Human nerve growth factor delivery to the retina: Quantitative methodology and mathematical modeling in preclinical settings.

Nerve growth factor (NGF) plays a critical neuroprotective role in retinal health, supporting neuronal survival and regeneration. Recombinant human NGF (rhNGF) holds promise for treating retinal degenerative diseases such as glaucoma, retinitis pigmentosa, and optic neuropathies. However, efficient retinal delivery of rhNGF remains a major challenge due to anatomical barriers and rapid clearance from conventional routes.

First-generation and preclinical evaluation of an EphA5-targeted antibody-drug conjugate in solid tumors.

Contemporary cancer treatment strategies are shifting toward targeted therapies to improve efficacy and minimize toxicity. Here, we report the design and preclinical evaluation of MBRC-101, a first-in-class antibody-drug conjugate (ADC) targeting EphA5, a receptor tyrosine kinase with an established role in embryonic development but not extensively studied in cancer. We show that EphA5 is expressed in multiple solid tumors, including cancers of the aerodigestive (non-small cell lung, head and neck, gastric, colon, and pancreatic) and genitourinary (bladder and ovary) tracts, as well as most breast cancer subsets (including triple-negative tumors), with limited expression in normal tissues.

Human protein interactome structure prediction at scale with Boltz-2.

In humans, protein-protein interactions mediate numerous biological processes and are central to both normal physiology and disease. Extensive research efforts have aimed to elucidate the human protein interactome, and comprehensive databases now catalog these interactions at scale. However, structural coverage of the human protein interactome is limited and remains challenging to resolve through experimental methodology alone.

Conformational ligand-directed targeting of calcium-dependent receptors in acute trauma.

Background: Trauma is a leading cause of mortality, but injury-specific molecular targets remain largely unknown. We hypothesized that distinctive yet unrecognized tissue targets accessible to circulating ligands might emerge during trauma, thereby underscoring a trauma-related proteome.

Methods: We screened a peptide library to discover targets in a porcine model of major trauma: compound femur fracture with hemorrhagic shock.

Rational Design of Safer Inorganic Nanoparticles via Mechanistic Modeling-Informed Machine Learning.

The safety of inorganic nanoparticles (NPs) remains a critical challenge for their clinical translation. To address this, we developed a machine learning (ML) framework that predicts NP toxicity both and , leveraging physicochemical properties and experimental conditions. A curated cytotoxicity dataset was used to train and validate binary classification models, with top-performing models undergoing explainability analysis to identify key determinants of toxicity and establish structure-toxicity relationships.

Brain-derived textiloma post glioblastoma resection and application of oxidized regenerated cellulose: A pilot, bedside-to-bench, translational study.

Oxidized regenerated cellulose (ORC; marketed as Surgicel® and Tabotamp®) is routinely used as an intraoperative hemostatic agent. Rarely, residual ORC has been associated with a foreign body reaction generating cystic or granulomatous lesions (i.e.

High-throughput prediction of peptide structural conformations with AlphaFold2.

Protein structure prediction artificial intelligence/machine learning (AI/ML) approaches has sparked substantial research interest in structural biology and adjacent disciplines. More recently, AlphaFold2 (AF2) has been adapted for the prediction of multiple structural conformations-beyond the original scope of predicting single-state structures. This is accomplished by using multiple random seeds and subsampling the multiple sequence alignment (MSA).

Generative artificial intelligence performs rudimentary structural biology modeling.

Natural language-based generative artificial intelligence (AI) has become increasingly prevalent in scientific research. Intriguingly, capabilities of generative pre-trained transformer (GPT) language models beyond the scope of natural language tasks have recently been identified. Here we explored how GPT-4 might be able to perform rudimentary structural biology modeling.

Generative artificial intelligence performs rudimentary structural biology modeling.

Natural language-based generative artificial intelligence (AI) has become increasingly prevalent in scientific research. Intriguingly, capabilities of generative pre-trained transformer (GPT) language models beyond the scope of natural language tasks have recently been identified. Here we explored how GPT-4 might be able to perform rudimentary structural biology modeling.

Mathematical modeling of cancer immunotherapy for personalized clinical translation.

Encouraging advances are being made in cancer immunotherapy modeling, especially in the key areas of developing personalized treatment strategies based on individual patient parameters, predicting treatment outcomes and optimizing immunotherapy synergy when used in combination with other treatment approaches. Here we present a focused review of the most recent mathematical modeling work on cancer immunotherapy with a focus on clinical translatability. It can be seen that this field is transitioning from pure basic science to applications that can make impactful differences in patients' lives.

Ceramide as an endothelial cell surface receptor and a lung-specific lipid vascular target for circulating ligands.

The vascular endothelium from individual organs is functionally specialized, and it displays a unique set of accessible molecular targets. These serve as endothelial cell receptors to affinity ligands. To date, all identified vascular receptors have been proteins.

Integrated metabolic and genetic analysis reveals distinct features of human differentiated thyroid cancer.

Background: Differentiated thyroid cancer (DTC) affects thousands of lives worldwide each year. Typically, DTC is a treatable disease with a good prognosis. Yet, some patients are subjected to partial or total thyroidectomy and radioiodine therapy to prevent local disease recurrence and metastasis.

Preclinical optimization of a diode laser-based clamp-free partial nephrectomy in a large animal model.

Kidney cancer is a common urologic malignancy with either laparoscopic (LPN) or robotic partial nephrectomy as therapeutic options of choice for localized tumors. However, renal resection and suturing are challenging steps of the procedure that can lead to complications such as prolonged warm ischemia, bleeding, and urinary fistulas. LPN with a diode laser is an efficient technique due to its cutting and/or coagulation attributes.

Modeling of ACE2 and antibodies bound to SARS-CoV-2 provides insights into infectivity and immune evasion.

Given the COVID-19 pandemic, there is interest in understanding ligand-receptor features and targeted antibody-binding attributes against emerging SARS-CoV-2 variants. Here, we developed a large-scale structure-based pipeline for analysis of protein-protein interactions regulating SARS-CoV-2 immune evasion. First, we generated computed structural models of the Spike protein of 3 SARS-CoV-2 variants (B.

A modeling-based approach to optimize COVID-19 vaccine dosing schedules for improved protection.

While the development of different vaccines slowed the dissemination of SARS-CoV-2, the occurrence of breakthrough infections has continued to fuel the COVID-19 pandemic. To secure at least partial protection in the majority of the population through 1 dose of a COVID-19 vaccine, delayed administration of boosters has been implemented in many countries. However, waning immunity and emergence of new variants of SARS-CoV-2 suggest that such measures may induce breakthrough infections due to intermittent lapses in protection.

Dysregulation of the PRUNE2/PCA3 genetic axis in human prostate cancer: from experimental discovery to validation in two independent patient cohorts.

Background: We have previously shown that the long non-coding (lnc)RNA (; formerly ) functions as a trans-dominant negative oncogene by targeting the previously unrecognized prostate cancer suppressor gene (a homolog of the gene), thereby forming a functional unit within a unique allelic locus in human cells. Here, we investigated the / regulatory axis from early (tumorigenic) to late (biochemical recurrence) genetic events during human prostate cancer progression.

Methods: The reciprocal and gene expression relationship in paired prostate cancer and adjacent normal prostate was analyzed in two independent retrospective cohorts of clinically annotated cases post-radical prostatectomy: a single-institutional discovery cohort (n=107) and a multi-institutional validation cohort (n=497).

Tissue resident iNKT17 cells facilitate cancer cell extravasation in liver metastasis via interleukin-22.

During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy.

A modeling-based approach to optimize COVID-19 vaccine dosing schedules for improved protection.

While the development of different vaccines has slowed the dissemination of SARS-CoV-2, the occurrence of breakthrough infections continues to fuel the pandemic. As a strategy to secure at least partial protection, with a single dose of a given COVID-19 vaccine to maximum possible fraction of the population, administration of subsequent doses (or boosters) has been implemented in many countries. However, waning immunity and emergence of new variants of SARS-CoV-2 suggest that such measures may jeopardize the attainment of herd immunity due to intermittent lapses in protection.

Leveraging the scientific findings to develop therapeutic strategies for dormant breast cancer cells.

Breast cancer (BC) metastasis can occur decades before clinical diagnosis. During this time, the cancer cells (BCCs) can remain dormant for decades. This type of dormancy also occurs during remission where the dormant BCCs adapt cycling quiescence within the tissue microenvironment.

Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an -of-1 clinical trial.

Background: Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases.

Methods: We examined the genomic landscape of a patient cohort of LMs ( = 30 cases) that underwent comprehensive genomic profiling using a large-panel next-generation sequencing assay. Immunohistochemical analyses were completed in parallel.

Genetic and Structural Analysis of SARS-CoV-2 Spike Protein for Universal Epitope Selection.

Evaluation of immunogenic epitopes for universal vaccine development in the face of ongoing SARS-CoV-2 evolution remains a challenge. Herein, we investigate the genetic and structural conservation of an immunogenically relevant epitope (C662-C671) of spike (S) protein across SARS-CoV-2 variants to determine its potential utility as a broad-spectrum vaccine candidate against coronavirus diseases. Comparative sequence analysis, structural assessment, and molecular dynamics simulations of C662-C671 epitope were performed.

Translational Modeling Identifies Synergy between Nanoparticle-Delivered miRNA-22 and Standard-of-Care Drugs in Triple-Negative Breast Cancer.

Purpose: Downregulation of miRNA-22 in triple-negative breast cancer (TNBC) is associated with upregulation of eukaryotic elongation 2 factor kinase (eEF2K) protein, which regulates tumor growth, chemoresistance, and tumor immunosurveillance. Moreover, exogenous administration of miRNA-22, loaded in nanoparticles to prevent degradation and improve tumor delivery (termed miRNA-22 nanotherapy), to suppress eEF2K production has shown potential as an investigational therapeutic agent in vivo.

Methods: To evaluate the translational potential of miRNA-22 nanotherapy, we developed a multiscale mechanistic model, calibrated to published in vivo data and extrapolated to the human scale, to describe and quantify the pharmacokinetics and pharmacodynamics of miRNA-22 in virtual patient populations.

Spatial and temporal dynamics of HDACs class IIa following mild traumatic brain injury in adult rats.

The fundamental role of epigenetic regulatory mechanisms involved in neuroplasticity and adaptive responses to traumatic brain injury (TBI) is gaining increased recognition. TBI-induced neurodegeneration is associated with several changes in the expression-activity of various epigenetic regulatory enzymes, including histone deacetylases (HDACs). In this study, PET/CT with 6-([F]trifluoroacetamido)-1- hexanoicanilide ([F]TFAHA) to image spatial and temporal dynamics of HDACs class IIa expression-activity in brains of adult rats subjected to a weight drop model of diffuse, non-penetrating, mild traumatic brain injury (mTBI).