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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Centromere/kinetochore protein genes for cancer diagnosis, prognosis and treatment selection

The invention described in the application relates to a panel of gene expression markers for patient with a tumor. The invention thus provides methods and compositions, e.g., kits, for evaluating gene expression levels of the markers and methods of using such gene expression levels to evaluate the likelihood of disease progression or response to chemotherapy or radiation therapy. Such information can be used in determining prognosis and treatment options for cancer patients.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Disentangling Alzheimer’s disease neurodegeneration from typical brain ageing using machine learning

Abstract Neuroimaging biomarkers that distinguish between changes due to typical brain ageing and Alzheimer’s disease are valuable for determining how much each contributes to cognitive decline. Supervised machine learning models can derive multivariate patterns of brain change related to the two processes, including the Spatial Patterns of Atrophy for Recognition of Alzheimer’s Disease (SPARE-AD) and of Brain Aging (SPARE-BA) scores investigated herein. However, the substantial overlap between brain regions affected in the two processes confounds measuring them independently. We present a methodology, and associated results, towards disentangling the two. T1-weighted MRI scans of 4054 participants (48–95 years) with Alzheimer’s disease, mild cognitive impairment (MCI), or cognitively normal (CN) diagnoses from the Imaging-based coordinate SysTem for AGIng and NeurodeGenerative diseases (iSTAGING) consortium were analysed. Multiple sets of SPARE scores were investigated, in order to probe imaging signatures of certain clinically or molecularly defined sub-cohorts. First, a subset of clinical Alzheimer’s disease patients (n = 718) and age- and sex-matched CN adults (n = 718) were selected based purely on clinical diagnoses to train SPARE-BA1 (regression of age using CN individuals) and SPARE-AD1 (classification of CN versus Alzheimer’s disease) models. Second, analogous groups were selected based on clinical and molecular markers to train SPARE-BA2 and SPARE-AD2 models: amyloid-positive Alzheimer’s disease continuum group (n = 718; consisting of amyloid-positive Alzheimer’s disease, amyloid-positive MCI, amyloid- and tau-positive CN individuals) and amyloid-negative CN group (n = 718). Finally, the combined group of the Alzheimer’s disease continuum and amyloid-negative CN individuals was used to train SPARE-BA3 model, with the intention to estimate brain age regardless of Alzheimer’s disease-related brain changes. The disentangled SPARE models, SPARE-AD2 and SPARE-BA3, derived brain patterns that were more specific to the two types of brain changes. The correlation between the SPARE-BA Gap (SPARE-BA minus chronological age) and SPARE-AD was significantly reduced after the decoupling (r = 0.56–0.06). The correlation of disentangled SPARE-AD was non-inferior to amyloid- and tau-related measurements and to the number of APOE ε4 alleles but was lower to Alzheimer’s disease-related psychometric test scores, suggesting the contribution of advanced brain ageing to the latter. The disentangled SPARE-BA was consistently less correlated with Alzheimer’s disease-related clinical, molecular and genetic variables. By employing conservative molecular diagnoses and introducing Alzheimer’s disease continuum cases to the SPARE-BA model training, we achieved more dissociable neuroanatomical biomarkers of typical brain ageing and Alzheimer’s disease.

Hwang, Gyujoon↗
DOE OSTI2023

Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that often develop in patients with neurofibromatosis type 1 (NF1). To address the critical need for novel therapeutics in MPNST, we aimed to establish an ex vivo 3D platform that accurately captured the genomic diversity of MPNST and could be utilized in a medium-throughput manner for drug screening studies to be validated in vivo using patient-derived xenografts (PDX). Genomic analysis was performed on all PDX-tumor pairs. Selected PDX were harvested for assembly into 3D microtissues. Based on prior work in our labs, we evaluated drugs (trabectedin, olaparib, and mirdametinib) ex vivo and in vivo. For 3D microtissue studies, cell viability was the endpoint as assessed by Zeiss Axio Observer. For PDX drug studies, tumor volume was measured twice weekly. Bulk RNA sequencing was performed to identify pathways enriched in cells. We developed 13 NF1-associated MPNST-PDX and identified mutations or structural abnormalities in NF1 (100%), SUZ12 (85%), EED (15%), TP53 (15%), CDKN2A (85%), and chromosome 8 gain (77%). We successfully assembled PDX into 3D microtissues, categorized as robust (>90% viability at 48 h), good (>50%), or unusable (<50%). We evaluated drug response to “robust” or “good” microtissues, namely MN-2, JH-2-002, JH-2-079-c, and WU-225. Drug response ex vivo predicted drug response in vivo, and enhanced drug effects were observed in select models. These data support the successful establishment of a novel 3D platform for drug discovery and MPNST biology exploration in a system representative of the human condition.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Effect of oral plaque control on postoperative pneumonia following lung cancer surgery

Abstract Background There have been few studies on the relationship between oral status and postoperative pneumonia (POP) in patients with lung cancer, and whether improving their oral condition assists with a lower incidence of POP before lung cancer surgery remains controversial. This retrospective study was conducted by a stomatologist to assess the effect of controlling oral pathogenic bacteria of patients with lung cancer to prevent POP. Methods A total of 235 patients with lung cancer who underwent lobectomy by open thoracotomy between July 2015 and December 2018 were selected and given the choice of being in the experimental or control group. A total of 122 participants in the experimental group received professional oral plaque control, and 113 participants in the control group did not receive plaque control. All clinical data of participants in both groups were retrospectively studied to determine the incidence of POP at the thirtieth day of discharge from hospital. Results Eight in the experimental group and six in the control group were excluded from the study. It was found that four of 114 patients suffered from POP in the experimental group (incidence = 3.51%). A total of 17 of 107 patients in the control group had pulmonary infection (incidence = 15.89%). Odds ratio was 0.19. The incidence of POP in the experimental group was significantly lower than that of the control group ( P < 0.05). Conclusions Professional oral plaque control is associated with a lower incidence of POP following lung cancer surgery and is therefore a favorable factor for preventing POP, and should be carried out before the surgical treatment of lung cancer. Key points Professional oral plaque control was associated with a lower incidence of POP following lung cancer surgery, and it is recommended this should be carried out before the surgical treatment of lung cancer.

Jia, Chunling↗
DOE OSTI2021

Diagnostic, Prognostic, and Therapeutic Use of Radiopharmaceuticals in the Context of SARS-CoV-2

The coronavirus disease 2019 (COVID-19) outbreak has devastated the healthcare systems and economies of over 200 countries in just a few months. The etiological agent of COVID-19, SARS-CoV-2, is a highly contagious virus that can be transmitted by asymptomatic and symptomatic carriers alike. While in vitro testing techniques have allowed for population-wide screening, prognostic tools are required to assess the disease severity and therapeutic response, contributing to improve the patient clinical outcomes. Moreover, no specific antiviral against COVID-19 exists at the time of publication, severely limiting treatment against the infection. Hence, there is an urgent clinical need for innovative therapeutic strategies that may contribute to manage the COVID-19 outbreak and prevent future pandemics. In this work, we critically examine recent diagnostic, prognostic, and therapeutic advancements for COVID-19 in the field of radiopharmaceuticals. First, we summarize the gold standard techniques used to diagnose COVID-19, including in vitro assays and imaging techniques, and then discuss how radionuclide-based nuclear imaging provides complementary information for prognosis and treatment management of infected patients. Second, we introduce new emerging types of radiotherapies that employ radioimmunoconjugates, which have shown selective cytotoxic response in oncological studies, and critically analyze how these compounds could be used as therapeutic agents against SARS-CoV-2. Finally, this Perspective further discusses the emerging applications of radionuclides to study the behavior of pulmonary SARS-CoV-2 aerosol particles.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2026

DLK1 is a GATA1s-driven dependency and therapeutic target in Down syndrome–associated myeloid leukemia

Children with Down syndrome have a markedly increased risk of developing myeloid leukemia. Although having an excellent prognosis, 10% to 20% develop relapsed or refractory disease with poor survival, highlighting the need for new targeted approaches. The pathogenesis of myeloid leukemia of Down syndrome (ML-DS) is tightly linked to fetal hematopoiesis and mutations in GATA1, generating the truncated GATA1 short (GATA1s) isoform. We identified Delta-like noncanonical Notch ligand 1 (DLK1) as a direct GATA1s target. DLK1, a paternally imprinted transmembrane protein, is highly expressed in fetal liver CD34 + cells but absent in adult hematopoiesis, making it an attractive immunotherapeutic target. Chromatin profiling revealed GATA1s occupancy at a distal enhancer within the DLK1-DIO3 locus, driving aberrant DLK1 upregulation in ML-DS. Functional studies demonstrated that DLK1 is a leukemia dependency, as its genetic ablation impaired proliferation and engraftment, induced apoptosis, and altered Notch and β-catenin signaling. Therapeutically, a DLK1-directed antibody-drug conjugate–induced selective cytotoxicity, abrogated colony formation, and significantly prolonged survival in refractory ML-DS patient-derived xenograft (PDX) models, achieving durable remissions at higher doses. These findings establish DLK1 as a leukemia-specific vulnerability and provide preclinical proof-of-concept for DLK1-targeted therapies in ML-DS and other leukemias with fetal-like expression programs.

Biological and medical sciences↗
DOE OSTI2021

Baseline [ 18 F]GTP1 tau PET imaging is associated with subsequent cognitive decline in Alzheimer’s disease

Background: The role and implementation of tau PET imaging for predicting subsequent cognitive decline in Alzheimer’s disease (AD) remains uncertain. This study was designed to evaluate the relationship between baseline [ 18 F]GTP1 tau PET and subsequent longitudinal change across multiple cognitive measures over 18 months. Methods: Our analyses incorporated data from 67 participants, including cognitively normal controls (n = 10) and β-amyloid (Aβ)-positive individuals ([ 18 F] florbetapir Aβ PET) with prodromal (n = 26), mild (n = 16), or moderate (n = 15) AD. Baseline measurements included cortical volume (MRI), tau burden ([ 18 F]GTP1 tau PET), and cognitive assessments [Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), 13-item version of the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)]. Cognitive assessments were repeated at 6-month intervals over an 18-month period. Associations between baseline [ 18 F]GTP1 tau PET indices and longitudinal cognitive performance were assessed via univariate (Spearman correlations) and multivariate (linear mixed effects models) approaches. The utility of potential prognostic tau PET cut points was assessed with ROC curves. Results: Univariate analyses indicated that greater baseline [ 18 F]GTP1 tau PET signal was associated with faster rates of subsequent decline on the MMSE, CDR, and ADAS-Cog13 across regions of interest (ROIs). In multivariate analyses adjusted for baseline age, cognitive performance, cortical volume, and Aβ PET SUVR, the prognostic performance of [ 18 F]GTP1 SUVR was most robust in the whole cortical gray ROI. When AD participants were dichotomized into low versus high tau subgroups based on baseline [ 18 F]GTP1 PET standardized uptake value ratios (SUVR) in the temporal (cutoff = 1.325) or whole cortical gray (cutoff = 1.245) ROIs, high tau subgroups demonstrated significantly more decline on the MMSE, CDR, and ADAS-Cog13. Conclusions: Our results suggest that [ 18 F]GTP1 tau PET represents a prognostic biomarker in AD and are consistent with data from other tau PET tracers. Tau PET imaging may have utility for identifying AD patients at risk for more rapid cognitive decline and for stratification and/or enrichment of participant selection in AD clinical trials.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Characterizing Sub-Cohorts via Data Normalization and Representation Learning

The process of identifying a cohort of interest is a very challenging task. It requires manually inspecting many patient records of complex structure that might include medical coding errors and missing data. This paper presents a computational pipeline for refining the process of cohort selection based on medical concepts recorded in the electronic health records (EHRs). The pipeline extracts EHR data for a given cohort and normalizes this data using standard vocabularies. Then a stacked denoising autoencoder is used to embed the normalized patient vectors in a low dimensional space, where the patients are subsequently clustered into sub-cohorts. The goal is to represent the cohort in a standard format and abstract variants of sub-populations. As a use-case, we applied the pipeline to 1.8 million Veterans diagnosed with major depressive disorder (MDD), and identified four meaningful sub-cohorts using the features learned by the autoencoder. Then, each sub-cohort was explored using a set of keywords for interpretation.

Rush III, Everett↗
DOE OSTI2021

Effects of periodontitis on postoperative pneumonia in patients with lung and esophageal cancer

Abstract Background Few studies have been conducted on the relationship between chronic periodontitis and postoperative pneumonia (POP) in patients with lung and esophageal cancer. Furthermore, it remains controversial as to whether improving the periodontal condition of patients with lung and esophageal cancer before surgery reduces the incidence of POP. This retrospective study was conducted to assess the effects of periodontal therapy in patients with lung and esophageal cancer to prevent POP. Methods A total of 265 patients with lung or esophageal cancer complicated with chronic periodontitis who underwent open thoracotomy between July 2015 and June 2019 were selected and given the choice of being in the experimental or control group. A total of 141 participants in the experimental group received periodontal therapy, and 124 participants in the control group did not receive periodontal therapy. All clinical data of participants in both groups were retrospectively studied to determine the incidence of POP on the 30th day after discharge from hospital. Results Eight patients in the experimental and six in the control group, respectively, were excluded from the study. It was found that four of the 133 patients suffered from POP in the experimental group (incidence: 3.01%). A total of 18 of 118 patients in the control group had a pulmonary infection (incidence: 15.25%). POP incidence in the experimental group was significantly lower than that in the control group, and in the level analysis of different types of periodontitis, surgical methods, and diseases ( p < 0.05). Conclusions Periodontal treatment is associated with a lower incidence of POP following lung and esophageal cancer surgery. Improving the periodontal condition of patients helps prevent POP. The presence of periodontitis is an important predisposing factor for POP in patients after open thoracotomy. Periodontal examination and therapy are recommended before the surgical treatment of lung or esophageal cancer.

Jia, Chunling↗
DOE OSTI2021

EP300/CBP is crucial for cAMP-PKA pathway to alleviate podocyte dedifferentiation via targeting Notch3 signaling

Podocyte injury is the hallmark of proteinuric glomerular diseases. Notch3 is neo-activated simultaneously in damaged podocytes and podocyte's progenitor cells of FSGS, indicating a unique role of Notch3. We previously showed that activation of cAMP-PKA pathway alleviated podocyte injury possibly via inhibiting Notch3 expression. However, the mechanisms are unknown. In the present study, Notch3 signaling was significantly activated in ADR-induced podocytes in vitro and in PAN nephrosis rats and patients with idiopathic FSGS in vivo, concomitantly with podocyte dedifferentiation. In cultured podocytes, pCPT-cAMP, a selective cAMP-PKA activator, dramatically blocked ADR-induced activation of Notch3 signaling as well as inhibition of cAMP-PKA pathway, thus alleviating the decreased cell viability and podocyte dedifferentiation. Bioinformatics analysis revealed EP300/CBP, a transcriptional co-activator, as a central hub for the crosstalk between these two signaling pathways. Additionally, CREB/KLF15 in cAMP-PKA pathway competed with RBP-J the major transcriptional factor of Notch3 signaling for binding to EP300/CBP. EP300/CBP siRNA significantly inhibited these two signaling transduction pathways and disrupted the interactions between the above major transcriptional factors. These data indicate a crucial role of EP300/CBP in regulating the crosstalk between cAMP-PKA pathway and Notch3 signaling and modulating the phenotypic change of podocytes, and enrich the reno-protective mechanisms of cAMP-PKA pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Improving five-year survival prediction via multitask learning across HPV-related cancers

Oncology is a highly siloed field of research in which sub-disciplinary specialization has limited the amount of information shared between researchers of distinct cancer types. This can be attributed to legitimate differences in the physiology and carcinogenesis of cancers affecting distinct anatomical sites. However, underlying processes that are shared across seemingly disparate cancers probably affect prognosis. The objective of the current study is to investigate whether multitask learning improves 5-year survival cancer patient survival prediction by leveraging information across anatomically distinct HPV related cancers. Furthermore, data were obtained from the Surveillance, Epidemiology, and End Results (SEER) program database. The study cohort consisted of 29,768 primary cancer cases diagnosed in the United States between 2004 and 2015. Ten different cancer diagnoses were selected, all with a known association with HPV risk. In the analysis, the cancer diagnoses were categorized into three distinct topography groups of varying specificity. The most specific topography grouping consisted of 10 original cancer diagnoses differentiated by the first two digits of the ICD-O-3 topography code. The second topography grouping consisted of cancer diagnoses categorized into six distinct organ groups. Finally, the third topography grouping consisted of just two groups, head-neck cancers and ano-genital cancers. The tasks were to predict 5-year survival for patients within the different topography groups using 14 predictive features which were selected among descriptive variables available in the SEER database. The information from the predictive features was shared between tasks in three different ways, resulting in three distinct predictive models: 1) Information was not shared between patients assigned to different tasks (single task learning); 2) Information was shared between all patients, regardless of task (pooled model); 3) Only relevant information was shared between patients grouped to different tasks (multitask learning). Prediction performance was evaluated with Brier scores. All three models were evaluated against one another on each of the three distinct topography-defined tasks. The results showed that multitask classifiers achieved relative improvement for the majority of the scenarios studied compared to single task learning and pooled baseline methods. In this study, we have demonstrated that sharing information among anatomically distinct cancer types can lead to improved predictive survival models.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Pediatric dosing for locally acting drugs in submissions to the U.S. Food and Drug Administration between 2002 and 2020

Abstract Deriving pediatric doses for locally acting drugs (LADs) presents a unique challenge because limited systemic exposure hinders commonly used approaches such as pharmacokinetic matching to adults. This study systematically evaluated drug development practices used for pediatric dose selection of LADs approved by the U.S. Food and Drug Administration from 2002 to 2020. The three study objectives were: (1) to determine the dose selection approach for the labeled pediatric dose, (2) to examine the studied pediatric dose(s), and (3) to evaluate the characteristics of the pediatric clinical programs used to support the labeled pediatric dose. A total of 187 pediatric submissions were characterized for the labeled and studied pediatric doses of LADs. The pediatric dose was predominantly labeled as a flat dose (91%) and at a single‐dose level (67%) similar to adults. The majority (68.4%) of the submissions had the same labeled dose for pediatrics and adults. Independent pharmacodynamic/efficacy studies in pediatric patients commonly (64.2%) provided supportive evidence for the labeled pediatric dose. Inhalation, nasal, and injectable submissions had the highest number of clinical trials, lowest usage of an extrapolation of efficacy approach, and utilized diverse approaches in selecting the studied pediatric doses. This article highlights approaches for LAD dosing in pediatric patients and can be used to inform drug development of these products in the pediatric population.

Research & Experimental Medicine↗
DOE OSTI2021

A Prospective Trial Demonstrating the Benefit of Personalized Selection Of Breath-Hold Technique for Upper-Abdominal Radiation Therapy Using the Active Breathing Coordinator

For upper abdominal tumors, our institutional-standard motion reduction method is the expiration breath-hold (EBH) technique, using Active Breathing Coordinator (ABC). However, an individual patient's breath-hold (BH) reproducibility (R{sub BH}) may be improved in deep inspiration or inspiration breath-hold (DIBH or IBH). This trial compared the tumor position R{sub BH}, stability (S{sub BH}), and breath-hold time (T{sub BH}) of 3 BH methods, using ABC, to personalize the selection of technique, by using a preplanning screening assessment.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET

A bispecific antibody (BsAb) targeting the epidermal growth factor receptor (EGFR) and mesenchymal–epithelial transition factor (MET) pathways represents a novel approach to overcome resistance to targeted therapies in patients with non–small cell lung cancer. In this study, we sequentially screened a panel of BsAbs in a combinatorial approach to select the optimal bispecific molecule. The BsAbs were derived from different EGFR and MET parental monoclonal antibodies. Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity toward MET. Hits were identified and further screened based on their potential to induce untoward cell proliferation and cross-phosphorylation of EGFR by MET via receptor colocalization in the absence of ligand. After the final step, we selected the EGFR and MET arms for the lead BsAb and added low fucose Fc engineering to generate amivantamab (JNJ-61186372). The crystal structure of the anti-MET Fab of amivantamab bound to MET was solved, and the interaction between the two molecules in atomic details was elucidated. Amivantamab antagonized the hepatocyte growth factor (HGF)-induced signaling by binding to MET Sema domain and thereby blocking HGF β-chain—Sema engagement. The amivantamab EGFR epitope was mapped to EGFR domain III and residues K443, K465, I467, and S468. Furthermore, amivantamab showed superior antitumor activity over small molecule EGFR and MET inhibitors in the HCC827-HGF in vivo model. Based on its unique mode of action, amivantamab may provide benefit to patients with malignancies associated with aberrant EGFR and MET signaling.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Individuals with Alzheimer's disease and low tau burden: Characteristics and implications

Abnormal amyloid-beta (Aβ) and tau deposition define Alzheimer's Disease (AD), but non-elevated tau is relatively frequent in patients on the AD pathway. We examined characteristics and regional patterns of 397 Aβ+ unimpaired and impaired individuals with low tau (A+T-) in relation to their higher tau counterparts (A+T+). Seventy-one percent of Aβ+ unimpaired and 42% of impaired Aβ+ individuals were categorized as A+T- based on global tau. In impaired individuals only, A+T- status was associated with older age, male sex, and greater cardiovascular risk. α-synuclein was linked to poorer cognition, particularly when tau was low. Tau burden was most frequently elevated in a common set of temporal regions regardless of T+/T- status. Low tau is relatively common in patients on the AD pathway and is linked to comorbidities that contribute to impairment. These findings have implications for the selection of individuals for Aβ- and tau-modifying therapies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Validation of a Proteomic Signature of Lung Cancer Risk from Bronchial Specimens of Risk-Stratified Individuals

A major challenge in lung cancer prevention and cure hinges on identifying the at-risk population that ultimately develops lung cancer. Previously, we reported proteomic alterations in the cytologically normal bronchial epithelial cells collected from the bronchial brushings of individuals at risk for lung cancer. The purpose of this study is to validate, in an independent cohort, a selected list of 55 candidate proteins associated with risk for lung cancer with sensitive targeted proteomics using selected reaction monitoring (SRM). Bronchial brushings collected from individuals at low and high risk for developing lung cancer as well as patients with lung cancer, from both a subset of the original cohort (batch 1: n = 10 per group) and an independent cohort of 149 individuals (batch 2: low risk (n = 32), high risk (n = 34), and lung cancer (n = 83)), were analyzed using multiplexed SRM assays. ALDH3A1 and AKR1B10 were found to be consistently overexpressed in the high-risk group in both batch 1 and batch 2 brushing specimens as well as in the biopsies of batch 1. Validation of highly discriminatory proteins and metabolic enzymes by SRM in a larger independent cohort supported their use to identify patients at high risk for developing lung cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines

Molecular-glue degraders are small molecules that induce a specific interaction between an E3 ligase and a target protein, resulting in the target proteolysis. The discovery of molecular glue degraders currently relies mostly on screening approaches. Here, we describe screening of a library of cereblon (CRBN) ligands against a panel of patient-derived cancer cell lines, leading to the discovery of SJ7095, a potent degrader of CK1α, IKZF1 and IKZF3 proteins. Through a structure-informed exploration of structure activity relationship (SAR) around this small molecule we develop SJ3149, a selective and potent degrader of CK1α protein in vitro and in vivo. The structure of SJ3149 co-crystalized in complex with CK1α + CRBN + DDB1 provides a rationale for the improved degradation properties of this compound. In a panel of 115 cancer cell lines SJ3149 displays a broad antiproliferative activity profile, which shows statistically significant correlation with MDM2 inhibitor Nutlin-3a. These findings suggest potential utility of selective CK1α degraders for treatment of hematological cancers and solid tumors.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Neutralizing Antibodies to SARS-CoV-2 Selected from a Human Antibody Library Constructed Decades Ago

Combinatorial antibody libraries not only effectively reduce antibody discovery to a numbers game, but enable documentation of the history of antibody responses in an individual. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has prompted a wider application of this technology to meet the public health challenge of pandemic threats in the modern era. Herein, a combinatorial human antibody library constructed 20 years before the coronavirus disease 2019 (COVID-19) pandemic is used to discover three highly potent antibodies that selectively bind SARS-CoV-2 spike protein and neutralize authentic SARS-CoV-2 virus. Compared to neutralizing antibodies from COVID-19 patients with generally low somatic hypermutation (SHM), these three antibodies contain over 13–22 SHMs, many of which are involved in specific interactions in their crystal structures with SARS-CoV-2 spike receptor binding domain. The identification of these somatically mutated antibodies in a pre-pandemic library raises intriguing questions about the origin and evolution of these antibodies with respect to their reactivity with SARS-CoV-2.

60 APPLIED LIFE SCIENCES↗