The Minnesota Critical Care Working Group 1: Monitoring and Coordinating Statewide Critical Care Surge Response in the COVID-19 Pandemic, March 2020 Through July 1, 2021.

Background: In response to the COVID-19 pandemic and as part of the statewide health care coalition response, the Minnesota Critical Care Working Group (CCWG), composed of interprofessional leaders from the state's nine largest health systems, was established and entrusted to plan and coordinate critical care support for Minnesota from March 2020 through July 1, 2021.

Research Question: Can a statewide CCWG develop contingency and crisis-level surge strategies and indicators in response to the COVID-19 pandemic while evolving into a highly collaborative team?

Study Design And Methods: CCWG members (intensivists, ethicists, nurses, Minnesota Department of Health and Minnesota Hospital Association leaders) met by audio video conferencing as often as daily assessing COVID-19 and non-COVID-19 hospitalization data, developed surge indicators reflecting contingency vs crisis conditions, and planned responses collaboratively. A foundation of collaboration and teamwork developed which facilitated an effective statewide response.

The Minnesota Critical Care Working Group 2: Crisis Conditions During the COVID-19 Pandemic, July 2021 through March 2022.

Background: The Minnesota Statewide Healthcare Coordination Center requested that the Minnesota Critical Care Working Group (CCWG) and Ethics Working Group (EWG), comprising interprofessional leaders from Minnesota's 9 largest health systems, plan and coordinate critical care operations during the COVID-19 pandemic, including the fall 2021 surge.

Research Question: Can a statewide working group collaboratively analyze real-time evidence to identify crisis conditions and to engage state leadership to implement care processes?

Study Design And Methods: The CCWG and EWG met via videoconferencing during the severe surge of fall 2021 to analyze evidence and plan for potential crisis care conditions. Five sources of evidence informed their actions: group consensus on operating conditions, federal teletracking data, the Medical Operations Coordination Center (MOCC) patient placement data, and 2 surveys created and distributed to hospitals and health care professionals.

Glioma-neuronal circuit remodeling induces regional immunosuppression.

Neuronal activity-driven mechanisms impact glioblastoma cell proliferation and invasion , and glioblastoma remodels neuronal circuits . Distinct intratumoral regions maintain functional connectivity via a subpopulation of malignant cells that mediate tumor-intrinsic neuronal connectivity and synaptogenesis through their transcriptional programs . However, the effects of tumor-intrinsic neuronal activity on other cells, such as immune cells, remain unknown.

Genetically Engineered Extracellular Vesicles Harboring Transmembrane Scaffolds Exhibit Differences in Their Size, Expression Levels of Specific Surface Markers and Cell-Uptake.

Background: Human cell-secreted extracellular vesicles (EVs) are versatile nanomaterials suitable for disease-targeted drug delivery and therapy. Native EVs, however, usually do not interact specifically with target cells or harbor therapeutic drugs, which limits their potential for clinical applications. These functions can be introduced to EVs by genetic manipulation of membrane protein scaffolds, although the efficiency of these manipulations and the impacts they have on the properties of EVs are for the most part unknown.

Inhibition of D-2HG leads to upregulation of a proinflammatory gene signature in a novel HLA-A2/HLA-DR1 transgenic mouse model of IDH1R132H-expressing glioma.

Background: Long-term prognosis of WHO grade II, isocitrate dehydrogenase (IDH)-mutated low-grade glioma (LGG) is poor due to high risks of recurrence and malignant transformation into high-grade glioma. Immunotherapy strategies are attractive given the relatively intact immune system of patients with LGG and the slow tumor growth rate. However, accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) in IDH-mutated gliomas leads to suppression of inflammatory pathways in the tumor microenvironment, thereby contributing to the 'cold' tumor phenotype.

Novel EGFRvIII-CAR transgenic mice for rigorous preclinical studies in syngeneic mice.

Background: Rigorous preclinical studies of chimeric antigen receptor (CAR) immunotherapy will require large quantities of consistent and high-quality CAR-transduced T (CART) cells that can be used in syngeneic mouse glioblastoma (GBM) models. To this end, we developed a novel transgenic (Tg) mouse strain with a fully murinized CAR targeting epidermal growth factor receptor variant III (EGFRvIII).

Methods: We first established the murinized version of EGFRvIII-CAR and validated its function using a retroviral vector (RV) in C57BL/6J mice bearing syngeneic SB28 GBM expressing EGFRvIII.

Genetic labeling of extracellular vesicles for studying biogenesis and uptake in living mammalian cells.

Molecular imaging methods are powerful tools for gaining insight into the cellular organization of living cells. To understand the biogenesis and uptake of extracellular vesicles (EVs) as well as to engineer cell-derived vesicles for targeted drug delivery and therapy, genetic labeling with fluorescent proteins has increasingly been used to determine the structures, locations, and dynamics of EVs in vitro and in vivo. Here, we report a genetic method for the stable labeling of EVs to study their biogenesis and uptake in living human cells.

Fibrotic myofibroblasts manifest genome-wide derangements of translational control.

Background: As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast-the primary effector of the fibroproliferative response.

Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive lung disease in which fibroblasts accumulate in the alveolar wall within a type I collagen-rich matrix. Although lung fibroblasts derived from patients with IPF display durable pathological alterations in proliferative function, the molecular mechanisms differentiating IPF fibroblasts from their normal counterparts remain unknown. Polymerized type I collagen normally inhibits fibroblast proliferation, providing a physiological mechanism to limit fibroproliferation after tissue injury.

PTEN regulates fibroblast elimination during collagen matrix contraction.

During tissue repair, excess fibroblasts are eliminated by apoptosis. This physiologic process limits fibrosis and restores normal anatomic patterns. Replicating physiologic apoptosis associated with tissue repair, fibroblasts incorporated into type I collagen matrices undergo apoptosis in response to collagen matrix contraction.

Role of integrin-linked kinase in regulating phosphorylation of Akt and fibroblast survival in type I collagen matrices through a beta1 integrin viability signaling pathway.

A beta1 integrin phosphatidylinositol 3-kinase/Akt pathway regulates fibroblast survival in collagen matrices. When fibroblasts attach to collagen, Akt becomes phosphorylated, providing a survival signal. In contrast, in response to mechanical forces generated during collagen contraction, Akt is dephosphorylated and fibroblasts undergo apoptosis.