Glucocorticoid-induced acute diuresis in rats in relation to the reduced renal expression of sodium-dependent cotransporter genes.

Although several studies have shown that glucocorticoids exert diuretic effects in animals and humans, the underlying mechanism responsible for the acute diuretic effect remains obscure. Here we examined the mechanism in terms of gene-expression. We observed that glucocorticoids, including dexamethasone (Dex) and prednisolone (PSL), acutely induced diuresis in rats in a dose-dependent manner. Free water clearance values were negative after Dex or PSL treatment, similar to those observed after treatment with osmotic diuretics (furosemide and acetazolamide). Dex significantly increased the urinary excretion of sodium, potassium, chloride, glucose, and inorganic phosphorus. Renal microarray analysis revealed that Dex significantly altered the renal expression of genes related to transmembrane transport activity. The mRNA levels of sodium/phosphate (NaPi-2a/Slc34a1, NaPi-2b/Slc34a2, and NaPi-2c/Slc34a3) and sodium/glucose cotransporters (Sglt2/Slc5a2) were significantly reduced in the Dex-treated kidney, being negatively correlated with the urinary excretion of their corresponding solutes. Dex did not affect renal expression of the natriuretic peptide receptor 1 (Npr1) gene, or the expression, localization, and phosphorylation of aquaporin-2 (AQP2), a water channel protein. These findings suggest that the acute diuretic effects of glucocorticoids might be mediated by reduced expression of sodium-dependent cotransporter genes.

The predictive value of E2F7 in immunotherapy efficacy for lung adenocarcinoma: An observational study.

Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. In recent years, immunotherapy has greatly changed the treatment pattern of advanced LUAD. However, only a small proportion of LUAD patients benefitted from immune checkpoint inhibitor therapy. There is an urgent need to develop a biomarker to predict immune therapy response. E2F7 has been shown to be closely related to immune cell infiltration and immune checkpoint expression in tumors. However, it is unclear whether the E2F7 expression is related to the immunotherapy efficacy in LUAD. Therefore, we conducted this study to investigate the clinical characteristics, function, and immunotherapy responsiveness of E2F7 expression, and to explore the potential of E2F7 as an immunotherapy response biomarker in LUAD. We analyzed the clinical characteristics and biological function of E2F7 expression based on data from the Cancer Genome Atlas and Gene Expression Omnibus database. In addition, we used single-cell sequencing data to analyze the immune regulatory effects of E2F7 in LUAD. Furthermore, we analyzed the immunotherapy response prediction ability of E2F7 expression based on the immunotherapy database. Compared to normal lung tissue, E2F7 was specifically overexpressed in LUAD, and its expression was associated with higher malignancy and poor efficacy. E2F7 high expression was an independent risk factor affecting the prognosis of LUAD. E2F7 was enriched in cell division and cell cycle functions. In addition, the expressions of immune checkpoints were correlated with the E2F7 expression. E2F7 was highly expressed in myeloid cells, and E2F7 highly expressed myeloid cells were associated with immune and inflammatory responses. Moreover, the expression level of E2F7 can effectively distinguish different immune therapy responses in LUAD patients. E2F7 was upregulated in LUAD, and high expression of E2F7 was associated with higher malignancy and poor efficacy. E2F7 high expression was an independent risk factor affecting the prognosis of LUAD. Moreover, E2F7 may exert its immunosuppressive effect by affecting the function of myeloid cells. These results indicated the potential role of E2F7 as a biomarker for predicting LUAD immunotherapy responses.

Peripheral NK cells identified as the predictor of response in extensive-stage small cell lung cancer patients treated with first-line immunotherapy plus chemotherapy.

PURPOSE: Although immunotherapy improves outcomes in extensive-stage small-cell lung cancer (ES-SCLC), the search for biomarkers predicting treatment success is crucial. Natural killer (NK) cells are potential indicators in various cancers, however, their precise role in ES-SCLC prognosis remains unclear. METHODS: In this retrospective study, 33 patients with ES-SCLC treated with first-line immuno-chemotherapy were enrolled. The peripheral NK cell percentage and its longitudinal dynamics were analyzed using flow cytometry. Progression-free survival (PFS) and overall survival (OS) were calculated as hazard ratio (HR) and compared statistically. RESULTS: The median PFS was better in the group with normal baseline NK cell levels than the low group (7.0 vs. 4.6 months; HR = 0.17; 95% CI 0.07-0.41; P < 0.0001), but there was no association with OS (14.9 vs. 10.3 months; HR = 0.55; 95% CI 0.23-1.31; P = 0.171). Furthermore, the NK cell% for 95.0% of patients increased after immunochemotherapy in the clinical response group (P = 0.0047), which led to a better median PFS (6.3 vs. 2.1 months; HR = 0.23; 95% CI 0.05-0.98; P < 0.0001) and OS (14.9 vs. 5.9 months; HR = 0.20; 95% CI 0.04-1.02; P < 0.0001). Similar trends were observed with NK cell% changes up to disease progression, improving PFS (6.5 vs. 4.3; HR = 0.41; 95% CI 0.12-0.92; P = 0.0049) and OS (17.4 vs. 9.7; HR = 0.42; 95% CI 0.17-1.02; P < 0.0001). CONCLUSION: In patients with ES-SCLC, the percentage and changes in peripheral NK cells can predict the response to combined immunotherapy and chemotherapy.

Interface-induced dual-pinning mechanism enhances low-frequency electromagnetic wave loss.

Improving the absorption of electromagnetic waves at low-frequency bands (2-8 GHz) is crucial for the increasing electromagnetic (EM) pollution brought about by the innovation of the fifth generation (5G) communication technology. However, the poor impedance matching and intrinsic attenuation of material in low-frequency bands hinders the development of low-frequency electromagnetic wave absorbing (EMWA) materials. Here we propose an interface-induced dual-pinning mechanism and establish a magnetoelectric bias interface by constructing bilayer core-shell structures of NiFe2O4 (NFO)@BiFeO3 (BFO)@polypyrrole (PPy). Such heterogeneous interface could induce distinct magnetic pinning of the magnetic moment in the ferromagnetic NFO and dielectric pinning of the dipole rotation in PPy. The establishment of the dual-pinning effect resulted in optimized impedance and enhanced attenuation at low-frequency bands, leading to better EMWA performance. The minimum reflection loss (RLmin) at thickness of 4.43 mm reaches -65.30 dB (the optimal absorption efficiency of 99.99997%), and the effective absorption bandwidth (EAB) can almost cover C-band (4.72 ~ 7.04 GHz) with low filling of 15.0 wt.%. This work proposes a mechanism to optimize low-frequency impedance matching with electromagnetic wave (EMW) loss and pave an avenue for the research of high-performance low-frequency absorbers.

Advances in genetic profile and therapeutic strategy of pulmonary large cell neuroendocrine carcinoma.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine carcinoma (HGNEC) accounting for 3% of primary lung cancer, and characterized by strong invasion, high heterogeneity, and extremely poor prognosis. At present, the diagnosis and treatment of LCNEC remains controversial and refer to therapeutic strategy of small cell lung cancer (SCLC), lacking precise therapy. Recently, the genetic analysis and clinical trials of LCNEC gradually emerged, providing more evidence for precise diagnosis and treatment. Here, we review the diagnosis, molecular characteristics, and treatment of LCNEC based on the existing research and frontier progress to provide a potential direction for future diagnosis and treatment of LCNEC.

Modeling and oblique transmission characteristics of an underwater wireless optical communication channel based on ocean depth layering.

Underwater wireless optical communication is widely considered in the field of underwater communication due to its high bandwidth and low latency. In a real transmission link, the temperature and salinity of seawater, chlorophyll concentration, and bubble density vary with ocean depth. Therefore, the depth of the optical transmitter in seawater and the tilt angle of the beam will exhibit different beam transmission characteristics. In this paper, an underwater oblique-range layered channel model considering the combined effects of dynamic turbulence, absorption, and scattering is developed based on real data of seawater at different depths measured by the Global Ocean Observing Buoy Argo and the Woods Hole Oceanographic Institution BCO-DMO. The effects of transmission distance, transmitter tilt angle, and transmitter depth on the oblique-range transmission characteristics of the beam in seawater are discussed. The simulation results show that, at the same transmission distance, the beam centroid displacement increases with an increase in transmitter depth only when the transmitter is located above the interior of the thermocline. When the transmitter is located below the interior of the thermocline, the influence of the transmitter tilt angle on the beam centroid displacement decreases. This indicates that at different depths within the interior of the thermocline, the optical beam transmission characteristics exhibit significant variations.

Dynamic phenotypic reprogramming and chemoresistance induced by lung fibroblasts in small cell lung cancer.

Small cell lung cancer (SCLC) is heterogenous in phenotype and microenvironment. Dynamic phenotypic reprogramming, leading to heterogeneity, is prevalent in SCLC, while the mechanisms remain incompletely understood. Cancer-associated fibroblasts (CAFs) possess comprehensive roles in cancer progression, while their function in phenotypic reprogramming of SCLC remain elusive. Here, we obtained transcriptome data of SCLC tissues from publicly available databases, subsequently estimated abundance of CAFs. We found CAF-abundant SCLC exhibited non-neuroendocrine (Non-NE) characteristics. Supporting this, the positive correlation of expression level of α-SMA, the CAF marker, and expression level of REST, protein typically expressed in Non-NE type SCLC, was identified in SCLC tissue arrays. Moreover, we revealed that fibroblasts inhibited NE markers expression and cell proliferation of SCLC cells in the co-culture system comprising lung fibroblasts and SCLC cells, indicating a phenotypic reprogramming from NE to Non-NE. During this process, fibroblast-derived IL-6 activated the JAK2/STAT3 signaling, upregulated c-MYC expression, and subsequently activated the NOTCH pathway, driving phenotypic reprogramming. Moreover, CAF-enriched SCLC exhibited increased immune cell infiltration, elevated expression of immune activation-related signatures, and checkpoint molecules. Our data also highlighted the chemoresistance induced by fibroblasts in SCLC cells, which was effectively reversed by JAK inhibitor. In conclusion, fibroblasts induced phenotypic reprogramming of SCLC cells from NE to Non-NE, likely contributes to inflamed immune microenvironment and chemoresistance. These findings provide novel insights into the clinical implications of CAFs in SCLC.

C-Myc-induced hypersialylation of small cell lung cancer facilitates pro-tumoral phenotypes of macrophages.

Immunosuppressive myeloid cell populations have been documented in small cell lung cancer (SCLC) subtypes, playing a key role in remolding the tumor microenvironment (TME). However, the cancer-associated transcriptional features of monocytes and tumor-associated macrophages (TAMs) in SCLC remain poorly understood. Herein, we analyzed the molecular features and functions of monocyte/macrophage subsets aiming to inhibit monocyte recruitment and pro-tumor behavior of macrophages. We observe that NEUROD1-high SCLC subtype (SCLC-N) exhibits subtype-specific hypersialylation induced by the unique target c-Myc (MYC) of NEUROD1. The hypersialylation can alter macrophage phenotypes and pro-tumor behavior by regulating the expression of the immune-inhibiting lectin receptors on monocyte-derived macrophages (MDMs) in SCLC-N. Inhibiting the aberrant sialic acid metabolic pathways in SCLC can significantly enhance the phagocytosis of macrophages. This study provides a comprehensive overview of the cancer-specific immune signature of monocytes and macrophages and reveals tumor-associated biomarkers as potential therapeutic targets for SCLC.

Potential value of efficacy prediction and treatment of natural killer cells in extensive stage small cell lung cancer.

Although the emergence of immunotherapy has broken the deadlock of extensive stage small cell lung cancer (ES-SCLC), the study of markers for predicting efficacy is the key to the breakthrough of immunotherapy, and exploring more innovative, efficient and safe treatment models is also an important research direction of ES-SCLC. As an important part of inherent immunity, natural killer (NK) cells have become a hot spot because activated NK cells can directly kill tumor cells and may also influence tumor microenvironment immunomodulation. To date, emerging experimental research on NK cells in tumor therapy and immunoregulation has been published, but specific reviews of its role in ES-SCLC are limited. Hence, in this review, we briefly summarize the current status of immunotherapy and the exploration of biomarker in ES-SCLCs, with focus on the potential value of efficacy prediction and treatment of NK cells, and finally discuss the limitations and development prospects of NK cells in ES-SCLC immunotherapy research.

A microsatellite DNA-derived oligodeoxynucleotide attenuates lipopolysaccharide-induced acute lung injury in mice by inhibiting the HMGB1-TLR4-NF-κB signaling pathway.

Acute lung injury (ALI) with uncontrolled inflammatory response has high morbidity and mortality rates in critically ill patients. Pathogen-associated molecular patterns (PAMPs) are involved in the development of uncontrolled inflammatory response injury and associated lethality. In this study, we investigated the inhibit effect of MS19, a microsatellite DNA-derived oligodeoxynucleotide (ODN) with AAAG repeats, on the inflammatory response induced by various PAMPs in vitro and in vivo. In parallel, a microsatellite DNA with AAAC repeats, named as MS19-C, was used as controls. We found that MS19 extensively inhibited the expression of inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α induced by various PAMPs stimulation, including DNA viruses, RNA viruses, bacterial components lipopolysaccharide (LPS), and curdlan, as well as the dsDNA and dsRNA mimics, in primed bone marrow-derived macrophage (BMDM). Other than various PAMPs, MS19 also demonstrated obvious effects on blocking the high mobility group box1 (HMGB1), a representative damage-associated-molecular pattern (DAMP), nuclear translocation and secretion. With the base substitution from G to C, MS19-C has been proved that it has lost the inhibitory effect. The inhibition is associated with nuclear factor kappa B (NF-κB) signaling but not the mitogen-activated protein kinase (MAPK) transduction. Moreover, MS19 capable of inhibiting the IL-6 and TNF-α production and blocking the HMGB1 nuclear translocation and secretion in LPS-stimulated cells was used to treat mice ALI induced by LPS in vivo. In the ALI mice model, MS19 significantly inhibited the weight loss and displayed the dramatic effect on lessening the ALI by reducing consolidation, hemorrhage, intra-alveolar edema in lungs of the mice. Meanwhile, MS19 could increase the survival rate of ALI by downregulating the inflammation cytokines HMGB1, TNF-a, and IL-6 production in the bronchoalveolar lavage fluid (BALF). The data suggest that MS19 might display its therapeutic role on ALI by inhibiting the HMGB1-TLR4-NF-κB signaling pathway.

Neutrophils recruited to immunization sites initiating vaccine-induced antibody responses by locally expressing BAFF.

Neutrophils played a key role in the innate immune responses. Less is known about whether and how the neutrophils recruited in the immunization sites affecting the vaccine-induced antibody responses. In the process of evaluating the efficacy of an oil-in-water emulsion-formulated vaccine in mice, we found that neutrophils were rapidly and massively recruited to immunization sites but were barely detected in the draining lymph nodes. Interestingly, B cell-activating factor (BAFF) was abundantly expressed in the recruiting neutrophils at a very early stage. The initial neutrophil-derived BAFF firstly brought about the B cell responses in the local part, then subsequently in lymphoid organs. Activated B cells produced more BAFF through TLR9-IRF5 signaling pathway, thereby amplifying the vaccine-induced antibody responses. Suppressing BAFF in the neutrophils could weaken the B cell activation and reduce the antibody production. The data indicate that vaccines endow neutrophils with the potential to orchestrate antibody responses at immunization sites.

The Peer Effect on Dietary and Nutritional Cognition among Primary School Students.

This study uses data from a 2018 survey of 11,384 students in five Chinese provinces to investigate the peer effect on students' dietary and nutritional cognition. Children's eating habits have an important impact on their growth and health. Studies have shown that students' dietary behavior is mainly affected by their dietary and nutritional cognition. Therefore, studying the influencing factors of elementary school students' cognition of diet and nutrition has become an important research question. However, there are few discussions about the impact of peers' dietary and nutritional cognition on students' cognition of diet and nutrition. Consequently, this paper studied the peer effect on students' cognition of diet and nutrition. The results indicated that peers had a significant impact on the students' dietary and nutritional cognition. The endogeneity problem was solved using peers' parents' dietary and nutritional cognition scores and average educational level as instrumental variables. The impact of peer cognition on diet and nutrition was heterogeneous among different groups. The significance and degree of the peer effect differed based on peer relations, gender, age and school. The results indicated that in addition to family, school, teachers and other factors, peers were an important influencing factor.

c-Myc Targets HDAC3 to Suppress NKG2DL Expression and Innate Immune Response in N-Type SCLC through Histone Deacetylation.

SCLC is an aggressive malignancy with a very poor prognosis and limited effective therapeutic options. Despite the high tumor mutational burden, responses to immunotherapy are rare in SCLC patients, which may be due to the lack of immune surveillance. Here, we aimed to examine the role and mechanism of oncogene MYC in the regulation of NKG2DL, the most relevant NK-activating ligand in SCLC-N. Western Blotting, Immunofluorescence, flow cytometry, quantitative real-time PCR (qRT-PCR), Co-Immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and Cytotoxicity assay were used on H2227 cells, H446 cells, and other SCLC cell lines, and we found that c-Myc negatively regulated NKG2DL expression in SCLC-N cells. Mechanistically, c-Myc recruited HDAC3 to deacetylate H3K9ac at the promoter regions of MICA and MICB, suppressing the MICA/B expression of SCLC-N cells and the cytotoxicity of NK cells. Treatment with selective HDAC3 inhibitor up-regulated the expression of NKG2DL on SCLC-N cells and increased the cytotoxicity of NK cells. Furthermore, analysis of the CCLE and Kaplan-Meier plotter data performed the negative correlation between MYC and NKG2DL in SCLC-N cells and the correlation with the prognosis of lung cancer patients. Collectively, the results provided the new insight into the role and mechanism of c-Myc/HDAC3 axis in NKG2DL expression and innate immune escape of SCLC-N, suggesting the potential target for SCLC-N immunotherapy.

High-extinction-ratio low-voltage dual-racetrack modulator for low-power DAC-less PAM-4 modulation.

In a parallel-coupled dual-racetrack modulator, resonant light in two resonators can interfere with each other. In lieu of critical coupling, such interference is capable of producing high extinction ratios (ERs) for high-speed modulation. Experiments demonstrate ERs of over 9 dB at 50 Gb/s and 40-50% modulation depth enhancement compared with a single-resonator modulator at 50-56 Gb/s with a peak-to-peak driving voltage of 2.3 V. Furthermore, joint modulation of two racetracks offers the possibility to combine two separate bits of driving signals to generate four-level pulse-amplitude modulation (PAM-4) without an external digital-to-analog converter (DAC). To tackle the complex multi-variable transfer function of this modulator, a procedure for configuring PAM-4 states is theoretically developed. Finally, we demonstrate 100 Gb/s PAM-4 with an electro-optic modulation power consumption of < 40 fJ/bit for this device.

3D Ultralight Hollow NiCo Compound@MXene Composites for Tunable and High-Efficient Microwave Absorption.

The 3D hollow hierarchical architectures tend to be designed for inhibiting stack of MXene flakes to obtain satisfactory lightweight, high-efficient and broadband absorbers. Herein, the hollow NiCo compound@MXene networks were prepared by etching the ZIF 67 template and subsequently anchoring the Ti3C2Tx nanosheets through electrostatic self-assembly. The electromagnetic parameters and microwave absorption property can be distinctly or slightly regulated by adjusting the filler loading and decoration of Ti3C2Tx nanoflakes. Based on the synergistic effects of multi-components and special well-constructed structure, NiCo layered double hydroxides@Ti3C2Tx (LDHT-9) absorber remarkably achieves unexpected effective absorption bandwidth (EAB) of 6.72 GHz with a thickness of 2.10 mm, covering the entire Ku-band. After calcination, transition metal oxide@Ti3C2Tx (TMOT-21) absorber near the percolation threshold possesses minimum reflection loss (RLmin) value of - 67.22 dB at 1.70 mm within a filler loading of only 5 wt%. This work enlightens a simple strategy for constructing MXene-based composites to achieve high-efficient microwave absorbents with lightweight and tunable EAB.

Ginsenoside Rh2 Inhibits Glycolysis through the STAT3/c-MYC Axis in Non-Small-Cell Lung Cancer.

Ginsenoside Rh2 (Rh2) is one of the pharmacologically active components of ginseng with an antitumor effect. However, its effect on non-small-cell lung cancer (NSCLC), especially on aerobic glycolysis, which plays a crucial role in the proliferation and progression of tumor cells, has not been characterized. Here, we demonstrated that Rh2 inhibited the proliferation and metastasis of NSCLC cells by promoting apoptosis and suppressing epithelial-mesenchymal transition, respectively. Notably, Rh2 exerted a glycolysis inhibition effect through regulating GLUT1, PKM2, and LDHA, which are key enzymes of the glycolysis process. Furthermore, the metabolic shift function of Rh2 was dependent on the STAT3/c-Myc axis in NSCLC. This novel regulatory role of Rh2 provides a new perspective for NSCLC treatment and highlights the potentiality of Rh2 to be used as a tumor energy blocker. The combination of Rh2 with an STAT3 or c-Myc inhibitor revealed a promising therapeutic approach for patients with NSCLC.

Consideration of Surrogate Endpoints for Overall Survival Associated With First-Line Immunotherapy in Extensive-Stage Small Cell Lung Cancer.

BACKGROUND: The combination of immune checkpoint inhibitors (ICIs) and chemotherapy is known to improve overall survival (OS) in patients with extensive-stage small cell lung cancer (ES-SCLC). ICIs have different response patterns and survival kinetics characteristics from those of the traditional chemotherapy. In first-line treatment for ES-SCLC, there is an urgent need for surrogate endpoints for the early and accurate prediction of OS. This study aimed to assess progression-free survival (PFS), milestone OS rate, milestone restricted mean survival time (RMST), overall response rate (ORR), and disease control rate (DCR) as proposed surrogate endpoints for OS in ES-SCLC for first-line immunotherapy trials. METHODS: Between January 1, 2013, and December 2020, published articles on randomized clinical trials of ICIs plus chemotherapy in patients with ES-SCLC as first-line therapy were searched in PubMed. Abstracts from the ESMO, ASCO, and WCLC, reported from 2018 onwards, were also searched. A weighted regression analysis based on the weighted least squares method was performed on log-transformed estimates of treatment effect, and the determination coefficient (R2) was calculated to evaluate the association between treatment effect on the surrogate endpoint and OS. RESULTS: Seven trials, representing 3,009 patients, were included to make up a total of 16 analyzed arms. The ratio of the 12-month OS milestone rate (r = -0.790, P = 0.011, R2 = 0.717) and 12-month OS milestone RMST (r = 0.798, P = 0.010, R2 = 0.702) was strongly correlated with the hazard ratio (HR) for OS. The strongest association was observed between the ratio of the 24-month OS milestone RMST and the HR for OS (r = 0.922, P = 0.001, R2 = 0.825). No associations were observed between the HR for OS and PFS and the RR for ORR and DCR. CONCLUSIONS: The results suggested a strong correlation among the ratio of OS milestone rates at 12 months, ratios of OS milestone RMSTs at 12 and 24 months, and HR for OS. The results indicate that OS milestone rates and OS milestone RMSTs could be considered surrogate endpoints of OS in future first-line immunotherapy trials for ES-SCLC.

Variation of Signal Reflection on Electrodes of Silicon Mach-Zehnder Modulators: Influence of Nanoscale Variation and Mitigation Strategies.

Driving signal reflection on traveling wave electrodes (TWEs) is a critical issue in Mach-Zehnder modulators. Fabrication variation often causes a random variation in the electrode impedance and the signal reflection, which induces modulation characteristics variation. The variation of reflection could be intertwined with the variation of other electrode characteristics, such as microwave signal attenuation, resulting in complexity. Here, we characterize the (partial) correlation coefficients between the reflection and modulation characteristics at different bit rates. Decreasing correlation at higher bit rates is observed. Device physics analysis shows how the observed variation can be related to nanoscale variation of material properties, particularly in the embedded diode responsible for electro-optic modulation. We develop a detailed theory to analyze two variation modes of the diode (P-i-N diode or overlapping P/N regions), which reveal insight beyond simplistic diode models. Microwave signal attenuation tends to reduce the correlation with on-electrode reflection, particularly at high bit rates. The theory shows the relative importance of conductor-induced attenuation and "dielectric"-induced attenuation, with different dependence on the frequency and fabrication variation. Strategies on how to mitigate the effect of variation for better fabrication tolerance are discussed by considering three key factors: pre-shift in structural design, bias condition, and fabrication control accuracy.

Diversity of locally produced IFN-α subtypes in human nasopharyngeal epithelial cells and mouse lung tissues during influenza virus infection.

The excessively expressed interferon-α (IFN-α) might contribute to the uncontrolled inflammatory responses, causing pathological damage during influenza virus infection. However, the correlation of the pathological damage with the expression profile of IFN-α subtypes in the focus of infection with influenza viruses is poorly understood. To investigate this, we detected the IFN-α subtype dominance in human respiratory epithelial cells and mouse lungs, both of which were infected with influenza viruses. It was found that IFN-α1, IFN-α6, IFN-α14, and IFN-α16 were dominantly expressed in respiratory epithelial cells from the patients infected with IAV, whereas IFN-α5, IFN-α8, and IFN-α21 were dominantly expressed in respiratory epithelial cells from the patients infected with less pathogenic IBV and that IFN-α1, IFN-α9, and IFN-α15 were dominantly expressed in lungs of the mice infected with H1N1 IAV, and IFN-α2, IFN-α12, and IFN-α13 were dominantly expressed in lungs of the mice infected with less pathogenic H9N2 IAV. Compared with H9N2 IAV, H1N1 IAV induced higher mortality rates and more obvious body weight loss in the mice. In addition, IAV or H1N1 IAV induced a significantly higher level of CXCL10 mRNA in the human respiratory epithelial cells or the mouse lungs, respectively. In mice, the high level of Cxcl10 mRNA was accompanied by the abundant infiltrated neutrophils and more severe pathological changes in the lungs. Together, the data presented here indicate that the pathogenicity of influenza viruses is correlated with the IFN-α subtypes induced by influenza viruses. KEY POINTS: • Different influenza viruses induce differential inflammation responses. • Various influenza viruses induce diverse expression profiles of IFN-α subtypes. • The locally produced IFN-α subtypes correlated to the differential inflammation. Graphical abstract.

Rae1 drives NKG2D binding-dependent tumor development in mice by activating mTOR and STAT3 pathways in tumor cells.

Natural killer group 2 member D (NKG2D) ligands (NKG2DLs) on tumor cells engage NKG2D and mediate killing by NKG2D+ immune cells. However, tumor cells with high levels of NKG2DLs are still malignant and proliferate rapidly. We investigated the reason for NKG2DL-expressing cell progression. Tumor cells in mice were assessed for their NKG2DL expression, ability to attract immune cells, tumorigenicity, mTOR, and signal transducer and activator of transcription 3 (STAT3) signaling activation. Antibody blockade was used to determine the effect of NKG2DL-NKG2D interaction on signaling activation in vitro. Retinoic acid early inducible gene 1 (Rae1) was related to the expression of other NKG2DLs, the promotion of tumorigenicity, Mmp2 expression, mTOR and STAT3 phosphorylation in GL261 cells, and the recruitment of NKG2D+ cells in mice. Rae1 also induced NKG2DL expression, mTOR, and STAT3 phosphorylation in GL261 cells and LLC cells, but not in B16 and Pan02 cells, which did not express NKG2DLs, when cocultured with PBMCs; the induced phosphorylation was eliminated by Rae1-NKG2D blockade. Inhibition of mTOR and/or STAT3 decreased PBMC-induced migration and proliferation of GL261 cells in vitro. Rae1, a NKG2DL on tumor cells, plays a driving role in the expression of other NKG2DLs and in tumor development in mice by activating mTOR and STAT3 pathways, relying on its interaction with NKG2D on immune cells.