High airway bacterial loads in non-CF bronchiectasis are associated with airway and systemic inflammation and a greater risk of exacerbations. Short- and long-term antibiotic therapy reduce markers of airways and systemic inflammation.

SummaryThe integrin family of heterodimeric cell-surface receptors are fundamental in cell-cell and cell-matrix adhesion. Changes to either integrin-ligand affinity or integrin gene expression are central to a variety of disease processes, including inflammation, cardiovascular disease and cancer. In screening for novel activators of integrin-ligand affinity we identified the previously uncharacterised multitransmembrane domain protein Fam38A, located at the endoplasmic reticulum (ER). siRNA knockdown of Fam38A in epithelial cells inactivates endogenous b1 integrin, reducing cell adhesion. Fam38A mediates integrin activation by recruiting the small GTPase RRas to the ER, which activates the calcium-activated protease calpain by increasing Ca 2+ release from cytoplasmic stores. Fam38A-induced integrin activation is blocked by inhibition of either R-Ras or calpain activity, or by siRNA knockdown of talin, a welldescribed calpain substrate. This highlights a novel mechanism for integrin activation by Fam38A, utilising calpain and R-Ras signalling from the ER. These data represent the first description of a novel spatial regulator of R-Ras, of an alternative integrin activationsuppression pathway based on direct relocalisation of R-Ras to the ER, and of a mechanism linking R-Ras and calpain signalling from the ER with modulation of integrin-ligand affinity.

Respiratory syncytial virus is a leading cause of lower respiratory tract illness among infants, the elderly and immunocompromised individuals. Currently, there is no effective vaccine or disease modifying treatment available and novel interventions are urgently required. Cathelicidins are cationic host defence peptides expressed in the inflamed lung, with key roles in innate host defence against infection. We demonstrate that the human cathelicidin LL-37 has effective antiviral activity against RSV in vitro, retained by a truncated central peptide fragment. LL-37 prevented virus-induced cell death in epithelial cultures, significantly inhibited the production of new infectious particles and diminished the spread of infection, with antiviral effects directed both against the viral particles and the epithelial cells. LL-37 may represent an important targetable component of innate host defence against RSV infection. Prophylactic modulation of LL-37 expression and/or use of synthetic analogues post-infection may represent future novel strategies against RSV infection.

Lung cancer is one of the most common fatal diseases in the developed world. The disease is rarely cured by currently available therapies, with an overall survival rate of ∼10%. Characterizing novel proteins that offer crucial insights into the processes of lung tumour invasion and metastasis may therefore provide much-needed prognostic markers, and influence therapeutic strategies. Aberrant function of the integrin family of heterodimeric cell surface receptors is a common theme in cancer - investigation into novel integrin activity regulators may offer crucial insights into the processes of tumour invasion and metastasis and may reveal insights into potential therapeutic targets. We previously described that depletion of the novel multi-transmembrane domain protein Fam38A, located at the endoplasmic reticulum (ER), inactivates endogenous beta1 integrin affinity, reducing cell adhesion. We now show that depletion of Fam38A, also now known as Piezo1, causes anchorage independence and a switch to a reduced integrin-dependent mode of cell migration/invasion, a novel phenotype for this integrin-regulating protein. Normal lung epithelial cells show increased rates of migration by 2D time-lapse microscopy and increased capacity to invade into matrigel, despite having decreased integrin affinity. We confirm greatly depleted Fam38A expression in small cell lung cancer (SCLC) lines where a form of reduced integrin-dependent migration, i.e. amoeboid migration, is a known phenotype. We propose that loss of Fam38A expression may cause increased cell migration and metastasis in lung tumours.

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BACKGROUND AND PURPOSE:Stereotactic radiosurgery is known to control 85%-95% of intracranial metastatic lesions during a median survival of 6 -8 months. However, with the advent of newer systemic cancer therapies, survival is improving; this change mandates a longitudinal quantitative analysis of the radiographic response of brain metastases to radiosurgery.

A combination therapy approach is required to improve tumor immune infiltration and patient response to immune checkpoint inhibitors that target negative regulatory receptors. Galectin-3 is a b-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and whose expression correlates with poor survival particularly in patients with non-small cell lung cancer (NSCLC). To examine the role of galectin-3 inhibition in NSCLC, we tested the effects of galectin-3 depletion using genetic and pharmacologic approaches on syngeneic mouse lung adenocarcinoma and human lung adenocarcinoma xenografts. Galectin-3 À/À mice developed significantly smaller and fewer tumors and metastases than syngeneic C57/ Bl6 wild-type mice. Macrophage ablation retarded tumor growth, whereas reconstitution with galectin-3-positive bone marrow restored tumor growth in galectin-3 À/À mice, indicating that macrophages were a major driver of the antitumor response. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduced human and mouse lung adenocarcinoma growth and blocked metastasis in the syngeneic model. Treatment with GB1107 increased tumor M1 macrophage polarization and CD8 þ T-cell infiltration. Moreover, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFNg, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules. In summary, galectin-3 is an important regulator of lung adenocarcinoma progression. The novel galectin-3 inhibitor presented could provide an effective, nontoxic monotherapy or be used in combination with immune checkpoint inhibitors to boost immune infiltration and responses in lung adenocarcinoma and potentially other aggressive cancers. Significance: A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasis and augments response to PD-L1 blockade.

The diverse biological processes intrinsic to the development of multicellular organisms are coordinated by communication between adjacent cells involving a small number of evolutionarily conserved signaling pathways. The Notch signaling pathway is an important mechanism for mediating these intercellular signaling events to direct cell fate decisions (1). The components of the Notch pathway have been identified in a broad range of metazoans and have been extensively studied in insects, nematodes, and mammals (2-4). Consequently, Notch has been shown to be a key regulator of many developmental processes including somitogenesis, vasculogenesis, and neurogenesis (4 -6). In addition, the Notch pathway plays a critical role in mammalian immune development and carcinogenesis (7,8).The molecular components of the Notch pathway have been extensively studied and are highly conserved between species. NOTCH encodes a single-pass heterodimeric transmembrane receptor with an extracellular domain that contains epidermal growth factor-like repeats (9). Four NOTCH homologs (NOTCH-1-4) and two groups of ligands (Delta-like (Dll-1, -3, and -4) and Serrate-like (Jagged 1 and 2)) have been identified in mammals (10, 11). Notch-ligand interaction triggers two distinct proteolytic cleavage events (S2 and S3) that release the intracellular portion of Notch (NIC) 4 from the plasma membrane (12)(13)(14). NIC translocates to the nucleus where it binds to a transcriptional regulator CSL (CBF-1/Su(H)/LAG-1), displacing co-repressors and recruiting co-activators, thus inducing expression of Hairy-Enhancer of Split (HES) and HES-related proteins genes (15-18). Data from several groups suggest that Notch may also signal without cleavage at S3 or CSL-dependent transcription (19 -21). The molecular components of this "non-classical" Notch signaling pathway are not yet fully understood.Recent genetic studies have indicated important parallels between the developmental processes controlled by Notch and integrin-mediated adhesion. Integrins are heterodimeric transmembrane glycoproteins that mediate cell-cell and cell-matrix interactions and have been identified in insects, nematodes, and vertebrates (22). A key feature of integrins is their ability to modulate ligand binding affinity in response to intracellular signals, a process called activation (23). They are essential for embryogenesis and are involved in neurogenesis, myogenesis, and angiogenesis, processes also controlled by Notch (24 -26). ␣6␤1 and ␣5␤1 integrins are highly expressed on stem cells and regulate survival, migration, and differentiation (27,28). Notch has been shown to associate with ␤1 integrins in neural stem cells and expression of NOTCH 4 in endothelial cells increases adhesion to collagen (29,30