing LG, Burns DJ, Khan S, MacNeil IA, Rich BE, Kharbush SM, Soltani SM, Sullivan BF. Evaluation of pan-HER and c-MET inhibitors tested ex vivo in primary HER2- breast cancer cells with hyperactive c-MET and ErbB family signaling [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-05-05.

Abstract Background: Hyperactive c-Met signaling, including cross-talk between c-Met and ErbB family receptors, is suspected of contributing to tumor progression in a variety of cancer types. Clinical trials evaluating c-Met inhibitors alone and in combination with other targeted therapies, have produced mostly negative results in patients with amplified c-Met. This suggests other biological factors, such as c-Met and ErbB signaling activity, may be important to measure when identifying patients eligible for c-Met therapies. To measure the c-Met and ErbB signaling activity of a patient's live tumor cells, a new assay using an impedance biosensor, the CELx multi-pathway signaling function (CELx MP) test, was developed. The CELx MP test measures a patient's ex vivo live tumor cell response in real-time to specific ErbB and c-Met agonists to diagnose breast cancer tumors with hyperactive HER1, HER2, HER3, HER4, and c-MET signaling activity. In this study, to further elucidate the role of c-Met signaling and its potential involvement with ErbB signaling as a cancer driver, we studied in vivo response to a c-Met inhibitor (tepotinib), an EGFR inhibitor (erlotinib), a pan-HER inhibitor (neratinib), and a combination of these therapies using breast tumor xenograft models. Methods: HCC1954, a HER2+ cell line with hyperactive c-Met and EGFR signaling and normal HER3 and HER2-driven signaling, according to the CELx MP test, was studied. Sixty 4-5-week-old female NSG mice were injected with two million cells. Mice were randomly assigned to either a control group that received Captisol or one of five treatment groups that received either neratinib, tepotinib, erlotinib, erlotinib and tepotinib, or neratinib and tepotinib for 17 days. Results: The most effective treatment was the combination of neratinib plus tepotinib, where the average tumor size reduction relative to the control group was 71% (p=0.0003). The average tumor size in the neratinib plus tepotinib treated group was 37% smaller (p=0.049) than the neratinib treated group, and 67% smaller (p=0.0026) than the tepotinib treated group. In the erlotinib plus tepotinib treatment group, the average tumor size was 51% smaller than the control group tumors, but the difference was not statistically significant (p=0.11). No significant difference in tumor size was found between the control group and the erlotinib or tepotinib treated groups. Conclusions: The results demonstrate that hyperactive and coincident c-Met and EGFR signaling contributes to the progression of certain breast cancers. This breast cancer sub-type is more responsive to treatment with a c-Met inhibitor plus a pan-HER inhibitor than a c-Met inhibitor plus an EGFR inhibitor or any of the single agents studied. This suggests that when hyperactive c-Met signaling and a hyperactive ErbB family member is present in a patient's tumor, each of the ErbB pathways as well as the c-Met pathway must be inhibited to treat the tumor most effectively. These findings provide strong evidence that HER2-negative breast cancer patients with coincident hyperactive c-MET and ErbB signaling may respond to treatment with a combination of pan-HER and c-Met inhibitors. Citation Format: Laing LG, Burns DJ, Khan S, MacNeil IA, Rich BE, Kharbush SM, Soltani SM, Sullivan BF. Evaluating contribution of hyperactive c-Met and ErbB signaling to tumor progression in mouse breast tumor xenografts: An in vivo study of c-Met and ErbB targeted therapies [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-15.

NASA’s Management by Trajectory (MBT) concept will improve trajectory predictability by providing methods to keep aircraft on negotiated trajectories; however, the concept impacts roles and responsibilities. Most notably, MBT envisions a different distribution of responsibilities between the Radar-side and Data-side (herein called the negotiating) controllers. Cognitive engineering provides a rich history of research into understanding the roles that humans and automation play in complex systems and some principles for system design. This paper briefly summarizes this literature, focusing on principles underlying the proposed allocation of responsibilities in MBT and the source of automation and information requirements.