NAV-003, a bispecific antibody targeting a unique mesothelin epitope and CD3ε with improved cytotoxicity against humoral immunosuppressed tumors.

Mesothelin (MSLN) is a cell surface protein overexpressed in a number of cancer types. Several antibody- and cellular-based MSLN targeting agents have been tested in clinical trials where their therapeutic efficacy has been moderate at best. Previous studies using antibody and Chimeric Antigen Receptor-T cells (CAR-T) strategies have shown the importance of particular MSLN epitopes for optimal therapeutic response, while other studies have found that certain MSLN-positive tumors can produce proteins that can bind to subsets of IgG1-type antibodies and suppress their immune effector activities. In an attempt to develop an improved anti-MSLN targeting agent, we engineered a humanized divalent anti-MSLN/anti-CD3ε bispecific antibody that avoids suppressive factors, can target a MSLN epitope proximal to the tumor cell surface, and is capable of effectively binding, activating, and redirecting T cells to the surface of MSLN-positive tumor cells. NAV-003 has shown significantly improved tumor cell killing against lines producing immunosuppressive proteins in vitro and in vivo. Moreover, NAV-003 demonstrated good tolerability in mice and efficacy against patient-derived mesothelioma xenografts co-engrafted with human peripheral blood mononuclear cells. Together these data support the potential for NAV-003 clinical development and human proof-of-concept studies in patients with MSLN-expressing cancers.

NAV-001, a high-efficacy antibody-drug conjugate targeting mesothelin with improved delivery of a potent payload by counteracting MUC16/CA125 inhibitory effects.

Subsets of tumor-produced cell surface and secreted proteins can bind to IgG1 type antibodies and suppress their immune-effector activities. As they affect antibody and complement-mediated immunity, we call these proteins humoral immuno-oncology (HIO) factors. Antibody-drug conjugates (ADCs) use antibody targeting to bind cell surface antigens, internalize into the cell, then kill target cells upon liberation of the cytotoxic payload. Binding of the ADC antibody component by a HIO factor may potentially hamper ADC efficacy due to reduced internalization. To determine the potential effects of HIO factor ADC suppression, we evaluated the efficacy of a HIO-refractory, mesothelin-directed ADC (NAV-001) and a HIO-bound, mesothelin-directed ADC (SS1). The HIO factor MUC16/CA125 binding to SS1 ADC was shown to have a negative effect on internalization and tumor cell killing. The MUC16/CA125 refractory NAV-001 ADC was shown to have robust killing of MUC16/CA125 expressing and non-expressing tumor cells in vitro and in vivo at single, sub-mg/kg dosing. Moreover, NAV-001-PNU, which contains the PNU-159682 topoisomerase II inhibitor, demonstrated good stability in vitro and in vivo as well as robust bystander activity of resident cells while maintaining a tolerable safety profile in vivo. Single-dose NAV-001-PNU demonstrated robust tumor regression of a number of patient-derived xenografts from different tumor types regardless of MUC16/CA125 expression. These findings suggest that identification of HIO-refractory antibodies to be used in ADC format may improve therapeutic efficacy as observed by NAV-001 and warrants NAV-001-PNU's advancement to human clinical trials as a monotherapy to treat mesothelin-positive cancers.

Changes in HIV Prevention and Sexual Experiences During the COVID-19 Pandemic: A Mixed-Methods Study.

BACKGROUND: STI and HIV services and infection rates were affected during the COVID-19 pandemic, because of changes in access to health care and individual behavior. Understanding how individuals made decisions around prevention and sexual activities during different phases of the pandemic is useful to addressing the rising rates of STIs and HIV. SETTING: Federally-qualified health center focused on sexual and gender minority health, Chicago IL, 2021. METHODS: Patients with a history of PrEP use who were contacted by the PrEP retention team as part of standard care were invited to complete an online survey. A subset of survey participants were then contacted to complete one-on-one interviews. Participants were asked about two distinct periods: November 2020 to January 2021 and February to June 2021. RESULTS: From the 356 survey participants (mostly young, insured, and experienced with PrEP), more than half maintained their number of sex partners during the early pandemic and most also maintained PrEP use; during the later pandemic; most reported more or the same number of sex partners and almost all maintained PrEP use. From interviews, we identified diverse and changing experiences regarding sexual practices throughout the pandemic; whereas many participants changed PrEP use in accordance with sexual practices, many others maintained PrEP use as a habit. COVID-19 prevention was also a factor in sexual activities, particularly prevaccination. CONCLUSION: Many PrEP users try to align their HIV prevention with their sexual exposures and establish PrEP as a long-term habit. Removing financial and access barriers is important to improve PrEP use and STI testing.

Density measurements for the National Ignition Facility (NIF) opacity platform.

The Opacity Platform on the National Ignition Facility (NIF) has been developed to measure opacities at varying densities and temperatures relevant to the solar interior and thermal cooling rates in white dwarf stars. The typical temperatures reached at NIF range between 150 and 210 eV, which allow these measurements to be performed experimentally. The captured opacities are crucial to validating radiation-hydrodynamic models that are used in astrophysics. The NIF opacity platform has a unique new capability that allows in situ measurement of the sample expansion. The sample expansion data are used to better understand the plasma conditions in our experiments by inferring the sample density throughout the duration of the laser drive. We present the details of the density measurement technique, data analysis, and recent results for Fe and MgO.

Polyphenic risk score shows robust predictive ability for long-term future suicidality.

Suicides are preventable tragedies, if risk factors are tracked and mitigated. We had previously developed a new quantitative suicidality risk assessment instrument (Convergent Functional Information for Suicidality, CFI-S), which is in essence a simple polyphenic risk score, and deployed it in a busy urban hospital Emergency Department, in a naturalistic cohort of consecutive patients. We report a four years follow-up of that population (n = 482). Overall, the single administration of the CFI-S was significantly predictive of suicidality over the ensuing 4 years (occurrence- ROC AUC 80%, severity- Pearson correlation 0.44, imminence-Cox regression Hazard Ratio 1.33). The best predictive single phenes (phenotypic items) were feeling useless (not needed), a past history of suicidality, and social isolation. We next used machine learning approaches to enhance the predictive ability of CFI-S. We divided the population into a discovery cohort (n = 255) and testing cohort (n = 227), and developed a deep neural network algorithm that showed increased accuracy for predicting risk of future suicidality (increasing the ROC AUC from 80 to 90%), as well as a similarity network classifier for visualizing patient's risk. We propose that the widespread use of CFI-S for screening purposes, with or without machine learning enhancements, can boost suicidality prevention efforts. This study also identified as top risk factors for suicidality addressable social determinants. Supplementary Information: The online version contains supplementary material available at 10.1007/s44192-022-00016-z.

Diffusion MRI Microstructural Abnormalities at Term-Equivalent Age Are Associated with Neurodevelopmental Outcomes at 3 Years of Age in Very Preterm Infants.

BACKGROUND AND PURPOSE: Microstructural white matter abnormalities on DTI using Tract-Based Spatial Statistics at term-equivalent age are associated with cognitive and motor outcomes at 2 years of age or younger. However, neurodevelopmental tests administered at such early time points are insufficiently predictive of mild-moderate motor and cognitive impairment at school age. Our objective was to evaluate the microstructural antecedents of cognitive and motor outcomes at 3 years' corrected age in a cohort of very preterm infants. MATERIALS AND METHODS: We prospectively recruited 101 very preterm infants (<32 weeks' gestational age) and performed DTI at term-equivalent age. The Differential Ability Scales, 2nd ed, Verbal and Nonverbal subtests, and the Bayley Scales of Infant and Toddler Development, 3rd ed, Motor subtest, were administered at 3 years of age. We correlated DTI metrics from Tract-Based Spatial Statistics with the Bayley Scales of Infant and Toddler Development, 3rd ed, and the Differential Ability Scales, 2nd ed, scores with correction for multiple comparisons. RESULTS: Of the 101 subjects, 84 had high-quality DTI data, and of these, 69 returned for developmental testing (82%). Their mean (SD) gestational age was 28.4 (2.5) weeks, and birth weight was 1121.4 (394.1) g. DTI metrics were significantly associated with Nonverbal Ability in the corpus callosum, posterior thalamic radiations, fornix, and inferior longitudinal fasciculus and with Motor scores in the corpus callosum, internal and external capsules, posterior thalamic radiations, superior and inferior longitudinal fasciculi, cerebral peduncles, and corticospinal tracts. CONCLUSIONS: We identified widespread microstructural white matter abnormalities in very preterm infants at term that were significantly associated with cognitive and motor development at 3 years' corrected age.

DANTE as a primary temperature diagnostic for the NIF iron opacity campaign.

The Opacity Platform on the National Ignition Facility (NIF) has been developed to measure iron opacities at varying densities and temperatures relevant to the solar interior and to verify recent experimental results obtained at the Sandia Z-machine, that diverge from theory. The first set of NIF experiments collected iron opacity data at ∼150 eV to 160 eV and an electron density of ∼7 × 1021 cm-3, with a goal to study temperatures up to ∼210 eV, with electron densities of up to ∼3 × 1022 cm-3. Among several techniques used to infer the temperature of the heated Fe sample, the absolutely calibrated DANTE-2 filtered diode array routinely provides measurements of the hohlraum conditions near the sample. However, the DANTE-2 temperatures are consistently low compared to pre-shot LASNEX simulations for a range of laser drive energies. We have re-evaluated the estimated uncertainty in the reported DANTE-2 temperatures and also the error generated by varying channel participation in the data analysis. An uncertainty of ±5% or better can be achieved with appropriate spectral coverage, channel participation, and metrology of the viewing slot.

Toward 3D data visualization using virtual reality tools.

Virtual Reality (VR) offers the opportunity to display data, instrumentation, and experimental setups in three dimensions and gives the user the ability to interact with the objects. This technology moves visualization beyond two-dimensional projections on a flat screen with a fixed field of view in which a keyboard or another similar controller is needed to change the view. Advances in both hardware and software for VR make it possible for the non-expert to develop visualization tools for scientific applications both for viewing and for sharing data or diagnostic hardware between users in three dimensions. This manuscript describes application development using two VR software tools, Unity gaming engine and A-frame, for visualizing data and high energy physics targets.

Adverse effects of perinatal illness severity on neurodevelopment are partially mediated by early brain abnormalities in infants born very preterm.

BACKGROUND: We sought to determine the mediating effects of magnetic resonance imaging (MRI) biomarkers at term gestation on the relationship between perinatal illness severity and neurodevelopment. METHODS: The Clinical Risk Index for Babies-second edition (CRIB-II) was correlated with indices of brain maturation or injury and neurodevelopment at 2-year follow-up in infants born less than 32 weeks gestation. Using a counterfactual mediation analysis, associations between CRIB-II, MRI biomarkers, and neurodevelopment were confirmed, followed by an assessment of the mediating effects of MRI biomarkers on the relationship between CRIB-II and neurodevelopment. RESULTS: CRIB-II correlated significantly with neurodevelopment and MRI biomarkers of brain injury or cortical maturation. Two MRI biomarkers, cortical surface area and global injury score, were associated with neurodevelopmental scores at follow-up and included in mediation analyses. CONCLUSION: Biomarkers of cortical maturation or brain injury at term-equivalent age mediated a substantial portion of the risks conveyed by perinatal illness severity on neurodevelopmental outcomes at 2 years corrected age.