Circulating tumor cells (CTCs) are tumor cells that shed from the primary tumor and intravasate into the peripheral blood circulation system responsible for metastasis. Sensitive detection of CTCs from clinical samples can serve as an effective tool in cancer diagnosis and prognosis through liquid biopsy. Current CTC detection technologies mainly reply on the biomarker-mediated platforms including magnetic beads, microfluidic chips or size-sensitive microfiltration which can compromise detection sensitivity due to tumor heterogeneity. A more sensitive, biomarker independent CTCs isolation technique has been recently developed with the surface-charged superparamagnetic nanoprobe capable of different EMT subpopulation CTC capture from 1 mL clinical blood. In this review, this new strategy is compared with the conventional techniques on biomarker specificity, impact of protein corona, effect of glycolysis on cell surface charge, and accurate CTC identification. Correlations between CTC enumeration and molecular profiling in clinical blood and cancer prognosis are provided for clinical cancer management.

Pulmonary fibrosis results from dysregulated lung repair and involves multiple cell types. The role of endothelial cells (EC) in lung fibrosis is poorly understood. Using single cell RNA-sequencing we identified endothelial transcription factors involved in lung fibrogenesis, including FOXF1, SMAD6, ETV6 and LEF1. Focusing on FOXF1, we found that FOXF1 is decreased in EC within human idiopathic pulmonary fibrosis (IPF) and mouse bleomycin-injured lungs. Endothelial-specific Foxf1 inhibition in mice increased collagen depositions, promoted lung inflammation, and impaired R-Ras signaling. In vitro, FOXF1-deficient EC increased proliferation, invasion and activation of human lung fibroblasts, and stimulated macrophage migration by secreting IL-6, TNFα, CCL2 and CXCL1. FOXF1 inhibited TNFα and CCL2 through direct transcriptional activation of Rras gene promoter. Transgenic overexpression or endothelial-specific nanoparticle delivery of Foxf1 cDNA decreased pulmonary fibrosis in bleomycin-injured mice. Nanoparticle delivery of FOXF1 cDNA can be considered for future therapies in IPF.

The main clinical characteristics of COVID‐19 are respiratory symptoms that can lead to serious cardiovascular damages and severe worsening of other medical conditions. One of the major strategies in preparedness and response to COVID 19 is effective utilization of personal protective equipment (PPE) among which the masks of different kinds are on the top of the list especially for activities in the public places. However, the underlying mechanisms of masks in preventing virus transmission have not been well identified and the current experimental data still show inconsistent outcomes that may mislead the public. For instance, the early understanding of the mask functions was limited especially in the escalating phase of the COVID 19 pandemic, resulting in quite controversial remarks on masks. Although extensive studies in mask functions have been carried out ever since the COVID‐19 outbreaks, most of the investigations appear to have focused on exhalation isolation of individuals who may have been infected with the disease. Less emphasis was laid on inhalation protection from virus transmission, an important aspect that undergirds the public health policies and protective strategies. This review provides the most up‐to‐date information on the transmission modes of COVID‐19 virus in terms of droplets and aerosols. The roles of masks in disease prevention and transmission reduction are evaluated on various types, structures and functions. More important, both aspects of exhalation isolation and inhalation protection are discussed based on virus transmission modes and the effectiveness of different types of masks under varied environmental conditions.

Pulmonary endothelial progenitor cells (EPCs) are critical for neonatal lung angiogenesis and represent a subset of general capillary cells (gCAPs). Molecular mechanisms through which EPCs stimulate lung angiogenesis are unknown. Herein, we used single-cell RNA sequencing to identify the BMP9/ACVRL1/SMAD1 pathway signature in pulmonary EPCs. BMP9 receptor, ACVRL1, and its downstream target genes were inhibited in EPCs from Foxf1^WT/S52F mutant mice, a model of alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Expression of ACVRL1 and its targets were reduced in lungs of ACDMPV subjects. Inhibition of FOXF1 transcription factor reduced BMP9/ACVRL1 signaling and decreased angiogenesis in vitro. FOXF1 synergized with ETS transcription factor FLI1 to activate ACVRL1 promoter. Nanoparticle-mediated silencing of ACVRL1 in newborn mice decreased neonatal lung angiogenesis and alveolarization. Treatment with BMP9 restored lung angiogenesis and alveolarization in ACVRL1-deficient and Foxf1^WT/S52F mice. Altogether, EPCs promote neonatal lung angiogenesis and alveolarization through FOXF1-mediated activation of BMP9/ACVRL1 signaling.

Rationale: Advances in neonatal critical care have greatly improved the survival of preterm infants, but the long-term complications of prematurity, including bronchopulmonary dysplasia (BPD), cause mortality and morbidity later in life. Although VEGF (vascular endothelial growth factor) improves lung structure and function in rodent BPD models, severe side effects of VEGF therapy prevent its use in patients with BPD. Objectives: To test whether nanoparticle delivery of proangiogenic transcription factor FOXM1 (forkhead box M1) or FOXF1 (forkhead box F1), both downstream targets of VEGF, can improve lung structure and function after neonatal hyperoxic injury. Methods: Newborn mice were exposed to 75% O2 for the first 7 days of life before being returned to a room air environment. On Postnatal Day 2, polyethylenimine-(5) myristic acid/polyethylene glycol-oleic acid/cholesterol nanoparticles containing nonintegrating expression plasmids with Foxm1 or Foxf1 cDNAs were injected intravenously. The effects of the nanoparticles on lung structure and function were evaluated using confocal microscopy, flow cytometry, and the flexiVent small-animal ventilator. Measurements and Main Results: The nanoparticles efficiently targeted endothelial cells and myofibroblasts in the alveolar region. Nanoparticle delivery of either FOXM1 or FOXF1 did not protect endothelial cells from apoptosis caused by hyperoxia but increased endothelial proliferation and lung angiogenesis after the injury. FOXM1 and FOXF1 improved elastin fiber organization, decreased alveolar simplification, and preserved lung function in mice reaching adulthood. Conclusions: Nanoparticle delivery of FOXM1 or FOXF1 stimulates lung angiogenesis and alveolarization during recovery from neonatal hyperoxic injury. Delivery of proangiogenic transcription factors has promise as a therapy for BPD in preterm infants.

Background: Pulmonary hypertension (PH) is a common complication in patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a severe congenital disorder associated with mutations in the FOXF1 gene. Although the loss of alveolar microvasculature causes PH in patients with ACDMPV, it is unknown whether increasing neonatal lung angiogenesis could prevent PH and right ventricular (RV) hypertrophy. Methods: We used echocardiography, RV catheterization, immunostaining, and biochemical methods to examine lung and heart remodeling and RV output in Foxf1 ^WT/S52F mice carrying the S52F Foxf1 mutation (identified in patients with ACDMPV). The ability of Foxf1 ^WT/S52F mutant embryonic stem cells to differentiate into respiratory cell lineages in vivo was examined using blastocyst complementation. Intravascular delivery of nanoparticles with a nonintegrating Stat3 expression vector was used to improve neonatal pulmonary angiogenesis in Foxf1 ^WT/S52F mice and determine its effects on PH and RV hypertrophy. Results: Foxf1 ^WT/S52F mice developed PH and RV hypertrophy after birth. The severity of PH in Foxf1 ^WT/S52F mice directly correlated with mortality, low body weight, pulmonary artery muscularization, and increased collagen deposition in the lung tissue. Increased fibrotic remodeling was found in human ACDMPV lungs. Mouse embryonic stem cells carrying the S52F Foxf1 mutation were used to produce chimeras through blastocyst complementation and to demonstrate that Foxf1 ^WT/S52F embryonic stem cells have a propensity to differentiate into pulmonary myofibroblasts. Intravascular delivery of nanoparticles carrying Stat3 cDNA protected Foxf1 ^WT/S52F mice from RV hypertrophy and PH, improved survival, and decreased fibrotic lung remodeling. Conclusions: Nanoparticle therapies increasing neonatal pulmonary angiogenesis may be considered to prevent PH in ACDMPV.