IL-3-driven T cell-basophil crosstalk enhances antitumor immunity.

Cytotoxic T lymphocytes (CTLs) are pivotal in combating cancer, yet their efficacy is often hindered by the immunosuppressive tumor microenvironment, resulting in exhaustion. This study investigates the role of interleukin (IL)-3 in orchestrating anti-tumor immunity through CTL modulation. Intratumoral CTLs undergo a progressive decline in IL-3 production, which is correlated with impaired cytotoxic function. Augmenting IL-3 supplementation, through intraperitoneal administration of recombinant IL-3, IL-3-expressing tumor cells, or IL-3-engineered CD8+ T cells, confers protection against tumor progression, concomitant with increased CTL activity. CTLs are critical in this therapeutic efficacy as IL-3 demonstrates no impact on tumor growth in Rag1 knockout mice or following CD8+ T cell-depletion. Rather than acting directly, CTL-derived IL-3 exerts its influence on basophils, synergistically amplifying anti-tumor immunity within CTLs. Introducing IL-3-activated basophils retards tumor progression, whereas basophil depletion diminishes the effectiveness of IL-3 supplementation. Furthermore, IL-3 prompts basophils to produce IL-4, which subsequently elevates CTL IFN-γ production and viability. Notably, the importance of basophil-derived IL-4 is evident from the absence of benefits of IL-3-supplementatation in IL-4 knockout tumor-bearing mice. Overall, this research unveils IL-3-mediated CTL-basophil crosstalk in regulating anti-tumor immunity, and offers the prospect of harnessing IL-3 sustenance as a promising approach for optimizing and enhancing cancer immunotherapy.

cGAS suppresses hepatocellular carcinoma independent of its cGAMP synthase activity.

Cyclic GMP-AMP synthase (cGAS) is a key innate immune sensor that recognizes cytosolic DNA to induce immune responses against invading pathogens. The role of cGAS is conventionally recognized as a nucleotidyltransferase to catalyze the synthesis of cGAMP upon recognition of cytosolic DNA, which leads to the activation of STING and production of type I/III interferon to fight against the pathogen. However, given that hepatocytes are lack of functional STING expression, it is intriguing to define the role of cGAS in hepatocellular carcinoma (HCC), the liver parenchymal cells derived malignancy. In this study, we revealed that cGAS was significantly downregulated in clinical HCC tissues, and its dysregulation contributed to the progression of HCC. We further identified cGAS as an immune tyrosine inhibitory motif (ITIM) containing protein, and demonstrated that cGAS inhibited the progression of HCC and increased the response of HCC to sorafenib treatment by suppressing PI3K/AKT/mTORC1 pathway in cellular and animal models. Mechanistically, cGAS recruits SH2-containing tyrosine phosphatase 1 (SHP1) via ITIM, and dephosphorylates p85 in phosphatidylinositol 3-kinase (PI3K), which leads to the suppression of AKT-mTORC1 pathway. Thus, cGAS is identified as a novel tumor suppressor in HCC via its function independent of its conventional role as cGAMP synthase, which indicates a novel therapeutic strategy for advanced HCC by modulating cGAS signaling.

Effect of COVID-19 inactivated vaccine on peripheral blood anti-ß2-GPI antibody and outcomes in vitro fertilization-embryo transplantation.

Corona Virus Disease 2019 (COVID-19) is an acute respiratory infection and a global public health event. The level of aß2GPI is significantly up-regulated in COVID-19 patients. The impact of inactivated vaccination against COVID-19 on aß2GPI and in vitro fertilization and embryo transfer (IVF-ET) remains unknown amidst the universal administration of COVID-19 vaccines. We conducted a retrospective study to assess the impact of COVID-19 inactivated vaccination on aß2GPI levels and its effect on superovulation and pregnancy outcomes. We found aß2GPI level is significantly up-regulated after vaccination. There was no statistical difference in mature egg rate, 2PN fertilization rate, day 3 high-quality embryo rate, blastocyst formation rate, embryo implantation rate and miscarriage rate between the vaccine group and control group. Our findings showed vaccination with COVID-19 inactivated vaccine can elevate the level of aß2GPI in peripheral blood but have no effect on the outcomes of controlled ovarian hyperstimulation and pregnancy in IVF-ET.

MOTS-c: A potential anti-pulmonary fibrosis factor derived by mitochondria.

Pulmonary fibrosis (PF) is a serious lung disease characterized by diffuse alveolitis and disruption of alveolar structure, with a poor prognosis and unclear etiopathogenesis. While ageing, oxidative stress, metabolic disorders, and mitochondrial dysfunction have been proposed as potential contributors to the development of PF, effective treatments for this condition remain elusive. However, Mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), a peptide encoded by the mitochondrial genome, has shown promising effects on glucose and lipid metabolism, cellular and mitochondrial homeostasis, as well as the reduction of systemic inflammatory responses, and is being investigated as a potential exercise mimetic. Additionally, dynamic expression changes of MOTS-c have been closely linked to ageing and ageing-related diseases, indicating its potential as an exercise mimetic. Therefore, the review aims to comprehensively analyze the available literature on the potential role of MOTS-c in improving PF development and to identify specific therapeutic targets for future treatment strategies.

αCGRP deficiency aggravates pulmonary fibrosis by activating the PPARγ signaling pathway.

In order to explore whether αCGRP (Calca) deficiency aggravates pulmonary fibrosis (PF). Clinical data from patients with PF (n = 52) were retrospectively analyzed. Lung tissue from a bleomycin (BLM)-induced rat model was compared with that of Calca-knockout (KO) and wild type (WT) using immunohistochemistry, RNA-seq, and UPLC-MS/MS metabolomic analyses. The results showed that decreased αCGRP expression and activation of the type 2 immune response were detected in patients with PF. In BLM-induced and Calca-KO rats, αCGRP deficiency potentiated apoptosis of AECs and induced M2 macrophages. RNA-seq identified enrichment of pathways involved in nuclear translocation and immune system disorders in Calca-KO rats compared to WT. Mass spectrometry of lung tissue from Calca-KO rats showed abnormal lipid metabolism, including increased levels of LTB4, PDX, 1-HETE. PPAR pathway signaling was significantly induced in both transcriptomic and metabolomic datasets in Calca-KO rats, and immunofluorescence analysis confirmed that the nuclear translocation of PPARγ in BLM-treated and Calca-KO rats was synchronized with STAT6 localization in the cytoplasmic and nuclear fractions. In conclusion, αCGRP is protective against PF, and αCGRP deficiency promotes M2 polarization of macrophages, probably by activating the PPARγ pathway, which leads to activation of the type 2 immune response and accelerates PF development.

Analysis of risk factors of lower extremity deep venous thrombosis in patients undergoing hepatobiliary surgery.

This study analyzed records of 200 patients who underwent hepatobiliary surgery to identify factors that contribute to lower extremity venous thromboembolism (VTE). 19 patients (9.50%) developed lower extremity deep vein thrombosis. Univariate analysis revealed significant differences between the study group and the control group in terms of age, body mass index, previous thromboembolic history, hypertension, type 2 diabetes, hyperlipidemia, smoking history, times of lower extremity venipuncture, operation time, postoperative bedrest time, postoperative platelet count, postoperative D-dimer level, and postoperative C-reactive protein level (P<0.05). Multivariable logistic regression analysis identified age ≥60 years, body mass index ≥24 kg/m2, previous history of thromboembolism, hypertension, type 2 diabetes mellitus, hyperlipidemia, smoking history, number of lower extremity venipunctures ≥5, operation time ≥2 hours, postoperative bedrest time ≥48 hours, postoperative blood platelet count ≥300×109/L, postoperative D-dimer level ≥200 g/L, and postoperative C-reactive protein ≥8.0 mg/L as significant predisposing factors for lower extremity VTE. The study concludes that patients undergoing hepatobiliary surgery are at an increased risk of developing lower extremity VTE, and prevention strategies must be tailored to each patient's unique set of risk factors. This includes careful management of postoperative bed rest, monitoring of platelet count, D-dimer and C-reactive protein levels, controlling hypertension, type 2 diabetes mellitus, hyperlipidemia, and cessation of smoking. This study highlights the importance of early identification of patients at high risk of lower extremity VTE following hepatobiliary surgery and comprehensive prevention measures.

Selective deficiency of UCP-1 and adropin may lead to different subtypes of anti-neutrophil cytoplasmic antibody-associated vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease that is prone to respiratory and renal failures. Its major target antigens are serine protease 3 (PR3) and myeloperoxidase (MPO), but the determinants of PR3 and MPO subtypes are still unclear. Uncoupling protein-1 (UCP-1) and adropin (Adr) regulate mutually and play an important role in endothelial cell injury. In this study, adropin and UCP-1 knockout (AdrKO and UCP-1-KO) models were established on the basis of C57BL/6 J mice. The results showed that UCP-1-KO and AdrKO mice similar to AAV: significant inflammatory cell infiltration, vascular wall damage, and erythrocyte extravasation. The pathological basis of AdrKO was that endothelial cells adhered and activated neutrophils to release MPO, and the core gene was peroxisome proliferator-activated receptor gamma (PPARG). However, UCP-1-KO induced PR3 release, and the accumulation and expression of tissue factor on the vascular wall, and the core gene was peroxisome proliferator-activated receptor delta (PPARD). The present study verified that the subtypes of AAV may be genetically different diseases and it also provide novel experimental evidence for clinical differentiation of the two subtypes.

TRIM50 promotes NLRP3 inflammasome activation by directly inducing NLRP3 oligomerization.

Tripartite motif protein (TRIM) 50 is a new member of the tripartite motif family, and its biological function and the molecular mechanism it is involved in remain largely unknown. The NOD-like receptor family protein (NLRP)3 inflammasome is actively involved in a wide array of biological processes while mechanisms of its regulation remain to be fully clarified. Here, we demonstrate the role of TRIM50 in NLRP3 inflammasome activation. In contrast to the conventional E3 ligase functions of TRIM proteins, TRIM50 mediates direct oligomerization of NLRP3, thereby suppressing its ubiquitination and promoting inflammasome activation. Mechanistically, TRIM50 directly interacts with NLRP3 through its RING domain and induces NLRP3 oligomerization via its coiled-coil domain. Finally, we show that TRIM50 promotes NLRP3 inflammasome-mediated diseases in mice. We thus reveal a novel regulatory mechanism of NLRP3 via TRIM50 and suggest that modulating TRIM50 might represent a therapeutic strategy for NLRP3-dependent pathologies.

Trypsin may induce cytokine storm in M1 macrophages, resulting in critical coronavirus disease.

Trypsin is a protease-activated receptor-2 (PAR2) activator that upregulates the interleukin (IL)-17 receptor signal in the airway epithelial cells and amplifies the inflammatory response, but does not modify the growth kinetics of the metapneumovirus. How does the coronavirus spread from cell to cell is yet an enigma. The present study analyzed the possible role of trypsin in the activation of coronavirus in vitro and in vivo. We found that the overexpression of trypsin in A549 cells upregulated IL-17 and angiotensin-converting enzyme (ACE). In the humanized transgenic mice, trypsin activated M1 macrophages. Together, our results suggested that the upregulation of trypsin may support a new pathway for coronavirus transmission in patients.

Biocatalysis-mediated MOF-to-prussian blue transformation enabling sensitive detection of NSCLC-associated miRNAs with dual-readout signals.

Sensitive and accurate miRNAs assay is critical for early diagnosis of non-small-cell lung carcinomas (NSCLC). Herein, we demonstrate a photothermal and electrochemical dual-readout assay method for miRNA detection based on a novel biocatalysis-mediated MOF-to-prussian blue (PB) transformation (BMMPT) strategy and the catalytic hairpin assembly (CHA) amplification strategy. It is found that the Fe2+-based MOF (MOF-Fe2+) can act as the Fe2+ source to react with K3[Fe(CN)6], leading to the in-situ formation of prussian blue (PB) on MOF-Fe2+. Due the inherent near-infrared (NIR) photothermal conversion ability and electrochemical signal of PB, the resulting PB@MOF-Fe2+ is employed to arouse temperature readout or electrochemical signal. The presence of target miRNA-21 triggers the CHA reaction on magnetic beads (MBs), resulting the capture of numerous glucose oxidase (GOx) tags on MBs. The GOx tags then catalyze the generation of H2O2 using glucose as substrate. The H2O2 is used to inhibit the MOF-to-PB transformation process by oxidizing Fe2+ into Fe3+, leading to the decrease in temperature and electrochemical readout aroused by PB@MOF-Fe2+. By this means, a signal-off assay mode with dual readout is established for miRNA-21. Under the optimal conditions, using temperature readout or electrochemical readout, miRNA-21 can be detected at concentrations as low as 0.3 fM and 0.32 fM, respectively. Moreover, the developed method is successfully applied to evaluate the expression level of miRNA-21 in serum of NSCLC patients. This work not only provides a practical tool for NSCLC diagnosis but also presents the new features of MOF materials as signal transduction tags.

CGRP: A New Endogenous Cell Stemness Maintenance Molecule.

Stem cells have the ability of self-replication and multidirectional differentiation, but the mechanism of how stem cells "maintain" this ability and how to "decide" to give up this state and differentiate into cells with specific functions is still unknown. The Nobel Prize in physiology and medicine in 2021 was awarded to "temperature and tactile receptor," which made the pain receptor TRPV1-calcitonin gene-related peptide (CGRP) pathway active again. The activation and blocking technology of CGRP has been applied to many clinical diseases. CGRP gene has complex structure and transcription process, with multiple methylation and other modification sites. It has been considered as a research hotspot and difficulty since its discovery. Drug manipulation of TRPV1 and inhibition of CGRP might improve metabolism and prolong longevity. However, whether the TRPV1-neuropeptide-CGRP pathway is directly or indirectly involved in stem cell self-replication and multidirectional differentiation is unclear. Recent studies have found that CGRP is closely related to the migration and differentiation of tumor stem cells, which may be realized by turning off or turning on the CGRP gene expression in stem cells and activating a variety of ways to regulate stem cell niches. In this study, we reviewed the advances in researches concentrated on the biological effects of CGRP as a new endogenous switching of cell stemness.

Erratum: Clinical and pathological characteristics of IgG4-related interstitial lung disease.

[This corrects the article DOI: 10.3892/etm.2017.5554.].

Inhibiting Src-mediated PARP1 tyrosine phosphorylation confers synthetic lethality to PARP1 inhibition in HCC.

Hepatocellular carcinoma (HCC), a heterogeneous cancer with high mortality, is resistant to single targeted therapy; thus, combination therapy based on synthetic lethality is a promising therapeutic strategy for HCC. Poly (adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1) is the most recognized target for synthetic lethality; however, the therapeutic effect of PARP1 inhibition on HCC is disappointing. Therefore, exploring new synthetic lethal partners for the efficient manipulation of HCC is urgently required. In this study, we identified Src and PARP1 as novel synthetic lethal partners, and the combination therapy produced significant anti-tumor effects without causing obvious side effects. Mechanistically, Src interacted with PARP1 and phosphorylated PARP1 at the Y992 residue, which further mediated resistance to PARP1 inhibition. Overall, this study revealed that Src-mediated PARP1 phosphorylation induced HCC resistance to PARP1 inhibitors and indicated a therapeutic window of the Y992 phosphorylation of PARP1 for HCC patients. Moreover, synthetic lethal therapy by co-targeting PARP1 and Src have the potential to broaden the strategies for HCC and might benefit HCC patients with high Src activation and resistance to PARP1 inhibitors alone.

Potential benefits of precise corticosteroid therapy for critical COVID-19.

This study was aimed to explore the precise dose of corticosteroid therapy in critical COVID-19. A total of forty-five critical COVID-19 patients were enrolled. The process of critical COVID-19 was divided into alveolitis and fibrosis stages. Most nonsurvivors died in fibrosis phase. Nonsurvivors had more dyspnea symptoms, fewer days of hospitalization, shorter duration of alveolitis and fibrosis. High-dose daily corticosteroid therapy (≥150 mg/d) was associated with shorter survival time and lower lymphocyte count in fibrosis phase. Moreover, a high cumulative dose (≥604 mg) was tied to longer duration of virus shedding, lower oxygenation index (OI), higher incidence of tracheal intubation, fewer lymphocytes and higher levels of C-reactive protein (CRP) and lactate dehydrogenase (LDH). In alveolitis phase, the low-to-moderate-dose daily corticosteroid therapy and a small cumulative dose reduced lymphocytes. In conclusion, low-to-moderate dose corticosteroids may be beneficial in the fibrosis phase. High-dose corticosteroid therapy in the fibrosis phase aggravates the severity of critical COVID-19.

Early Prediction of Severe COVID-19 in Patients by a Novel Immune-Related Predictive Model.

During the progression of coronavirus disease 2019 (COVID-19), immune response and inflammation reactions are dynamic events that develop rapidly and are associated with the severity of disease. Here, we aimed to develop a predictive model based on the immune and inflammatory response to discriminate patients with severe COVID-19. COVID-19 patients were enrolled, and their demographic and immune inflammatory reaction indicators were collected and analyzed. Logistic regression analysis was performed to identify the independent predictors, which were further used to construct a predictive model. The predictive performance of the model was evaluated by receiver operating characteristic curve, and optimal diagnostic threshold was calculated; these were further validated by 5-fold cross-validation and external validation. We screened three key indicators, including neutrophils, eosinophils, and IgA, for predicting severe COVID-19 and obtained a combined neutrophil, eosinophil, and IgA ratio (NEAR) model (NEU [109/liter] - 150×EOS [109/liter] + 3×IgA [g/liter]). NEAR achieved an area under the curve (AUC) of 0.961, and when a threshold of 9 was applied, the sensitivity and specificity of the predicting model were 100% and 88.89%, respectively. Thus, NEAR is an effective index for predicting the severity of COVID-19 and can be used as a powerful tool for clinicians to make better clinical decisions. IMPORTANCE The immune inflammatory response changes rapidly with the progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and is responsible for clearance of the virus and further recovery from the infection. However, the intensified immune and inflammatory response in the development of the disease may lead to more serious and fatal consequences, which indicates that immune indicators have the potential to predict serious cases. Here, we identified both eosinophils and serum IgA as prognostic markers of COVID-19, which sheds light on new research directions and is worthy of further research in the scientific research field as well as clinical application. In this study, the combination of NEU count, EOS count, and IgA level was included in a new predictive model of the severity of COVID-19, which can be used as a powerful tool for better clinical decision-making.

Methylation of CALCA and CALCB in Pancreatic Ductal Adenocarcinoma.

Calcitonin gene-related peptide (CGRP) plays a diverse and intricate role in chronic low-grade inflammation and is closely related to specific cancers. It includes two subtypes, CALCA (αCGRP) and CALCB (ßCGRP), of which αCGRP expression accounts for more than 90%. Here, we show that methylation of CALCA and CALCB in pancreatic ductal adenocarcinoma was significantly higher than that in paracancer. Western blot and immunohistochemistry showed that CGRP, p-AKT, and p-CREB in the tumor tissues were lower than those in the paracarcinoma tissues. In vivo, the expressions of p-AKT and p-CREB in the pancreatic tissues of CALCA-KO rats were also lower than those of wild type. Methylation of CALCA and CALCB is increased in pancreatic adenocarcinoma, and under that condition, p-AKT and p-CREB levels were decreased.

CALCB rs3829222 T/T Genotype and Low Expression of CALCB Are High-Risk Factors for Adenoid Cystic Carcinoma of Salivary Gland.

OBJECTIVES: To investigate the relationship between polymorphisms of calcitonin-related peptide gene II (beta-calcitonin gene-related peptide (ßCGRP), CALCB) and serum CGRP levels in salivary adenoid cystic carcinoma. MATERIALS AND METHODS: Using the polymerase chain reaction (PCR) technique, the full-length amplification and genotype analysis of CALCB genes were performed in 39 patients with adenoid cystic carcinoma of salivary gland and 158 normal controls. The gene frequencies of major genotype of CALCB in adenoid cystic carcinoma of salivary gland and normal control group were analyzed. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate serum calcitonin gene-related peptide (CGRP) and its concentration of alpha and beta subtypes. RESULTS: Univariate logistic regression analysis showed that the CALCB rs2839222 T/T genotype was closely related to the occurrence of salivary adenoid cystic carcinoma, with a correlation coefficient of 3.89. CONCLUSIONS: The serum CGRP concentration in the salivary adenoid cystic carcinoma group was 1.56 times that of the normal control group. The αCGRP subtype was significant, which was 3.02 times that of the normal control. The polymorphism of ßCGRP gene is associated with genetic susceptibility to salivary adenoid cystic carcinoma, and serum CGRP and ßCGRP can be used as novel markers of salivary adenoid cystic carcinoma.

Sieve-Like CNT Film Coupled with TiO2 Nanowire for High-Performance Continuous-Flow Photodegradation of Rhodamine B under Visible Light Irradiation.

Continuous-flow photoreactors hold great promise for the highly efficient photodegradation of pollutants due to their continuity and sustainability. However, how to enable a continuous-flow photoreactor with the combined features of high photodegradation efficiency and durability as well as broad-wavelength light absorption and large-scale processing remains a significant challenge. Herein, we demonstrate a facile and effective strategy to construct a sieve-like carbon nanotube (CNT)/TiO2 nanowire film (SCTF) with superior flexibility (180° bending), high tensile strength (75-82 MPa), good surface wettability, essential light penetration and convenient visible light absorption. Significantly, the unique architecture, featuring abundant, well-ordered and uniform mesopores with ca. 70 µm in diameter, as well as a homogenous distribution of TiO2 nanowires with an average diameter of ca. 500 nm, could act as a "waterway" for efficient solution infiltration through the SCTF, thereby, enabling the photocatalytic degradation of polluted water in a continuous-flow mode. The optimized SCTF-2.5 displayed favorable photocatalytic behavior with 96% degradation of rhodamine B (RhB) within 80 min and a rate constant of 0.0394 min-1. The continuous-flow photodegradation device made using SCTF-2.5 featured exceptional photocatalytic behavior for the continuous degradation of RhB under simulated solar irradiation with a high degradation ratio (99.6%) and long-term stability (99.2% retention after working continuously for 72 h). This work sheds light on new strategies for designing and fabricating high-performance continuous-flow photoreactors toward future uses.

Bean-Pod-Inspired 3D-Printed Phase Change Microlattices for Solar-Thermal Energy Harvesting and Storage.

Effective and reliable encapsulation of phase change materials (PCMs) is essential and critical to the high-performance solar-thermal energy harvesting and storage. However, challenges remain pertaining to manufacturing scalability, high efficiency in energy storage/release, and anti-leakage of melted PCMs. Herein, inspired by natural legume, a facile and scalable extrusion-based core-sheath 3D printing strategy is demonstrated for directly constructing bean-pod-structured octadecane (OD)/graphene (BOG) phase change microlattices, with regular porous configuration as well as individual and effective encapsulation of OD "beans" into highly interconnected graphene network wrapping layer built by closely stacked and aligned graphene sheets. The unique architectural features enable the ready spreading of light into the interior of phase change microlattice, a high transversal thermal conductivity of 1.67 W m-1 K-1 , and rapid solar-thermal energy harvesting and transfer, thereby delivering a high solar-thermal energy storage efficiency, and a large phase change enthalpy of 190 J g-1 with 99.1% retention after 200 cycles. Most importantly, such encapsulated PCMs feature an exceptional thermal reliability and stability, with no leakage and shape variation even at 1000 thermal cycles and partial damage of BOG. This work validates the feasibility of scalably printing practical encapsulated PCMs, which may revolutionize the fabrication of composite PCMs for solar-thermal energy storage devices.

A review of the mechanism of DDIT4 serve as a mitochondrial related protein in tumor regulation.

DDIT4 is a mitochondrial and tumor-related protein involved in anti-tumor therapy resistance, proliferation, and invasion, etc. Its expression level increases under the stress such as chemotherapy, hypoxia, and DNA damage. A number of clinical studies have confirmed that DDIT4 can change the behavior of tumor cells and the prognosis of patients with cancer. However, the role of DDIT4 in promoting or suppressing cancer is still inconclusive. This article summarized the four characteristics of DDIT4 including a mitochondria-related protein, interactions with various protein molecules, immune and metabolic cell related proteins and participator in the oxygen sensing pathway, which may be related to the progress of cancer.