Building Career Paths for Ph.D., Basic and Translational Scientists in Clinical Departments in the United States: An Official American Thoracic Society Workshop Report.

To identify barriers and opportunities for Ph.D., basic and translational scientists to be fully integrated into clinical units.

Development and Optimization of Bifunctional Fusion Proteins to Locally Modulate Complement Activation in Diseased Tissue.

Sustained complement activation is an underlying pathologic driver in many inflammatory and autoimmune diseases. Currently approved anti-complement therapies are directed at the systemic blockade of complement. Consequently, these therapies provide widespread inhibition of complement pathway activity, beyond the site of ongoing activation and the intended pharmacodynamic (PD) effects.

A Phase IIb Randomized Clinical Study of an Anti-αβ Monoclonal Antibody in Idiopathic Pulmonary Fibrosis.

Treatment options for idiopathic pulmonary fibrosis (IPF) are limited. To evaluate the efficacy and safety of BG00011, an anti-αβ IgG1 monoclonal antibody, in the treatment of patients with IPF. In a phase IIb randomized, double-blind, placebo-controlled trial, patients with IPF (FVC ⩾50% predicted, on or off background therapy) were randomized 1:1 to once-weekly subcutaneous BG00011 56 mg or placebo.

Study protocol of a randomized controlled trial comparing two linkage models for HIV prevention and treatment in justice-involved persons.

Background: Persons involved in the justice system are at high risk for HIV and drug overdose upon release to the community. This manuscript describes a randomized controlled trial of two evidence-based linkage interventions for provision of HIV prevention and treatment and substance use disorder (SUD) services in four high risk communities to assess which is more effective at addressing these needs upon reentry to the community from the justice system.

Methods: This is a 5-year hybrid type 1 effectiveness-implementation randomized controlled trial that compares two models (Patient Navigation [PN] or Mobile Health Unit [MHU] service delivery) of linking justice-involved individuals to the continuum of community-based HIV and SUD prevention and treatment service cascades of care.

Long-acting buprenorphine vs. naltrexone opioid treatments in CJS-involved adults (EXIT-CJS).

The EXIT-CJS (N = 1005) multisite open-label randomized controlled trial will compare retention and effectiveness of extended-release buprenorphine (XR-B) vs. extended-release naltrexone (XR-NTX) to treat opioid use disorder (OUD) among criminal justice system (CJS)-involved adults in six U.S.

Earthquakes and extreme rainfall induce long term permeability enhancement of volcanic island hydrogeological systems.

Earthquakes affect near-surface permeability, however temporal permeability evolution quantification is challenging due to the scarcity of observations data. Using thirteen years of groundwater level observations, we highlight clear permeability variations induced by earthquakes in an aquifer and overlaying aquitard. Dynamic stresses, above a threshold value PGV > 0.

The αvβ6 integrin in cancer cell-derived small extracellular vesicles enhances angiogenesis.

Prostate cancer (PrCa) cells crosstalk with the tumour microenvironment by releasing small extracellular vesicles (sEVs). sEVs, as well as large extracellular vesicles (LEVs), isolated via iodixanol density gradients from PrCa cell culture media, express the epithelial-specific αvβ6 integrin, which is known to be induced in cancer. In this study, we show sEV-mediated protein transfer of αvβ6 integrin to microvascular endothelial cells (human microvascular endothelial cells 1 - HMEC1) and demonstrate that αvβ6 integrin expression is not caused by increased mRNA levels.

Thermal and seismic hints for chimney type cross-stratal fluid flow in onshore basins.

When modelling onshore sedimentary basins, modellers generally assume that semi-permeable layers (aquitards) greatly restrict vertical flow between aquifers. Aquitards are therefore considered as confining media and vertical flow is assumed to take place mainly within localised permeable faults, if any. In the offshore context, however, interpretation of seismic data frequently provides evidence of fluid flow between sedimentary layers via structurally disrupted formations (pervasive fractures) recognised as zones of reduced seismic amplitude and generically called "chimneys".

BAL Cell Gene Expression Is Indicative of Outcome and Airway Basal Cell Involvement in Idiopathic Pulmonary Fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal disease with a variable and unpredictable course.

Objectives: To determine whether BAL cell gene expression is predictive of survival in IPF.

Methods: This retrospective study analyzed the BAL transcriptome of three independent IPF cohorts: Freiburg (Germany), Siena (Italy), and Leuven (Belgium) including 212 patients.

Inhibition of integrin αβ changes fibril thickness of stromal collagen in experimental carcinomas.

Background: Chemotherapeutic efficacy can be improved by targeting the structure and function of the extracellular matrix (ECM) in the carcinomal stroma. This can be accomplished by e.g.

Uncoupling of the profibrotic and hemostatic effects of thrombin in lung fibrosis.

Fibrotic lung disease, most notably idiopathic pulmonary fibrosis (IPF), is thought to result from aberrant wound-healing responses to repetitive lung injury. Increased vascular permeability is a cardinal response to tissue injury, but whether it is mechanistically linked to lung fibrosis is unknown. We previously described a model in which exaggeration of vascular leak after lung injury shifts the outcome of wound-healing responses from normal repair to pathological fibrosis.

Targeting of Aberrant αvβ6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells.

Expression of the αvβ6 integrin is upregulated in several solid tumors. In contrast, physiologic expression of this epithelial-specific integrin is restricted to development and epithelial re-modeling. Here, we describe, for the first time, the development of a chimeric antigen receptor (CAR) that couples the recognition of this integrin to the delivery of potent therapeutic activity in a diverse repertoire of solid tumor models.

Fibronectin-guided migration of carcinoma collectives.

Functional interplay between tumour cells and their neoplastic extracellular matrix plays a decisive role in malignant progression of carcinomas. Here we provide a comprehensive data set of the human HNSCC-associated fibroblast matrisome. Although much attention has been paid to the deposit of collagen, we identify oncofetal fibronectin (FN) as a major and obligate component of the matrix assembled by stromal fibroblasts from head and neck squamous cell carcinomas (HNSCC).

Inhibition of v5 Integrin Attenuates Vascular Permeability and Protects against Renal Ischemia-Reperfusion Injury.

Ischemia-reperfusion injury (IRI) is a leading cause of AKI. This common clinical complication lacks effective therapies and can lead to the development of CKD. The v5 integrin may have an important role in acute injury, including septic shock and acute lung injury.

Amplification of TGFβ Induced ITGB6 Gene Transcription May Promote Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating, progressive disease with poor survival rates and limited treatment options. Upregulation of αvβ6 integrins within the alveolar epithelial cells is a characteristic feature of IPF and correlates with poor patient survival. The pro-fibrotic cytokine TGFβ1 can upregulate αvβ6 integrin expression but the molecular mechanisms driving this effect have not previously been elucidated.

αvβ6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor.

Androgen receptor signaling fuels prostate cancer and is a major therapeutic target. However, mechanisms of resistance to therapeutic androgen ablation are not well understood. Here, using a prostate cancer mouse model, Pten(pc-/-), carrying a prostate epithelial-specific Pten deletion, we show that the αvβ6 integrin is required for tumor growth in vivo of castrated as well as of noncastrated mice.

High expression of integrin β6 in association with the Rho-Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers.

Integrin αvβ6 is involved in the transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast. In addition, integrin β6 (ITGB6) is of prognostic value in invasive breast cancers, particularly in HER2+ subtype. However, pathways mediating the activity of integrin αvβ6 in clinical progression of invasive breast cancers need further elucidation.

Reduced Ets Domain-containing Protein Elk1 Promotes Pulmonary Fibrosis via Increased Integrin αvβ6 Expression.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with high mortality. Active TGFβ1 is considered central to the pathogenesis of IPF. A major mechanism of TGFβ1 activation in the lung involves the epithelially restricted αvβ6 integrin.

Integrin αvβ6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis.

Unlabelled: Integrin αvβ6 is rapidly up-regulated on cells of epithelial lineage during tissue injury, where one of its primary functions is activation of latent transforming growth factor beta 1 (TGFβ1). In human liver cirrhosis, αvβ6 is overexpressed by cells comprising the ductular reaction, and its inhibition suppresses experimental biliary fibrosis in rodents. Here, we show that αvβ6 is expressed on the actively proliferating subset of hepatic progenitor cells and is required for their progenitor function in vivo and in vitro through integrin αvβ6-dependent TGFβ1 activation.

αvβ6 integrin may be a potential prognostic biomarker in interstitial lung disease.

Idiopathic pulmonary fibrosis (IPF) and fibrotic nonspecific interstitial pneumonitis are progressive interstitial lung diseases (ILDs) with limited treatment options and poor survival. However, the rate of disease progression is variable, implying there may be different endotypes of disease. We hypothesised that immunophenotyping biopsies from ILD patients might reveal distinct endotypes of progressive fibrotic disease, which may facilitate stratification when undertaking clinical trials of novel therapies for IPF.