Limited cross-variant immunity from SARS-CoV-2 Omicron without vaccination.

SARS-CoV-2 Delta and Omicron are globally relevant variants of concern. Although individuals infected with Delta are at risk of developing severe lung disease, infection with Omicron often causes milder symptoms, especially in vaccinated individuals1,2. The question arises of whether widespread Omicron infections could lead to future cross-variant protection, accelerating the end of the pandemic. Here we show that without vaccination, infection with Omicron induces a limited humoral immune response in mice and humans. Sera from mice overexpressing the human ACE2 receptor and infected with Omicron neutralize only Omicron, but not other variants of concern, whereas broader cross-variant neutralization was observed after WA1 and Delta infections. Unlike WA1 and Delta, Omicron replicates to low levels in the lungs and brains of infected animals, leading to mild disease with reduced expression of pro-inflammatory cytokines and diminished activation of lung-resident T cells. Sera from individuals who were unvaccinated and infected with Omicron show the same limited neutralization of only Omicron itself. By contrast, Omicron breakthrough infections induce overall higher neutralization titres against all variants of concern. Our results demonstrate that Omicron infection enhances pre-existing immunity elicited by vaccines but, on its own, may not confer broad protection against non-Omicron variants in unvaccinated individuals.

Neutrophil reduction attenuates the severity of lung injury in the early phase of pneumococcal pneumonia in mice.

Neutrophils are the first leukocytes to be recruited to sites of inflammation in response to chemotactic factors released by activated macrophages and pulmonary epithelial and endothelial cells in bacterial pneumonia, a common cause of acute respiratory distress syndrome (ARDS). Although neutrophilic inflammation facilitates the elimination of pathogens, neutrophils also may cause bystander tissue injury. Even though the presence of neutrophils in alveolar spaces is a key feature of acute lung injury and ARDS especially from pneumonia, their contribution to the pathogenesis of lung injury is uncertain. The goal of this study was to elucidate the role of neutrophils in a clinically relevant model of bacterial pneumonia. We investigated the effect of reducing neutrophils in a mouse model of pneumococcal pneumonia treated with antibiotics. Neutrophils were reduced with anti-lymphocyte antigen 6 complex locus G6D (Ly6G) monoclonal antibody 24 h before and immediately preceding infection. Mice were inoculated intranasally with Streptococcus pneumoniae and received ceftriaxone 12 h after bacterial inoculation. Neutrophil reduction in mice treated with ceftriaxone attenuated hypoxemia, alveolar permeability, epithelial injury, pulmonary edema, and inflammatory biomarker release induced by bacterial pneumonia, even though bacterial loads in the distal air spaces of the lung were modestly increased as compared with antibiotic treatment alone. Thus, when appropriate antibiotics are administered, lung injury in the early phase of bacterial pneumonia is mediated in part by neutrophils. In the early phase of bacterial pneumonia, neutrophils contribute to the severity of lung injury, although they also participate in host defense.NEW & NOTEWORTHY Neutrophil accumulation is a key feature of ARDS, but their contribution to the pathogenesis is still uncertain. We investigated the effect of reducing neutrophils in a clinically relevant mouse model of pneumococcal pneumonia treated with antibiotics. When appropriate antibiotics were administered, neutrophil reduction with Ly6G antibody markedly attenuated lung injury and improved oxygenation. In the early phase of bacterial pneumonia, neutrophils contribute to the severity of lung injury, although they also participate in host defense.

Ultrasensitive fiber sensor with enhanced Vernier effect for simultaneous measurements of transverse load and temperature.

Based on enhanced Vernier effect, a compact fiber sensor with ultrahigh sensitivity is proposed for simultaneous transverse load (TL) and temperature measurements. A single mode fiber (SMF) is spliced with a segment of hollow-core fiber (HCF) coated with polydimethylsiloxane (PDMS), some PDMS is injected into the HCF, forming a Vernier sensor with an air cavity adjacent to a PDMS cavity. It is shown that TL and temperature changes give rise to opposite and remarkable different variations in lengths of the two cavities, thereby enhancing Vernier effect and in favor of simultaneous measurements of TL and temperature. Moreover, the limited sensitivity magnification due to the length mismatch between the two cavities is compensated for by reconstructing the Vernier envelope with a broadened free spectrum range (FSR) from output signal. As a result, the highest TL sensitivity reported so far of -2637.47 nm/N and a good condition number of 69.056 for the sensitivity coefficient matrix have been achieved.

Inter- and Intra-donor variability in bone marrow-derived mesenchymal stromal cells: implications for clinical applications.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) are attractive as a therapeutic modality in multiple disease conditions characterized by inflammation and vascular compromise. Logistically they are advantageous because they can be isolated from adult tissue sources, such as bone marrow (BM). The phase 2a START clinical trial determined BM-MSCs to be safe in patients with moderate-to-severe acute respiratory distress syndrome (ARDS). Herein, we examine a subset of the clinical doses of MSCs generated for the phase 2a START trial from three unique donors (1-3), where one of the donors' donated BM on two separate occasions (donor 3 and 3W). METHODS: The main objective of this study was to correlate properties of the cells from the four lots with plasma biomarkers from treated patients and relevant to ARDS outcomes. To do this we evaluated MSC donor lots for (i) post-thaw viability, (ii) growth kinetics, (iii) metabolism, (iv) surface marker expression, (v) protein expression, (vi) immunomodulatory ability and (vii) their functional effects on regulating endothelial cell permeability. RESULTS: MSC-specific marker expression and protection of thrombin-challenged endothelial barrier permeability was similar among all four donor lots. Inter and intra-donor variability was observed in all the other in vitro assays. Furthermore, patient plasma ANG-2 and protein C levels at 6 hours post-transfusion were correlated to cell viability in an inter- and intra-donor dependent manner. CONCLUSIONS: These findings highlight the potential of donor dependent (inter-) and collection dependent (intra-) effects in patient biomarker expression.

Biological effects of corticosteroids on pneumococcal pneumonia in Mice-translational significance.

BACKGROUND: Streptococcus pneumoniae is the most common bacterial cause of community acquired pneumonia and the acute respiratory distress syndrome (ARDS). Some clinical trials have demonstrated a beneficial effect of corticosteroid therapy in community acquired pneumonia, COVID-19, and ARDS, but the mechanisms of this benefit remain unclear. The primary objective of this study was to investigate the effects of corticosteroids on the pulmonary biology of pneumococcal pneumonia in a mouse model. A secondary objective was to identify shared transcriptomic features of pneumococcal pneumonia and steroid treatment in the mouse model and clinical samples. METHODS: We carried out comprehensive physiologic, biochemical, and histological analyses in mice to identify the mechanisms of lung injury in Streptococcus pneumoniae with and without adjunctive steroid therapy. We also studied lower respiratory tract gene expression from a cohort of 15 mechanically ventilated patients (10 with Streptococcus pneumoniae and 5 controls) to compare with the transcriptional studies in the mice. RESULTS: In mice with pneumonia, dexamethasone in combination with ceftriaxone reduced (1) pulmonary edema formation, (2) alveolar protein permeability, (3) proinflammatory cytokine release, (4) histopathologic lung injury score, and (5) hypoxemia but did not increase bacterial burden. Transcriptomic analyses identified effects of steroid therapy in mice that were also observed in the clinical samples. CONCLUSIONS: In combination with appropriate antibiotic therapy in mice, treatment of pneumococcal pneumonia with steroid therapy reduced hypoxemia, pulmonary edema, lung permeability, and histologic criteria of lung injury, and also altered inflammatory responses at the protein and gene expression level. The transcriptional studies in patients suggest that the mouse model replicates some of the features of pneumonia in patients with Streptococcus pneumoniae and steroid treatment. Overall, these studies provide evidence for the mechanisms that may explain the beneficial effects of glucocorticoid therapy in patients with community acquired pneumonia from Streptococcus Pneumoniae.

Mono-, di- and trimetallic coinage nanoparticles prepared via the Brust-Schiffrin method.

The Brust-Schiffrin two-phase method is a facile way to prepare thiolate-protected metal nanoparticles, but its mechanism remains controversial. In this work, we demonstrate the use of the Brust-Schiffrin method based on coordination compound theory. We confirmed that the formation of stable complexes is the driving force for a series chemical reaction in the organic phase. We found that the stable Cu(I)-thiolate complex decreased the half-cell reduction potential of Cu(I)/Cu(0). Thus, when thiol ligands were in excess, thiolate-protected Cu(I) clusters formed rather than Cu(0)-cored nanoparticles. The thiolate-protected metal-hydride nanoclusters were the intermediate between the metal complexes and nanoparticles. The "metallophilic" interactions of the d10 closed-shell electronic configuration of the metal coordination centers were proposed as the driving force for nanocluster and nanoparticle formation. To confirm this mechanism, we synthesized Au, Ag, and Cu monometallic nanoparticles and bi- and trimetallic nanoparticles. We found that although thiolate-protected Cu(I) nanoclusters are not easily reduced, they can combine with Au and/or Ag nanoclusters to form nanoparticles. The proposed mechanism is expected to provide deeper insight into the Brust-Schiffrin method and further extend its application to metals other than Au, Ag and Cu.

Compact Vernier sensor with an all-fiber reflective scheme for simultaneous measurements of temperature and strain.

We propose an all-fiber reflective sensing scheme to simultaneously measure temperature and strain. A length of polarization-maintaining fiber serves as the sensing element, and a piece of hollow-core fiber assists with introducing Vernier effect. Both theoretical deductions and simulative studies have demonstrated the feasibility of the proposed Vernier sensor. Experimental results have shown that the sensor can deliver sensitivities of -88.73 nm/°C and 1.61 nm/µÎµ for temperature and strain, respectively. Further, Both theoretical analyses and experimental results have suggested the capability of simultaneous measurement for such a sensor. Significantly, the proposed Vernier sensor not only presents high sensitivities, but also exhibits a simple structure, compact size and light weight, as well as demonstrates ease of fabrication and hence high repeatability, thus holding great promise for widespread applications in daily life and industry world.

Effect of the optical power factors on the laser-linewidth measurements.

In this paper, the effects of optical power factors like laser power, the powers of the laser beams in the two arms of the optical system, and the power of the photodetector on laser-linewidth measurements are studied. From the experiments, it can be found that when the average optical input power for the photodetector is about 50% of its linear saturation power, the measured laser line width is a minimum. When the optical powers of the laser beams in the two arms are equal in short-delay self-homodyne system, the measured laser line width is narrowest. In the low output power range of the laser, its line width decreases with the increase in optical power. By comparing experiments, it can also be clear that the conventional measurement method is seriously affected by different noise types, which causes the measured line width to become wider and not change even if the laser linewidth changes. However, based on the short-delay coherent envelope method, the measured coherent envelope changes significantly when the laser line width changes slightly, and its corresponding laser-linewidth values are also clearly visible. It confirms the low noise and high resolution of the short-delay self-homodyne coherent-envelope laser-measurement method. The outcomes of this study can provide helpful information for precision ultra-narrow laser-linewidth measurements.

The oral bacterial microbiota facilitates the stratification for ulcerative colitis patients with oral ulcers.

BACKGROUND: Clinically, a large part of inflammatory bowel disease (IBD) patients is complicated by oral lesions. Although previous studies proved oral microbial dysbiosis in IBD patients, the bacterial community in the gastrointestinal (GI) tract of those IBD patients combined with oral ulcers has not been profiled yet. METHODS: In this study, we enrolled four groups of subjects, including healthy controls (CON), oral ulcer patients (OU), and ulcerative colitis patients with (UC_OU) and without (UC) oral ulcers. Bio-samples from three GI niches containing salivary, buccal, and fecal samples, were collected for 16S rRNA V3-V4 region sequencing. Bacterial abundance and related bio-functions were compared, and data showed that the fecal microbiota was more potent than salivary and buccal microbes in shaping the host immune system. ~ 22 UC and 10 UC_OU 5-aminosalicylate (5-ASA) routine treated patients were followed-up for six months; according to their treatment response (a decrease in the endoscopic Mayo score), they were further sub-grouped as responding and non-responding patients. RESULTS: We found those UC patients complicated with oral ulcers presented weaker treatment response, and three oral bacterial genera, i.e., Fusobacterium, Oribacterium, and Campylobacter, might be connected with treatment responding. Additionally, the salivary microbiome could be an indicator of treatment responding in 5-ASA routine treatment rather than buccal or fecal ones. CONCLUSIONS: The fecal microbiota had a strong effect on the host's immune indices, while the oral bacterial microbiota could help stratification for ulcerative colitis patients with oral ulcers. Additionally, the oral microbiota had the potential role in reflecting the treatment response of UC patients. Three oral bacteria genera (Fusobacterium, Oribacterium, and Campylobacter) might be involved in UC patients with oral ulcers lacking treatment responses, and monitoring oral microbiota may be meaningful in assessing the therapeutic response in UC patients.

Aerosolized vitamin E acetate causes oxidative injury in mice and in alveolar macrophages.

Although vitamin E acetate (VEA) is suspected to play a causal role in the development of electronic-cigarette, or vaping, product use-associated lung injury (EVALI), the underlying biological mechanisms of pulmonary injury are yet to be determined. In addition, no study has replicated the systemic inflammation observed in humans in a murine EVALI model, nor investigated potential additive toxicity of viral infection in the setting of exposure to vaping products. To identify the mechanisms driving VEA-related lung injury and test the hypothesis that viral infection causes additive lung injury in the presence of aerosolized VEA, we exposed mice to aerosolized VEA for extended times, followed by influenza infection in some experiments. We used mass spectrometry to evaluate the composition of aerosolized VEA condensate and the VEA deposition in murine or human alveolar macrophages. Extended vaping for 28 days versus 15 days did not worsen lung injury but caused systemic inflammation in the murine EVALI model. Vaping plus influenza increased lung water compared with virus alone. Murine alveolar macrophages exposed to vaped VEA hydrolyzed the VEA to vitamin E with evidence of oxidative stress in the alveolar space and systemic circulation. Aerosolized VEA also induced cell death and chemokine release and reduced efferocytotic function in human alveolar macrophages in vitro. These findings provide new insights into the biological mechanisms of VEA toxicity.

Impact of e-cigarette aerosol on primary human alveolar epithelial type 2 cells.

Electronic cigarettes (e-cigarettes) are designed to simulate combustible cigarette smoking and to aid in smoking cessation. Although the number of e-cigarette users has been increasing, the potential health impacts and biological effects of e-cigarettes are still not fully understood. Previous research has focused on the biological effects of e-cigarettes on lung cancer cell lines and distal airway epithelial cells; however, there have been few published studies on the effect of e-cigarettes on primary lung alveolar epithelial cells. The primary purpose of this study was to investigate the direct effect of e-cigarette aerosol on primary human lung alveolar epithelial type 2 (AT2) cells, both alone and in the presence of viral infection. The Melo-3 atomizer caused direct AT2 cell toxicity, whereas the more popular Juul pod's aerosol did not have a detectable cytotoxic effect on AT2 cells. Juul nicotine aerosol also did not increase short-term susceptibility to viral infection. However, 3 days of exposure upregulated genes central to the generation of reactive oxygen species, lipid peroxidation, and carcinogen metabolism and downregulated key innate immune system genes related to cytokine and chemokine signaling. These findings have implications for the potentially injurious impact of long-term use of popular low-power e-cigarette pods on the human alveolar epithelium. Gene expression data might be an important endpoint for evaluating the potential harmful effects of vaping devices that do not cause overt toxicity.

Controlled fiber core mode and surface mode interaction for enhanced SERS performance.

Three-dimensional surface-enhanced Raman scattering (SERS) platform based on microstructure fibers has many advantages for rapid liquid detection due to its microfluidic channels and light guidance. The fiber mode field distribution determines the light-analyte interaction strength but has rarely been studied in SERS applications. In this paper, we numerically and experimentally investigate the mode field distribution in suspended-core fibers decorated with gold nanoparticles. The interaction between the core mode and surface mode is controlled by changing the density of gold nanoparticles on the inner surface. The avoided crossing wavelength shifts linearly to red with the decrease of the nanoparticle spacing. With an optimized nanoparticle spacing of 20 nm, the avoided crossing occurs near the laser wavelength of 633 nm, which greatly increases the power ratio in the liquid channels and hence improves the SERS performance. The detection limit for crystal violet was 10-9 M, and the enhancement factor was 108. The avoided crossing mechanism can be applied to all fiber SERS probes for sensitivity improvement.

Influence of Alkali Metal Doping and BN Substitution on the Second-Order Nonlinear Optical Properties of Graphyne: A Theoretical Perspective.

The electronic and nonlinear optical (NLO) properties of BN-substituted graphynes and the corresponding alkali-doped hybrid systems have been determined using density functional theory. When the carbon atoms in the graphyne are replaced by BN pairs, the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gap (Egap) increases to some extent, and the static first hyperpolarizabilities (ß0) of the novel systems hardly increase. However, when an alkali atom is introduced on the surface of BN-substituted graphyne, the doping effect can effectively modulate the electronic and NLO properties. Doping the alkali atom can significantly narrow the wide Egap of BN-substituted graphynes in the range of 1.03-2.03 eV. Furthermore, the doping effect brings considerable ß0 values to these alkali-doped systems, which are 52-3609 au for Li-doped systems and 3258-211 053 au for Na/K-doped ones. The result reveals that the ß0 values of alkali-doped complexes are influenced by the atomic number of alkali metals and the proportion of BN pairs. The nature of the excellent NLO responses of alkali-doped complexes can be understood by the low excitation energy of the crucial excited state and the analysis of the first hyperpolarizability density. Besides, these alkali-doped complexes have a deep-ultraviolet working region. Therefore, the combined effect of alkali metal doping and BN substitution can be an excellent strategy to design novel high-performance NLO materials based on graphyne.

Precise laser linewidth measurement by feature extraction with short-delay self-homodyne.

We propose a precision measurement method of laser linewidth based on short-delay self-homodyne, using the second peak-valley difference (SPVD) feature of the coherent power spectrum to fit laser linewidth. The SPVD model of the self-homodyne coherent envelope spectrum was established. One-to-one correspondence among the values of SPVD, the delay length, and the laser linewidth was determined theoretically and through simulations, while the reliability and stability of the method was verified experimentally. By comparing the detected results, it is found that the fitted laser linewidth obtained by the self-homodyne system is closer to its true value than that obtained by the self-heterodyne system. Hence, the simpler structure of the short-delay self-homodyne coherent envelope laser linewidth measurement method proposed is expected to substitute the previous laser linewidth measurement method, including complex short-delay self-heterodyne coherent envelope laser linewidth measurement method and traditional self-homodyne/heterodyne laser linewidth measurement method, to achieve more precise laser linewidth value.

Inhibition of the lipoxin A4 and resolvin D1 receptor impairs host response to acute lung injury caused by pneumococcal pneumonia in mice.

Resolution of the acute respiratory distress syndrome (ARDS) from pneumonia requires repair of the injured lung endothelium and alveolar epithelium, removal of neutrophils from the distal airspaces of the lung, and clearance of the pathogen. Previous studies have demonstrated the importance of specialized proresolving mediators (SPMs) in the regulation of host responses during inflammation. Although ARDS is commonly caused by Streptococcus pneumoniae, the role of lipoxin A4 (LXA4) and resolvin D1 (RvD1) in pneumococcal pneumonia is not well understood. In the present experimental study, we tested the hypothesis that endogenous SPMs play a role in the resolution of lung injury in a clinically relevant model of bacterial pneumonia. Blockade of formyl peptide receptor 2 (ALX/FPR2), the receptor for LXA4 and RvD1, with the peptide WRW4 resulted in more pulmonary edema, greater protein accumulation in the air spaces, and increased bacteria accumulation in the air spaces and the blood. Inhibition of this receptor was also associated with decreased levels of proinflammatory cytokines. Even in the presence of antibiotic treatment, WRW4 inhibited the resolution of lung injury. In summary, these experiments demonstrated two novel findings: LXA4 and RvD1 contribute to the resolution of lung injury due to pneumococcal pneumonia, and the mechanism of their benefit likely includes augmenting bacterial clearance and reducing pulmonary edema via the restoration of lung alveolar-capillary barrier permeability.

A neutrophil subset defined by intracellular olfactomedin 4 is associated with mortality in sepsis.

Sepsis is a heterogeneous syndrome clinically and biologically, but biomarkers of distinct host response pathways for early prognostic information and testing targeted treatments are lacking. Olfactomedin 4 (OLFM4), a matrix glycoprotein of neutrophil-specific granules, defines a distinct neutrophil subset that may be an independent risk factor for poor outcomes in sepsis. We hypothesized that increased percentage of OLFM4+ neutrophils on sepsis presentation would be associated with mortality. In a single-center, prospective cohort study, we enrolled adults admitted to an academic medical center from the emergency department (ED) with suspected sepsis [identified by 2 or greater systemic inflammatory response syndrome (SIRS) criteria and antibiotic receipt] from March 2016 through December 2017, followed by sepsis adjudication according to Sepsis-3. We collected 200 µL of whole blood within 24 h of admission and stained for the neutrophil surface marker CD66b followed by intracellular staining for OLFM4 quantitated by flow cytometry. The predictors for 60-day mortality were 1) percentage of OLFM4+ neutrophils and 2) OLFM4+ neutrophils at a cut point of ≥37.6% determined by the Youden Index. Of 120 enrolled patients with suspected sepsis, 97 had sepsis and 23 had nonsepsis SIRS. The mean percentage of OLFM4+ neutrophils was significantly increased in both sepsis and nonsepsis SIRS patients who died (P ≤ 0.01). Among sepsis patients with elevated OLFM4+ (≥37.6%), 56% died, compared with 18% with OLFM4+ <37.6% (P = 0.001). The association between OLFM4+ and mortality withstood adjustment for age, sex, absolute neutrophil count, comorbidities, and standard measures of severity of illness (SOFA score, APACHE III) (P < 0.03). In summary, OLFM4+ neutrophil percentage is independently associated with 60-day mortality in sepsis and may represent a novel measure of the heterogeneity of host response to sepsis.

Microfluid-based soft metasurface for tunable optical activity in THz wave.

Metasurfaces are usually planar structures and do not possess intrinsic chirality and therefore hardly generate optical activity. Here we realized a tunable optical activity in a terahertz wave through a microfluid-based soft metasurface. The meta-atom is a chiral structured microchannel made of soft polydimethylsiloxane and injected with the liquid metal Galinstan. A microfluid pressure system is bonded to the metasurface to reconfigure all meta-atoms simultaneously. By pumping glycerol liquid into the pressure system, the metasurface is deformed from a planar structure to a three dimensional one, which manifests intrinsic chirality for optical activity realization. By controlling the injected glycerol volume, a polarization rotation from 0°to 14° at 0.19 THz is demonstrated. The soft metasurface with tunable optical activity can be flexibly applied in various applications such as polarization microscopy, bio-detection and material analysis, etc.

Signal processing assisted Vernier effect in a single interferometer for sensitivity magnification.

The Vernier effect magnifies optical sensitivity by the superposition of two spectra with slightly shifted frequencies from a sensing interferometer (SIM) and a reference interferometer (RIM). In this study, we demonstrate that the Vernier effect can be obtained through a single interferometer, which detects the changed signal and provides an artificial reference spectrum (ARS) to be superposed with the changed signal spectrum. The ARS extracted by spatial frequency down-conversion of one sensing spectrum in the signal processing is not affected by environmental changes and can be detuned at an arbitrarily small amount with the measured signal spectrum. This approach is simpler and accurate and provides ultrahigh sensitivity. To validate the principle, a Mach-Zehnder (MZ) interferometer based on a dual-mode microfiber was designed for sensing the refractive index (RI) change magnification, and a high sensitivity of 71354.58 nm/refractive index unit (RIU) was obtained with good linearity.

Exosomal lncRNA UCA1 from cancer-associated fibroblasts enhances chemoresistance in vulvar squamous cell carcinoma cells.

AIM: In the current work, we aimed to explore whether Cancer-associated fibroblasts (CAF) exosomes played crucial roles in vulvar squamous cell carcinoma (VSCC) chemoresistance via mediating long noncoding RNAs (lncRNA). METHODS: The IC50 value and cell apoptosis were assessed by the Cell Counting-8 Kit (CCK-8) assay and flow cytometry, respectively. Western blot analysis was used for the measurement of protein levels. The levels of urothelial cancer-associated 1 (UCA1), miR-103a and WEE1 G2 checkpoint kinase (WEE1) mRNA were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The target relationships among miR-103a, UCA1 and WEE1 were confirmed by dual-luciferase reporter assays. Xenograft model mice were established to observe the impact of exosomal UCA1 on cisplatin (CDDP) resistance in vivo. RESULTS: Our data indicated that CAF enhanced CDDP resistance of VSCC cells in vitro. Extracellular UCA1 was transferred by exosomes derived from CAF. Exosomal UCA1 derived from CAF conferred VSCC cell resistance to CDDP. Moreover, UCA1 functioned as a miR-103a sponge in VSCC cells. The promotion of exosomal UCA1 on VSCC cell resistance to CDDP was mediated by miR-103a. WEE1 was a direct target of miR-103a, and exosomal miR-103a from CAF weakened CDDP resistance of VSCC cells by WEE1. Furthermore, exosomal UCA1 regulated WEE1 expression through sponging miR-103a. Additionally, exosomal UCA1 enhanced tumor growth and CDDP resistance in vivo. CONCLUSION: Our findings suggested exosomal UCA1 derived from CAF conferred VSCC cell resistance to CDDP in vitro and in vivo at least partly through the miR-103a/WEE1 axis, highlighting a novel therapeutic method for improving the clinical benefits of CDDP chemotherapy in VSCC patients.

Dose-Dependent Pulmonary Toxicity of Aerosolized Vitamin E Acetate.

Electronic-cigarette, or vaping, product use-associated lung injury (EVALI) is a syndrome of acute respiratory failure characterized by monocytic and neutrophilic alveolar inflammation. Epidemiological and clinical evidence suggests a role of vitamin E acetate (VEA) in the development of EVALI, yet it remains unclear whether VEA has direct pulmonary toxicity. To test the hypotheses that aerosolized VEA causes lung injury in mice and directly injures human alveolar epithelial cells, we exposed adult mice and primary human alveolar epithelial type II (AT II) cells to an aerosol of VEA generated by a device designed for vaping oils. Outcome measures in mice included lung edema, BAL analysis, histology, and inflammatory cytokines; in vitro outcomes included cell death, cytokine release, cellular uptake of VEA, and gene-expression analysis. Comparison exposures in both models included the popular nicotine-containing JUUL aerosol. We discovered that VEA caused dose-dependent increases in lung water and BAL protein compared with control and JUUL-exposed mice in association with increased BAL neutrophils, oil-laden macrophages, multinucleated giant cells, and inflammatory cytokines. VEA aerosol was also toxic to AT II cells, causing increased cell death and the release of monocyte and neutrophil chemokines. VEA was directly absorbed by AT II cells, resulting in the differential gene expression of several inflammatory biological pathways. Given the epidemiological and clinical characteristics of the EVALI outbreak, these results suggest that VEA plays an important causal role.