Temporal Exploration of COPD Phenotypes: Insights from the COPDGene and SPIROMICS Cohorts.

Background: Chronic obstructive pulmonary disease (COPD) exhibits considerable progression heterogeneity. We hypothesized that elastic principal graph analysis (EPGA) would identify distinct clinical phenotypes and their longitudinal relationships.

Methods: Cross-sectional data from 8,972 tobacco-exposed COPDGene participants, with and without COPD, were used to train a model with EPGA, using thirty clinical, physiologic and CT features.

Local heterogeneity of normal lung parenchyma and small airways disease are associated with COPD severity and progression.

Background: Small airways disease (SAD) is a major cause of airflow obstruction in COPD patients and has been identified as a precursor to emphysema. Although the amount of SAD in the lungs can be quantified using our Parametric Response Mapping (PRM) approach, the full breadth of this readout as a measure of emphysema and COPD progression has yet to be explored. We evaluated topological features of PRM-derived normal parenchyma and SAD as surrogates of emphysema and predictors of spirometric decline.

WITHDRAWN: Oncogenic KRAS extrinsically induces an immunosuppressive microenvironment in lung adenocarcinoma.

This manuscript has been withdrawn by the authors due to a dispute over co-first authorship that is currently being arbitrated by the medical school at our institution. Therefore, the authors do not wish this work to be cited as reference for the project. Upon completion of the arbitration process, we will take steps to revert the current withdrawn status.

Modeling Molecular Pathogenesis of Idiopathic Pulmonary Fibrosis-Associated Lung Cancer in Mice.

Unlabelled: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive, often fatal loss of lung function due to overactive collagen production and tissue scarring. Patients with IPF have a sevenfold-increased risk of developing lung cancer. The COVID-19 pandemic has increased the number of patients with lung diseases, and infection can worsen prognoses for those with chronic lung diseases and disease-associated cancer.

Targeting DNA Repair and Survival Signaling in Diffuse Intrinsic Pontine Gliomas to Prevent Tumor Recurrence.

Therapeutic resistance remains a major obstacle to successful clinical management of diffuse intrinsic pontine glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed.

Topologic Parametric Response Mapping Identifies Tissue Subtypes Associated with Emphysema Progression.

Rationale And Objectives: Small airways disease (SAD) and emphysema are significant components of chronic obstructive pulmonary disease (COPD), a heterogenous disease where predicting progression is difficult. SAD, a principal cause of airflow obstruction in mild COPD, has been identified as a precursor to emphysema. Parametric Response Mapping (PRM) of chest computed tomography (CT) can help distinguish SAD from emphysema.

Histone H3 K27M-mediated regulation of cancer cell stemness and differentiation in diffuse midline glioma.

Therapeutic resistance remains a major obstacle to preventing progression of H3K27M-altered Diffuse Midline Glioma (DMG). Resistance is driven in part by ALDH-positive cancer stem cells (CSC), with high ALDH1A3 expression observed in H3K27M-mutant DMG biopsies. We hypothesized that ALDH-mediated stemness and resistance may in part be driven by the oncohistone itself.

Lung cancer lesion detection in histopathology images using graph-based sparse PCA network.

Early detection of lung cancer is critical for improvement of patient survival. To address the clinical need for efficacious treatments, genetically engineered mouse models (GEMM) have become integral in identifying and evaluating the molecular underpinnings of this complex disease that may be exploited as therapeutic targets. Assessment of GEMM tumor burden on histopathological sections performed by manual inspection is both time consuming and prone to subjective bias.

Therapeutic avenues for targeting treatment challenges of diffuse midline gliomas.

Diffuse midline glioma (DMG) is the leading cause of brain tumor-related deaths in children. DMG typically presents with variable neurologic symptoms between ages 3 and 10. Currently, radiation remains the standard therapy for DMG to halt progression and reduce tumor bulk to minimize symptoms.

Investigating the Incidence of Pulmonary Abnormalities as Identified by Parametric Response Mapping in Patients With Lung Cancer Before Radiation Treatment.

Purpose: Parametric response mapping (PRM) of high-resolution, paired inspiration and expiration computed tomography (CT) scans is a promising analytical imaging technique that is currently used in diagnostic applications and offers the ability to characterize and quantify certain pulmonary pathologies on a patient-specific basis. As one of the first studies to implement such a technique in the radiation oncology clinic, the goal of this work was to assess the feasibility for PRM analysis to identify pulmonary abnormalities in patients with lung cancer before radiation therapy (RT).

Methods And Materials: High-resolution, paired inspiration and expiration CT scans were acquired from 23 patients with lung cancer as part of routine treatment planning CT acquisition.

Quantitative CT Correlates with Local Inflammation in Lung of Patients with Subtypes of Chronic Lung Allograft Dysfunction.

Chronic rejection of lung allografts has two major subtypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), which present radiologically either as air trapping with small airways disease or with persistent pleuroparenchymal opacities. Parametric response mapping (PRM), a computed tomography (CT) methodology, has been demonstrated as an objective readout of BOS and RAS and bears prognostic importance, but has yet to be correlated to biological measures. Using a topological technique, we evaluate the distribution and arrangement of PRM-derived classifications of pulmonary abnormalities from lung transplant recipients undergoing redo-transplantation for end-stage BOS (N = 6) or RAS (N = 6).

Improved detection of air trapping on expiratory computed tomography using deep learning.

Background: Radiologic evidence of air trapping (AT) on expiratory computed tomography (CT) scans is associated with early pulmonary dysfunction in patients with cystic fibrosis (CF). However, standard techniques for quantitative assessment of AT are highly variable, resulting in limited efficacy for monitoring disease progression.

Objective: To investigate the effectiveness of a convolutional neural network (CNN) model for quantifying and monitoring AT, and to compare it with other quantitative AT measures obtained from threshold-based techniques.

Stereotactic Transcranial Focused Ultrasound Targeting System for Murine Brain Models.

An inexpensive, accurate focused ultrasound stereotactic targeting method guided by pretreatment magnetic resonance imaging (MRI) images for murine brain models is presented. An uncertainty of each sub-component of the stereotactic system was analyzed. The entire system was calibrated using clot phantoms.

The cytochrome P450 enzyme CYP24A1 increases proliferation of mutant KRAS-dependent lung adenocarcinoma independent of its catalytic activity.

We previously reported that overexpression of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) increases lung cancer cell proliferation by activating RAS signaling and that CYP24A1 knockdown inhibits tumor growth. However, the mechanism of CYP24A1-mediated cancer cell proliferation remains unclear. Here, we conducted cell synchronization and biochemical experiments in lung adenocarcinoma cells, revealing a link between CYP24A1 and anaphase-promoting complex (APC), a key cell cycle regulator.

Multicenter evaluation of parametric response mapping as an indicator of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation.

Parametric response mapping (PRM) is a novel computed tomography (CT) technology that has shown potential for assessment of bronchiolitis obliterans syndrome (BOS) after hematopoietic stem cell transplantation (HCT). The primary aim of this study was to evaluate whether variations in image acquisition under real-world conditions affect the PRM measurements of clinically diagnosed BOS. CT scans were obtained retrospectively from 72 HCT recipients with BOS and graft-versus-host disease from Fred Hutchinson Cancer Research Center, Karolinska Institute, and the University of Michigan.

Multimodal imaging provides insight into targeted therapy response in metastatic prostate cancer to the bone.

Metastatic prostate cancer to bone remains incurable, driving efforts to develop individualized, targeted therapies to improve clinical outcomes while limiting adverse side-effects. Due to the complexity in cellular signaling pathways and the interaction between cancer and its microenvironment, multiparametric imaging approaches for treatment response may improve understanding of the biological effects of therapy. An orthotopic model of castration resistant prostate cancer (CRPC) bone metastasis was treated with the tyrosine kinase inhibitor Cabozantinib (CABO).

Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors.

Purpose: ST-162 and ST-168 are small-molecule bifunctional inhibitors of MEK and PI3K signaling pathways that are being developed as novel antitumor agents. Previous small-molecule and biologic MEK inhibitors demonstrated ocular toxicity events that were dose limiting in clinical studies. We evaluated in vitro and in vivo ocular toxicity profiles of ST-162 and ST-168.

Structure-Guided Design and Initial Studies of a Bifunctional MEK/PI3K Inhibitor (ST-168).

The structure-based design of a new single entity, MEK/PI3K bifunctional inhibitor (, ), which displays improved MEK1 and PI3K isoform inhibition, is described. demonstrated a 2.2-fold improvement in MEK1 inhibition and a 2.