The deubiquitinase USP9X regulates RIT1 protein abundance and oncogenic phenotypes.

is a rare and understudied oncogene in lung cancer. Despite structural similarity to other RAS GTPase proteins such as KRAS, oncogenic RIT1 activity does not appear to be tightly regulated by nucleotide exchange or hydrolysis. Instead, there is a growing understanding that the protein abundance of RIT1 is important for its regulation and function.

The deubiquitinase USP9X regulates RIT1 protein abundance and oncogenic phenotypes.

is a rare and understudied oncogene in lung cancer. Despite structural similarity to other RAS GTPase proteins such as KRAS, oncogenic RIT1 activity does not appear to be tightly regulated by nucleotide exchange or hydrolysis. Instead, there is a growing understanding that the protein abundance of RIT1 is important for its regulation and function.

Therapy-induced APOBEC3A drives evolution of persistent cancer cells.

Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified, the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined.

Changes to Astrocyte-associated Protein Expression at Different Timepoints of Cuprizone Treatment.

Glial cells, including astrocytes, microglia, and oligodendrocytes, are brain cells that support and dynamically interact with neurons and each other. These intercellular dynamics undergo changes during stress and disease states. In response to most forms of stress, astrocytes will undergo some variation of activation, meaning upregulation in certain proteins expressed and secreted and either upregulations or downregulations to various constitutive and normal functions.

The PhenX Toolkit: Measurement Protocols for Assessment of Social Determinants of Health.

Introduction: Social determinants are structures and conditions in the biological, physical, built, and social environments that affect health, social and physical functioning, health risk, quality of life, and health outcomes. The adoption of recommended, standard measurement protocols for social determinants of health will advance the science of minority health and health disparities research and provide standard social determinants of health protocols for inclusion in all studies with human participants.

Methods: A PhenX (consensus measures for Phenotypes and eXposures) Working Group of social determinants of health experts was convened from October 2018 to May 2020 and followed a well-established consensus process to identify and recommend social determinants of health measurement protocols.

Genome-wide CRISPR screening reveals novel therapeutic targets in RIT1-driven lung cancer.

In recent work, we performed CRISPR/Cas9 screening in mutant cancer cells. We found that -mutant cells are vulnerable to loss of mitotic regulators, and mutant RIT1 synergizes with YAP1 (yes-associated protein 1) in oncogenesis. These findings can be leveraged to identify targeted therapies for -mutant cancer.

Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms.

Cancer-associated fibroblasts (CAFs) are highly heterogeneous. With the lack of a comprehensive understanding of CAFs' functional distinctions, it remains unclear how cancer treatments could be personalized based on CAFs in a patient's tumor. We have established a living biobank of CAFs derived from biopsies of patients' non-small lung cancer (NSCLC) that encompasses a broad molecular spectrum of CAFs in clinical NSCLC.

Hydrocephalus in a rat model of Meckel Gruber syndrome with a TMEM67 mutation.

Transmembrane protein 67 (TMEM67) is mutated in Meckel Gruber Syndrome type 3 (MKS3) resulting in a pleiotropic phenotype with hydrocephalus and renal cystic disease in both humans and rodent models. The precise pathogenic mechanisms remain undetermined. Herein it is reported for the first time that a point mutation of TMEM67 leads to a gene dose-dependent hydrocephalic phenotype in the Wistar polycystic kidney (Wpk) rat.

Landscape of Acquired Resistance to Osimertinib in -Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired Fusion.

We present a cohort of 41 patients with osimertinib resistance biopsies, including 2 with an acquired fusion. Although fusions have been identified in resistant -mutant non-small cell lung cancer (NSCLC), their role in acquired resistance to EGFR inhibitors is not well described. To assess the biological implications of fusions in an -mutant cancer, we expressed CCDC6-RET in PC9 ( del19) and MGH134 ( L858R/T790M) cells and found that CCDC6-RET was sufficient to confer resistance to EGFR tyrosine kinase inhibitors (TKI).

Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound Mutations in ALK-Positive Lung Cancer.

The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK.

Primary Patient-Derived Cancer Cells and Their Potential for Personalized Cancer Patient Care.

Personalized cancer therapy is based on a patient's tumor lineage, histopathology, expression analyses, and/or tumor DNA or RNA analysis. Here, we aim to develop an in vitro functional assay of a patient's living cancer cells that could complement these approaches. We present methods for developing cell cultures from tumor biopsies and identify the types of samples and culture conditions associated with higher efficiency of model establishment.

Effects of combination treatment with alendronate and raloxifene on skeletal properties in a beagle dog model.

A growing number of studies have investigated combination treatment as an approach to treat bone disease. The goal of this study was to investigate the combination of alendronate and raloxifene with a particular focus on mechanical properties. To achieve this goal we utilized a large animal model, the beagle dog, used previously by our laboratory to study both alendronate and raloxifene monotherapies.

Measurement of cardiovascular function using a novel view-sharing PET reconstruction method and tracer kinetic analysis.

Recent advancements in PET instrumentation have made the non-invasive assessment of cardiovascular function in small animals a reality. The majority of small animal PET systems use stationary detector gantries, thus affording high temporal resolution imaging of cardiac function. Systems designed to maximize spatial resolution and detection sensitivity employing rotating gantry designs are suboptimal when high temporal resolution imaging is needed.

Characterization of C-GSK1482160 for Targeting the P2X7 Receptor as a Biomarker for Neuroinflammation.

The purinergic receptor subtype 7 (P2X7R) represents a novel molecular target for imaging neuroinflammation via PET. GSK1482160, a potent P2X7R antagonist, has high receptor affinity, high blood-brain barrier penetration, and the ability to be radiolabeled with C. We report the initial physical and biologic characterization of this novel ligand.

Effects of renal sympathetic denervation on the stellate ganglion and brain stem in dogs.

Background: Renal sympathetic denervation (RD) is a promising method of neuromodulation for the management of cardiac arrhythmia.

Objective: We tested the hypothesis that RD is antiarrhythmic in ambulatory dogs because it reduces the stellate ganglion nerve activity (SGNA) by remodeling the stellate ganglion (SG) and brain stem.

Methods: We implanted a radiotransmitter to record SGNA and electrocardiogram in 9 ambulatory dogs for 2 weeks, followed by a second surgery for RD and 2 months SGNA recording.

Hepatic Responses of Juvenile Fundulus heteroclitus from Pollution-adapted and Nonadapted Populations Exposed to Elizabeth River Sediment Extract.

Atlantic killifish (Fundulus heteroclitus) inhabiting the Atlantic Wood Industries region of the Elizabeth River, Virginia, have passed polycyclic aromatic hydrocarbon (PAH) resistance to their offspring as evidenced by early life stage testing of developmental toxicity after exposure to specific PAHs. Our study focused on environmentally relevant PAH mixtures in the form of Elizabeth River sediment extract (ERSE). Juvenile (5 month) F1 progeny of pollution-adapted Atlantic Wood (AW) parents and of reference site (King's Creek [KC]) parents were exposed as embryos to ERSE.

Novel application of complementary imaging techniques to examine in vivo glucose metabolism in the kidney.

The metabolic status of the kidney is a determinant of injury susceptibility and a measure of progression for many disease processes; however, noninvasive modalities to assess kidney metabolism are lacking. In this study, we employed positron emission tomography (PET) and intravital multiphoton microscopy (MPM) to assess cortical and proximal tubule glucose tracer uptake, respectively, following experimental perturbations of kidney metabolism. Applying dynamic image acquisition PET with 2-fluoro-2-deoxyglucose (F-FDG) and tracer kinetic modeling, we found that an intracellular compartment in the cortex of the kidney could be distinguished from the blood and urine compartments in animals.

Evaluation of 11C-acetate and 18F-FDG PET/CT in mouse multidrug resistance gene-2 deficient mouse model of hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) remains a global health problem with unique diagnostic and therapeutic challenges, including difficulties in identifying the highest risk patients. Previous work from our lab has established the murine multidrug resistance-2 mouse (MDR2) model of HCC as a reasonable preclinical model that parallels the changes seen in human inflammatory associated HCC. The purpose of this study is to evaluate modalities of PET/CT in MDR2(-/-) mice in order to facilitate therapeutic translational studies from bench to bedside.

In Vivo UTE-MRI Reveals Positive Effects of Raloxifene on Skeletal-Bound Water in Skeletally Mature Beagle Dogs.

Raloxifene positively affects mechanical properties of the bone matrix in part through modification of skeletal-bound water. The goal of this study was to determine if raloxifene-induced alterations in skeletal hydration could be measured in vivo using ultra-short echotime magnetic resonance imaging (UTE-MRI). Twelve skeletally mature female beagle dogs (n = 6/group) were treated for 6 months with oral doses of saline vehicle (VEH, 1 mL/kg/d) or raloxifene (RAL, 0.

Longitudinal Bioluminescence Imaging of Primary Versus Abdominal Metastatic Tumor Growth in Orthotopic Pancreatic Tumor Models in NSG Mice.

Objectives: The purpose of the present study was to develop and validate noninvasive bioluminescence imaging methods for differentially monitoring primary and abdominal metastatic tumor growth in mouse orthotopic models of pancreatic cancer.

Methods: A semiautomated maximum entropy segmentation method was implemented for the primary tumor region of interest, and a rule-based method for manually drawing a region of interest for the abdominal metastatic region was developed for monitoring tumor growth in orthotopic models of pancreatic cancer. The 2 region-of-interest methods were validated by having 2 observers independently segment Panc-1 tumors, and the results were compared with the number of mesenteric lymph node nodules and histopathologic assessment of liver metastases.

The HMGB1-RAGE axis mediates traumatic brain injury-induced pulmonary dysfunction in lung transplantation.

Traumatic brain injury (TBI) results in systemic inflammatory responses that affect the lung. This is especially critical in the setting of lung transplantation, where more than half of donor allografts are obtained postmortem from individuals with TBI. The mechanism by which TBI causes pulmonary dysfunction remains unclear but may involve the interaction of high-mobility group box-1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE).

Multimodality imaging methods for assessing retinoblastoma orthotopic xenograft growth and development.

Genomic studies of the pediatric ocular tumor retinoblastoma are paving the way for development of targeted therapies. Robust model systems such as orthotopic xenografts are necessary for testing such therapeutics. One system involves bioluminescence imaging of luciferase-expressing human retinoblastoma cells injected into the vitreous of newborn rat eyes.

Beacon communities' public health initiatives: a case study analysis.

Introduction: The Beacon Communities for Public Health (BCPH) project was launched in 2011 to gain a better understanding of the range of activities currently being conducted in population- and public health by the Beacon Communities. The project highlighted the successes and challenges of these efforts with the aim of sharing this information broadly among the public health community.

Background: The Beacon Community Program, designed to showcase technology-enabled, community-based initiatives to improve outcomes, focused on: building and strengthening health information technology (IT) infrastructure and exchange capabilities; translating investments in health IT to measureable improvements in cost, quality, and population health; and, developing innovative approaches to performance measurement, technology, and care delivery.

The NIDDK Central Repository at 8 years--ambition, revision, use and impact.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository makes data and biospecimens from NIDDK-funded research available to the broader scientific community. It thereby facilitates: the testing of new hypotheses without new data or biospecimen collection; pooling data across several studies to increase statistical power; and informative genetic analyses using the Repository's well-curated phenotypic data. This article describes the initial database plan for the Repository and its revision using a simpler model.