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Introduction: Iloprost, a prostacyclin analog, has lung cancerpreventive activity in preclinical models and improved dysplasia in former smokers in a phase IIb trial. Oral iloprost is currently unavailable. We performed a phase Ib trial of inhaled iloprost in former smokers to assess tolerance and compliance. Methods: Participants self-administered nebulized iloprost (5ug) or placebo four (QID) or two (BID) times daily. As QID dosewas well tolerated and due to expiration of the placebo, the BID dosing and placebo were eliminated early on in the trial. Bronchoscopy with biopsyat six standard sites was performed at treatment initiation and two months post-iloprost, with exploratory histological analysis. Bulk RNA sequencing, single cell RNA sequencing and an in vitro assay of epithelial progenitor cell iloprost response were performed on a subset of biopsies in an exploratory investigation of response mechanisms and predictive biomarkers. Results and discussion: Thirty-four of a planned 48 participants were recruited to the trial. Inhaled iloprost was well tolerated with no adverse events > grade 2. Compliance was 67% in the QID group. The trial was not powered to detect histologic response and none was found. Bulk RNA sequencing of biopsies pre/post iloprost suggest that iloprost is immunomodulatory and downregulates cell proliferation pathways. Single cell RNA sequencing showed an increase in CD8-positive T cells with upregulation of genes in interferon g signaling. In vitro iloprost response by epithelial progenitor cells correlated with histologic response with kappa coefficient of 0.81 (95% CI 0.47, 1.0). Inhaled iloprost was well tolerated with suboptimal compliance. Molecular analysis suggested that iloprosthas immunomodulatory and antiproliferative effects. The progenitor cell iloprost response assay may be a promising avenue to develop predictive biomarkers. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa is an opportunistic human pathogen responsible for acute and chronic, hard to treat infections. Persistence of P. aeruginosa is due to its ability to develop into biofilms, which are sessile bacterial communities adhered to substratum and encapsulated in layers of self-produced exopolysaccharides. These biofilms provide enhanced protection from the host immune system and resilience towards antibiotics, which poses a challenge for treatment. Various strategies have been expended for combating biofilms, which involve inhibiting biofilm formation or promoting their dispersal. The current remediation approaches offer some hope for clinical usage, however, treatment and eradication of preformed biofilms is still a challenge. Thus, identifying novel targets and understanding the detailed mechanism of biofilm regulation becomes imperative. Structure-based drug discovery (SBDD) provides a powerful tool that exploits the knowledge of atomic resolution details of the targets to search for high affinity ligands. This review describes the available structural information on the putative target protein structures that can be utilized for high throughput in silico drug discovery against P. aeruginosa biofilms. Integrating available structural information on the target proteins in readily accessible format will accelerate the process of drug discovery. [ABSTRACT FROM AUTHOR]

The elevation of carbon dioxide (CO2) levels in the atmosphere is responsible for global warming which in turn causes abrupt climate change and consequently poses a threat to living organisms in the coming years. To reduce CO2 content in the atmosphere CO2 capture and separation is highly necessary. Among various methods of CO2 capture post-combustion capture is very much useful because of its operational simplicity and applicability in many industries and power sectors, such as coal-fired power plants. Polymers with high surface area, high volume and narrow pores are ideal solid sorbents for adsorption-driven post-combustion CO2 capture. Natural polymers, such as polysaccharides are cheap, abundant, and can be modified by various methods to produce porous materials and thus can be effectively utilized for CO2 capture while the surface area and the pore size of synthetic porous organic polymers can be tuned precisely for high CO2 capturing capacity. A significant amount of research activities has already been established in this field, especially in the last ten years and are still in progress. In this review, we have introduced the latest developments to the readers about synthetic techniques, post-synthetic modifications and CO2 capture capacities of various biopolymer-based materials and synthetic porous organic polymers (POPs) published in the last five years (2018–2022). This review will be beneficial to the researchers to design smart polymer-based materials to overcome the existing challenges in carbon capture and storage/sequestration. [ABSTRACT FROM AUTHOR]

Aim: To investigate the potential of an ultrashort aromatic peptide hydrogelator integrated with hyaluronic acid (HA) to serve as a scaffold for bone regeneration. Materials and Methods: Fluorenylmethyloxycarbonyl‐diphenylalanine (FmocFF)/HA hydrogel was prepared and characterized using microscopy and rheology. Osteogenic differentiation of MC3T3‐E1 preosteoblasts was investigated using Alizarin red, alkaline phosphatase and calcium deposition assays. In vivo, 5‐mm‐diameter calvarial critical‐sized defects were prepared in 20 Sprague–Dawley rats and filled with either FmocFF/HA hydrogel, deproteinized bovine bone mineral, FmocFF/Alginate hydrogel or left unfilled. Eight weeks after implantation, histology and micro‐computed tomography analyses were performed. Immunohistochemistry was performed in six rats to assess the hydrogel's immunomodulatory effect. Results: A nanofibrous FmocFF/HA hydrogel with a high storage modulus of 46 KPa was prepared. It supported osteogenic differentiation of MC3T3‐E1 preosteoblasts and facilitated calcium deposition. In vivo, the hydrogel implantation resulted in approximately 93% bone restoration. It induced bone deposition not only around the margins, but also generated bony islets along the defect. Elongated M2 macrophages lining at the periosteum–hydrogel interface were observed 1 week after implantation. After 3 weeks, these macrophages were dispersed through the regenerating tissue surrounding the newly formed bone. Conclusions: FmocFF/HA hydrogel can serve as a cell‐free, biomimetic, immunomodulatory scaffold for bone regeneration. [ABSTRACT FROM AUTHOR]

The article focuses on field cancerization in lung adenocarcinoma (ADC) and the early changes associated with or permissive of cancer development in the peripheral lung. Topics discussed include reduced progenitor cell function, altered immune responses, and the accumulation of cancer-associated mutations in the contralateral lungs of individuals with early-stage ADC identified through screening chest CT.

The N‐nitroso‐trischloroethylurea (NTCU)‐induced mouse model of squamous lung carcinoma recapitulates human disease from premalignant dysplasia through invasive tumors, making it suitable for preclinical chemoprevention drug testing. Pioglitazone is a peroxisome proliferator‐activated receptor γ (PPARγ) agonist shown to prevent lung tumors in preclinical models. We investigated pioglitazone's effect on lesion development and markers of potential preventive mechanisms in the NTCU model. Female FVB/N mice were exposed to vehicle, NTCU or NTCU + oral pioglitazone for 32 weeks. NTCU induces the appearance of basal cells in murine airways while decreasing/changing their epithelial cell makeup, resulting in development of bronchial dysplasia. H&E and keratin 5 (KRT5) staining were used to detect and grade squamous lesions in formalin fixed lungs. mRNA expression of epithelial to mesenchymal transition (EMT) markers and basal cell markers were measured by qPCR. Dysplasia persistence markers desmoglein 3 and polo like kinase 1 were measured by immunohistochemistry. Basal cell markers KRT14 and p63, club cell specific protein and ciliated cell marker acetylated tubulin were measured by immunofluorescence. Pioglitazone treatment significantly reduced squamous lesions and the presence of airway basal cells, along with increasing normal epithelial cells in the airways of NTCU‐exposed mice. Pioglitazone also significantly influenced EMT gene expression to promote a more epithelial, and less mesenchymal, phenotype. Pioglitazone reduced the presence of squamous dysplasia and maintained normal airway cell composition. This work increases the knowledge of mechanistic pathways in PPARγ agonism for lung cancer interception and provides a basis for further investigation to advance this chemoprevention strategy. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is caused by mutated CF transmembrane conductance regulator (CFTR) and is characterized by robust airway inflammation and accumulation of apoptotic cells. Phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, because it prevents postapoptotic necrosis and actively suppresses release of a variety of proinflammatory mediators, including IL-8. Because CF is associated with accumulation of apoptotic cells, inappropriate levels of IL-8, and robust inflammation, we sought to determine whether CFTR deficiency specifically impairs efferocytosis and its regulation of inflammatory mediator release. Here we show that CFTR deficiency directly interferes with efferocytosis by airway epithelium, an effect that is not due to altered binding of apoptotic cells to epithelial cells or altered expression of efferocytosis receptors. In contrast, expression of RhoA, a known negative regulator of efferocytosis, is substantially increased in CFTR-deficient cells, and inhibitors of RhoA or its downstream effector Rho kinase normalize efferocytosis in these cells. Impaired efferocytosis appears to be mediated through an amiloride-sensitive ion channel, because amiloride restores phagocytic competency in CFTR-deficient cells. Finally, ineffective efferocytosis in CFTR-deficient cells appears to have proinflammatory consequences, because apoptotic cells enhance IL-8 release by these cells, but not by wild-type controls. Therefore, in CF, dysregulated efferocytosis may lead to accumulation of apoptotic cells and impaired regulation of the inflammatory response and, ultimately, may suggest a new therapeutic target. efferocytosis; Rho GTPase; inflammation; epithelial cells doi: 10.1152/ajplung.00030.2009

The article presents a study which examined the effectiveness of art therapy and artistic engagement in addressing the anxiety and stress of COVID-19 patients and their treatment teams in Kolkata, India. Among the various art and performance activities during the study are drawing, poetry, music, and theatre. Also mentioned are the factors leading to stress and anxiety like fear of death and isolation, and the effectiveness of art as a tool to improve relisience of patients and their carers.