NK-cell Biofactory is an off-the-shelf allogeneic platform for cell-based synthesis of desired protein following recognition of a target cell while conserving the cytolytic activity. The molecular specificity of the platform can be redirected for treating a broad range of diseases.
The NK-92MI, a fast-growing cytolytic cell line with a track record of exerting clinical efficacy, is transformed into a vector for synthesizing calibrated amounts of desired engineered proteins at our disease site, that is, NK-cell Biofactory. This provides an allogeneic option to the previously published T-cell-based living vector that is limited by high manufacturing cost and product variability. The modularity of this pathway, which combines a “target” receptor with an “effector” function, enables reprogramming of the NK-cell Biofactory to target diseases with specific molecular biomarkers, such as cancer, viral infections, or auto-immune disorders, and overcome barriers that may affect the advancement of NK-cell therapies.
Harold Javitz
SRI Author
Impact of evening alcohol consumption on nocturnal autonomic and cardiovascular function in adult men and women: A dose–response laboratory investigation
Study Objectives: To investigate the dose-dependent impact of moderate alcohol intake on sleep-related cardiovascular (CV) function, in adult men and women.
Methods: A total of 26 healthy adults (30–60 years; 11 women) underwent 3 nights of laboratory polysomnographic (PSG) recordings in which different doses of alcohol (low: 1 standard drink for women and 2 drinks for men; high: 3 standard drinks for women and 4 drinks for men; placebo: no alcohol) were administered in counterbalanced order before bedtime. These led to bedtime average breath alcohol levels of up to 0.02% for the low doses and around 0.05% for the high doses. Autonomic and CV function were evaluated using electrocardiography, impedance cardiography, and beat-to-beat blood pressure monitoring.
Results: Presleep alcohol ingestion resulted in an overall increase in nocturnal heart rate (HR), suppressed total and high-frequency (vagal) HR variability, reduced baroreflex sensitivity, and increased sympathetic activity, with effects pronounced after high-dose alcohol ingestion (p’s < 0.05); these changes followed different dose- and measure-dependent nocturnal patterns in men and women. Systolic blood pressure showed greater increases during the morning hours of the high-alcohol dose night compared to the low-alcohol dose night and placebo, in women only (p’s < 0.05).
Conclusions: Acute evening alcohol consumption, even at moderate doses, has marked dose- and time-dependent effects on sleep CV regulation in adult men and women. Further studies are needed to evaluate the potential CV risk of repeated alcohol-related alterations in nighttime CV restoration in healthy individuals and in those at high risk for CV diseases, considering sex and alcohol dose and time effects.
Sleep Disturbance Predicts Depression Symptoms in Early Adolescence: Initial Findings From the Adolescent Brain Cognitive Development Study
Purpose: The aim of the study was to investigate associations between sleep disturbances and mental health in adolescents.
Methods: Data are from a national sample of 11,670 U.S. participants (5,594 females, aged 9-10 years, 63.5% white) in the Adolescent Brain Cognitive Development study. Initial longitudinal analyses were conducted for a subset of the sample (n = 4,951). Measures of youth sleep disturbance (disorders of initiating and maintaining sleep, sleep-wake transition disorders, and disorders of excessive somnolence) and “typical” total sleep time (number of hours slept on most nights in the past 6 months) were obtained from the parent-report Sleep Disturbance Scale (Data Release 2.0). Parent-report measures of youth mental health (depression, internalizing, and externalizing behaviors) from the Child Behavior Checklist and typical screen time were included.
Results: At baseline, greater sleep disturbance and shorter total sleep time were associated with greater internalizing, externalizing, and depression scores. After controlling for baseline mental health symptoms, baseline sleep disturbance significantly predicted depression and internalizing and externalizing scores at 1-year follow-up. A significant interaction with sex indicated that the association between disorders of excessive somnolence and depression 1 year later was steeper for girls, compared with boys (p < .001; 95% confidence interval 1.04-3.45).
Conclusions: Sleep disturbances predicted future mental health, particularly depression in this young sample, highlighting the potential to harness sleep as a tool to mitigate the persistence of depression across early adolescence and potentially prevent an adolescent onset of major depressive disorder.
Engineered Ovarian Cancer Cell Lines for Validation of CAR T Cell Function
A set of genetically engineered isogenic cell lines is developed to express either folate receptor alpha or mesothelin, and a control cell line negative for both antigens. These cell lines also express fluorescent and bioluminescent reporter transgenes. The cell lines are used to authenticate specificity and function of a T‐cell biofactory, a living vector that is developed to express proportionate amounts of engineered proteins upon engaging with disease cells through their specific antigenic biomarkers. The engineered cell lines are also used to assess the cytolytic function and specificity of primary T cells engineered with chimeric antigen receptors; and the specificity of monoclonal antibodies. The strategy described can be used to generate other cell lines to present different disease‐specific biomarkers for use as quality control tools.
Modular Antigen-Specific T-cell Biofactories for Calibrated In Vivo Synthesis of Engineered Proteins
An artificial cell-signaling pathway is developed that capitalizes on the T-cell’s innate extravasation ability and transforms it into a vector (T-cell Biofactory) for synthesizing calibrated amounts of engineered proteins in vivo. The modularity of this pathway enables reprogramming of the T-cell Biofactory to target biomarkers on different disease cells, e.g. cancer, viral infections, autoimmune disorders. It can be expected that the T-cell Biofactory leads to a “living drug” that extravasates to the disease sites, assesses the disease burden, synthesizes the calibrated amount of engineered therapeutic proteins upon stimulation by the diseased cells, and reduces targeting of normal cells.
Development of a biodosimeter for radiation triage using novel blood protein biomarker panels in humans and non-human primates
Purpose : In a significant nuclear event, hundreds of thousands of individuals will require rapid triage for absorbed radiation to ensure effective medical treatment and efficient use of medical resources. We are developing a rapid screening method to assess whether an individual received an absorbed dose of ≥2 Gy based on the analysis of a specific panel of blood proteins in a fingerstick blood sample.
Materials and methods : We studied a data set of 1051 human blood samples obtained from radiotherapy patients, normal healthy individuals, and several special population groups. We compared the findings in humans with those from irradiation studies in non-human primates (NHPs).
Results : We identified a panel of three protein biomarkers, salivary alpha amylase (AMY1), Flt3 ligand (FLT3L), and monocyte chemotactic protein 1 (MCP1), which are upregulated in human patients receiving fractionated doses of total body irradiation (TBI) therapy as a treatment for cancer. These proteins exhibited a similar radiation response in NHPs after single acute or fractionated doses of ionizing radiation.
Conclusion : Our work provides confidence in this biomarker panel for biodosimetry triage using fingerstick blood samples and in the use of NHPs as a model for irradiated humans.
Verizon Innovative Learning Minority Male Program Case Study Brief
The Verizon Innovative Learning Minority Male Program (VIL MM) provides minority, male, middle school students with opportunities to engage in science, technology, engineering and mathematics (STEM) learning experiences in university settings. The goals of the program are to increase students’ interest in STEM subjects, attending college, and STEM careers, while promoting technology proficiency. Program activities include instruction in mobile app development, 3D modeling and printing, engineering, robotics and computer science. Personal development is supported through mentorship.
Verizon Innovative Learning Minority Male Program: Summer Program Evaluation Executive Summary
SRI International’s Center for Technology in Learning, with support from the Verizon Education Foundation, developed this research brief as part of a two year evaluation of the 2016 Verizon Innovative Learning (VIL) Program. The goals of the VIL Program are to increase minority, male, middle school students’ problem solving skills, technology proficiency, and interest in STEM subjects and careers. This brief summarizes key findings from survey and assessment results collected during the 2016 summer program at twelve minority serving institutions (MSUs) between June and August of 2016. A description of the highlights, challenges and lessons learned during the summer are also provided. The aim of this research is to understand the experiences of participating minority, middle school male students by giving voice to the perspectives of participating stakeholders (e.g., students, educators, mentors, parents and administrators).
Vocational Education Course Taking and Post-High School Employment of Youth with Emotional Disturbances
Data from the National Longitudinal Transition Study–2 (NLTS2) were used to examine the patterns of career and technical education (CTE) course taking in high school by students receiving special education services for emotional disturbances (ED). Descriptive analyses indicate the extent of such course taking by students with ED and their engagement in a concentrated program of occupationally specific general education CTE, a level of CTE course taking that early research has linked to improved post–high school employment outcomes. Propensity scoring methods were used to determine the extent to which either type of CTE course taking was related to higher odds of full-time employment after high school and whether results differed with the length of time post high school. There was a significant positive effect for participating in a concentration of occupationally specific CTE in the first 2 post–high school years, but effects were non-significant for later years. Results showed no benefits of CTE course taking overall. The implications for high school programming and transition planning are discussed.
