Single-cell RNA sequencing reveals special basal cells and fibroblasts in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is the most predominant type of idiopathic interstitial pneumonia and has an increasing incidence, poor prognosis, and unclear pathogenesis. In order to investigate the molecular mechanisms underlying IPF further, we performed single-cell RNA sequencing analysis on three healthy controls and five IPF lung tissue samples. The results revealed a significant shift in epithelial cells (ECs) phenotypes in IPF, which may be attributed to the differentiation of alveolar type 2 cells to basal cells. In addition, several previously unrecognized basal cell subtypes were preliminarily identified, including extracellular matrix basal cells, which were increased in the IPF group. We identified a special population of fibroblasts that highly expressed extracellular matrix-related genes, POSTN, CTHRC1, COL3A1, COL5A2, and COL12A1. We propose that the close interaction between ECs and fibroblasts through ligand-receptor pairs may have a critical function in IPF development. Collectively, these outcomes provide innovative perspectives on the complexity and diversity of basal cells and fibroblasts in IPF and contribute to the understanding of possible mechanisms in pathological lung fibrosis.

Development of an instrument to measure the competencies of health professionals in the process of evidence-based healthcare: A Delphi study.

AIMS: To identify and reach consensus on dimensions and criteria of a competence assessment instrument for health professionals in relation to the process of evidence-based healthcare. DESIGN: A two-round Delphi survey was carried out from April to June 2023. METHODS: Consensus was sought from an expert panel on the instrument preliminarily established based on the JBI Model of Evidence-Based Healthcare and a rapid review of systematic reviews of relevant literature. The level of consensus was reflected by the concentration and coordination of experts' opinions and percentage of agreement. The instrument was revised significantly based on the combination of data analysis, the experts' comments and research group discussions. RESULTS: Sixteen national and three international experts were involved in the first-round Delphi survey and 17 experts participated in the second-round survey. In both rounds, full consensus was reached on the four dimensions of the instrument, namely evidence-generation, evidence-synthesis, evidence-transfer and evidence-implementation. In round-one, the instrument was revised from 77 to 61 items. In round-two, the instrument was further revised to have 57 items under the four dimensions in the final version. CONCLUSION: The Delphi survey achieved consensus on the instrument. The validity and reliability of the instrument needs to be tested in future research internationally. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Systematic assessment of nurses and other health professionals' competencies in different phases of evidence-based healthcare process based on this instrument provides implications for their professional development and multidisciplinary team collaboration in evidence-based practice and better care process and outcomes. IMPACT: This study addresses a research gap of lacking an instrument to systematically assess interprofessional competencies in relation to the process of EBHC. The instrument covers the four phases of EBHC process with minimal criteria, highlighting essential aspects of ability to be developed. Identification of health professionals' level of competence in these aspects helps strengthen their capacity accordingly so as to promote virtuous EBHC ecosystem for the ending purpose of improving global healthcare outcomes. REPORTING METHOD: This study was reported in line with the Conducting and REporting of DElphi studies (CREDES) guidance on Delphi studies. PATIENT AND PUBLIC CONTRIBUTION: No patient or public contribution.

A small molecule compound targeting hemagglutinin inhibits influenza A virus and exhibits broad-spectrum antiviral activity.

Influenza A virus (IAV) is a widespread pathogen that poses a significant threat to human health, causing pandemics with high mortality and pathogenicity. Given the emergence of increasingly drug-resistant strains of IAV, currently available antiviral drugs have been reported to be inadequate to meet clinical demands. Therefore, continuous exploration of safe, effective and broad-spectrum antiviral medications is urgently required. Here, we found that the small molecule compound J1 exhibited low toxicity both in vitro and in vivo. Moreover, J1 exhibits broad-spectrum antiviral activity against enveloped viruses, including IAV, respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human coronavirus OC43 (HCoV-OC43), herpes simplex virus type 1 (HSV-1) and HSV-2. In this study, we explored the inhibitory effects and mechanism of action of J1 on IAV in vivo and in vitro. The results showed that J1 inhibited infection by IAV strains, including H1N1, H7N9, H5N1 and H3N2, as well as by oseltamivir-resistant strains. Mechanistic studies have shown that J1 blocks IAV infection mainly through specific interactions with the influenza virus hemagglutinin HA2 subunit, thereby blocking membrane fusion. BALB/c mice were used to establish a model of acute lung injury (ALI) induced by IAV. Treatment with J1 increased survival rates and reduced viral titers, lung index and lung inflammatory damage in virus-infected mice. In conclusion, J1 possesses significant anti-IAV effects in vitro and in vivo, providing insights into the development of broad-spectrum antivirals against future pandemics.

Photoluminescence Enhancement of 0D Organic-Inorganic Metal Halides via Aggregation-Induced Emission and Halide Substitution.

0D organic-inorganic metal halides (OIMHs) provide unprecedented versatility in structures and photoluminescence properties. Here, a series of bluish-white emissive 0D OIMHs, (TPE-TPP)2Sb2BrxCl8-x (x = 1.16 to 8), are prepared by assembling the 1-triphenylphosphonium-4-(1,2,2-triphenylethenyl)benzene cation (TPE-TPP)+ with antimony halides anions. Based on experimental characterizations and theoretical calculations, the emission of the 0D OIMHs are attributed to the fluorescence of the organic cations with aggregation-induced emission (AIE) properties. The 0D structure minimized the molecular motion and intermolecular interactions between (TPE-TPP)+ cations, effectively suppressing the non-radiative recombination processes. Consequently, the photoluminescence quantum efficiency (PLQE) of (TPE-TPP)2Sb2Br1.16Cl6.84 is significantly enhanced to 55.4% as compared to the organic salt (TPE-TPP)Br (20.5%). The PLQE of (TPE-TPP)2Sb2BrxCl8-x can also be readily manipulated by halide substitution, due to the competitive processes between non-radiative recombination on the inorganic moiety and the energy transfer from inorganic to organic. In addition, electrically driven light-emitting diodes (LEDs) are fabricated based on (TPE-TPP)2Sb2Br1.16Cl6.84 emitter, which exhibited bluish-white emission with a maximum external quantum efficiency (EQE) of 1.1% and luminance of 335 cd m-2. This is the first report of electrically driven LED based on 0D OIMH with bluish-white emission.

Heterozygous variants in USP25 cause genetic generalized epilepsy.

USP25 encodes ubiquitin-specific proteases 25, a key member of deubiquitinating enzyme family and is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown etiology. Five heterozygous USP25 variants including two de novo and three co-segregated variants were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared to the East Asian population and all populations in the gnomAD database. The mean onset ages of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom except one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was ubiquitously expressed in mouse brain with two peaks on embryonic days (E14‒E16) and postnatal day 21, respectively. Similarly, USP25 expressed in fetus/early childhood stage with a second peak at approximately 12‒20 years old in human brain, consistent with the seizure onset age at infancy and juvenile in the patients. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knock-out mice, which showed increased seizure susceptibility compared to wild-type mice in pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we employed multiple functional detections. In HEK293T cells, the severe phenotype associated variant (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed a stable truncated dimers with increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del increased neuronal excitability in mice brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.

Analysis of CCND3 mutations in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL), accounts for 30-40% of newly diagnosed lymphomas, has an overall cure rate of approximately 60%. Despite previous reports suggesting a negative prognostic association between CCND3 mutations and Burkitt lymphoma, their prognostic implications in DLBCL remain controversial. To investigate this, we evaluated CCND3 mutation status in 2059 DLBCL patient samples from four database (integrated cohort) and additional 167 DLBCL patient samples in our center (JSPH cohort). The mutation was identified in 5.5% (113/2059) of the cases in the integrated cohort, with 86% (97/113) found in exon 5. Furthermore, P284, R271, I290 and Q276 are described as CCND3 mutation hotspots. CCND3 mutation was associated with decreased overall survival (OS) in the integrated cohort (P = 0.0407). Further subgroup analysis revealed that patients diagnosed as EZB subtype DLBCL by LymphGen algorithm with CCND3 mutations had poorer OS than patients diagnosed as EZB subtype without CCND3 mutations (P = 0.0140). Using the next-generation sequencing (NGS) in the JSPH cohort, it was found that both cell cycle and DNA replication pathways were highly upregulated in patients with CCND3 mutations. Our results suggest that CCND3 mutations can serve as a novel prognostic factor in DLBCL pathogenesis. Consequently, the development of personalized therapeutic strategies for DLBCL patients with CCND3 mutations might enhance their prognosis.

Multi-omic Analysis of Human B-cell Activation Reveals a Key Lysosomal BCAT1 Role in mTOR Hyperactivation by B-cell receptor and TLR9.

B-lymphocytes play major adaptive immune roles, producing antibody and driving T-cell responses. However, how immunometabolism networks support B-cell activation and differentiation in response to distinct receptor stimuli remains incompletely understood. To gain insights, we systematically investigated acute primary human B-cell transcriptional, translational and metabolomic responses to B-cell receptor (BCR), Toll-like receptor 9 (TLR9), CD40-ligand (CD40L), interleukin-4 (IL4) or combinations thereof. T-independent BCR/TLR9 co-stimulation, which drives malignant and autoimmune B-cell states, jointly induced PD-L1 plasma membrane expression, supported by NAD metabolism and oxidative phosphorylation. BCR/TLR9 also highly induced the transaminase BCAT1, which localized to lysosomal membranes to support branched chain amino acid synthesis and mTORC1 hyperactivation. BCAT1 inhibition blunted BCR/TLR9, but not CD40L/IL4-triggered B-cell proliferation, IL10 expression and BCR/TLR pathway-driven lymphoma xenograft outgrowth. These results provide a valuable resource, reveal receptor-mediated immunometabolism remodeling to support key B-cell phenotypes including PD-L1 checkpoint signaling, and identify BCAT1 as a novel B-cell therapeutic target.

Exploring the mechanism of enterotoxicity mediated by the microbiome-butyrate-PPAR axis in podophyllotoxin through the toxicological evidence chain (TEC) concept.

Podophyllotoxin (PPT) is a lignan derived from the roots and stems of the Podophyllum plant. However, its enterotoxicity restricts its clinical application. The underlying mechanisms by which PPT exerts its action remain largely elusive. This study aimed to evaluate the molecular mechanisms underlying PPT-induced enterotoxicity utilizing the concept of toxicological evidence chain. Changes in body weight, behavior, and histopathological and biochemical markers in rats were observed. Additionally, microbiome, metabolome, and transcriptome analyses were integrated to identify potential microorganisms, metabolic markers, and major pathways using a co-occurrence network. Our findings suggested that PPT induced pathological changes in rats, including weight loss, diarrhea, and inflammation accompanied by increased levels of IFN-γ, IL-5, IL-6, GRO/KC, and IL-12p70. The decrease in butyrate levels in the PPT group may be related to the enrichment of Firmicutes. The reduction of butyrate levels may impair the expression of PPARγ, subsequently promoting Escherichia-Shigella proliferation. Additionally, the suppression of PPARs pathway may result in the increased production of inflammatory factors, contributing to enterotoxicity. This study offers a novel understanding of the molecular mechanisms underlying PPT-induced enterotoxicity, making a significant contribution to developing strategies to mitigate PPT toxicity and prevent associated diseases.

Radiating blood flow signal: A new ultrasound feature of thyroid carcinoma.

OBJECTIVE: To summary radiating blood flow signals and evaluate their diagnostic value in differentiating benign and malignant thyroid nodules. MATERIALS AND METHODS: We retrospectively recruited consecutive patients undergoing US at 4 hospitals from 2018 to 2022. In a training dataset, the correlations of US features with malignant thyroid nodules were assessed by multivariate logistic analysis. Multivariate logistic regression models involving the ACR TI-RADS score, radiating blood flow signals and their combination were built and validated internally and externally. The AUC with 95% asymptotic normal confidence interval as well as sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) with 95% exact binomial confidence intervals were calculated. RESULTS: Among 2475 patients (1818 women, age: 42.47 ± 11.57; 657 men, age: 42.16 ± 11.69), there were 3187 nodules (2342 malignant nodules and 845 benign nodules). Radiating blood flow signals were an independent risk factor for diagnosing thyroid carcinoma. In the training set, the AUC of the model using the combination of radiating blood flow signals and the ACR TI-RADS score (0.95 95 % CI: [0.94, 0.97]; P < 0.001) was significantly higher than that of the ACR TI-RADS model (0.91 [0.89, 0.93]). In the two internal validation sets and the external validation set, the AUCs of the combination model were 0.97 [0.96, 0.98], 0.92 [0.88, 0.96], and 0.91 [0.86, 0.95], respectively, and were all significantly higher than that of the ACR TI-RADS score (0.92 [0.90, 0.95], 0.86 [0.81, 0.91], 0.84 [0.79, 0.89]; P < 0.001). CONCLUSION: Radiating blood flow is a new US feature of thyroid carcinomas that can significantly improve the diagnostic performance vs. the ACR TI-RADS score.

Clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma.

The clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma (ND-DLBCL) remains largely unexplored. One hundred ND-DLBCL patients were consecutively enrolled as training cohort and another 26 ND-DLBCL patients were prospectively enrolled in validation cohort. CSF-ctDNA positivity (CSF(+)) was identified in 25 patients (25.0%) in the training cohort and 7 patients (26.9%) in the validation cohort, extremely higher than CNS involvement rate detected by conventional methods. Patients with mutations of CARD11, JAK2, ID3, and PLCG2 were more predominant with CSF(+) while FAT4 mutations were negatively correlated with CSF(+). The downregulation of PI3K-AKT signaling, focal adhesion, actin cytoskeleton, and tight junction pathways were enriched in CSF(+) ND-DLBCL. Furthermore, pretreatment CSF(+) was significantly associated with poor outcomes. Three risk factors, including high CSF protein level, high plasma ctDNA burden, and involvement of high-risk sites were used to predict the risk of CSF(+) in ND-DLBCL. The sensitivity and specificity of pretreatment CSF-ctDNA to predict CNS relapse were 100% and 77.3%. Taken together, we firstly present the prevalence and the genomic and transcriptomic landscape for CSF-ctDNA(+) DLBCL and highlight the importance of CSF-ctDNA as a noninvasive biomarker in detecting and monitoring of CSF infiltration and predicting CNS relapse in DLBCL.

Physicochemical, Quality and Flavor Characteristics of Starch Noodles with Auricularia cornea var. Li. Powder.

Auricularia cornea var. Li., as an edible mushroom rich in various nutrients, could be widely used in noodle food. This study aimed to investigate the effect of Auricularia cornea var. Li. (AU) powder on the gel properties, structure and quality of starch noodles. Taking the sample without adding AU powder as a control, the addition of AU powder enhanced the peak viscosity, trough viscosity, final viscosity, breakdown, setback, peak time, gelatinization temperature, G' (storage modulus) and G'' (loss modulus). Meanwhile, the incorporation of AU powder significantly enhanced the stability of the starch gel structure and contributed to a more ordered microstructure also promoting the short-term aging of starch paste. In vitro digestion results displayed lower rapid digestibility (21.68%) but higher resistant starch content (26.58%) with the addition of AU powder and increased breaking rate, cooking loss, swelling index and a* and b* values. However, it decreased dry matter content and L*, particularly the reducing sugar content significantly increased to 4.01% (p < 0.05), and the total amino acid content rose to 349.91 mg/g. The GC-IMS library identified 51 VOCs, and the OPLS-DA model classified 18 VOCs (VIP > 1). Overall, the findings indicate that starch noodles with the addition of AU powder may provide greater nutritional quality, gel stability and starch antidigestibility.

Standardize the surgical technique and clarify the oncologic significance of robotic D3-D4 lymphadenectomy for upper rectum and sigmoid colon cancer with clinically more than N2 lymph node metastasis.

BACKGROUND: The territory of D3-D4 lymphadenectomy for upper rectal and sigmoid colon cancer varies, and its oncological efficacy is unclear. This prospective study aimed to standardize the surgical technique of robotic D3-D4 lymphadenectomy and clarify its oncologic significance. METHODS: Patients with upper rectal or sigmoid colon cancer with clinically suspected more than N2 lymph node metastasis were prospectively recruited to undergo standardized robotic D3-D4 lymphadenectomy. Immediately postsurgery, the retrieved lymph nodes were mapped to five N3-N4 nodal stations: the inferior mesenteric artery, para-aorta, inferior vena cava, infra-renal vein, and common iliac vessels. Patients were stratified according to their nodal metastasis status to compare their clinicopathological data and overall survival. Univariate and multivariate analyses were performed to determine the relative prognostic significance of the five specific nodal stations. Surgical outcomes and functional recovery of the patients were assessed using the appropriate variables. RESULTS: A total of 104 patients who successfully completed the treatment protocol were assessed. The standardized D3-D4 lymph node dissection harvested sufficient lymph nodes (34.4±7.2) for a precise pathologic staging. Based on histopathological analysis, 28 patients were included in the N3-N4 nodal metastasis-negative group and 33, 34, and nine patients in the single-station, double-station, and triple-station nodal metastasis-positive groups, respectively. Survival analysis indicated no significant difference between the single-station nodal metastasis-positive and N3-N4 nodal metastasis-negative groups in the estimated 5-year survival rate [53.6% (95% CI: 0.3353-0.7000) vs. 71.18% (95% CI: 0.4863-0.8518), P=0.563], whereas patients with double-station or triple-station nodal metastatic disease had poor 5-year survival rates (24.76 and 22.22%), which were comparable to those of AJCC/UICC stage IV disease than those with single-station metastasis-positive disease. Univariate analysis showed that the metastatic status of the five nodal stations was comparable in predicting the overall survival; in contrast, multivariate analysis indicated that common iliac vessels and infra-renal vein were the only two statistically significant predictors (P<0.05) for overall survival. CONCLUSIONS: Using a robotic approach, D3-D4 lymph node dissection could be safely performed in a standardized manner to remove the relevant N3-N4 lymphatic basin en bloc, thereby providing significant survival benefits and precise pathological staging for patients. This study encourages further international prospective clinical trials to provide more solid evidence that would facilitate the optimization of surgery and revision of the current treatment guidelines for such a clinical conundrum.

PRMT5 activates lipid metabolic reprogramming via MYC contributing to the growth and survival of mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an incurable and aggressive subtype of non-Hodgkin B-cell lymphoma. Increased lipid uptake, storage, and lipogenesis occur in a variety of cancers and contribute to rapid tumor growth. However, no data has been explored for the roles of lipid metabolism reprogramming in MCL. Here, we identified aberrant lipid metabolism reprogramming and PRMT5 as a key regulator of cholesterol and fatty acid metabolism reprogramming in MCL patients. High PRMT5 expression predicts adverse outcome prognosis in 105 patients with MCL and GEO database (GSE93291). PRMT5 deficiency resulted in proliferation defects and cell death by CRISPR/Cas9 editing. Moreover, PRMT5 inhibitors including SH3765 and EPZ015666 worked through blocking SREBP1/2 and FASN expression in MCL. Furthermore, PRMT5 was significantly associated with MYC expression in 105 MCL samples and the GEO database (GSE93291). CRISPR MYC knockout indicated PRMT5 can promote MCL outgrowth by inducing SREBP1/2 and FASN expression through the MYC pathway.

Itaconate inhibits corticosterone-induced necroptosis and neuroinflammation via up-regulating menin in HT22 cells.

Corticosterone (CORT) damages hippocampal neurons as well as induces neuroinflammation. The tricarboxylic acid cycle metabolite itaconate has an anti-inflammatory role. Necroptosis is a form of programmed cell death, also known as inflammatory cell death. Menin is a multifunctional scaffold protein, which deficiency aggravates neuroinflammation. In this study, we explored whether itaconate inhibits CORT-induced neuroinflammation as well as necroptosis and further investigated the mediatory role of Menin in this protective effect of itaconate by using an exposure of CORT to HT22 cells (a hippocampal neuronal cell line). The viability of HT22 cells was examined by the cell counting kit 8 (CCK-8). The morphology of HT22 cells was observed by transmission electron microscope (TEM). The expressions of necroptosis-related proteins (p-RIP1/RIP1, p-RIP3/RIP3, and p-MLKL/MLKL) were evaluated by western blotting. The contents of inflammatory factors were detected by an enzyme-linked immunosorbent assay (ELISA) kit. Our results showed that CORT increases the contents of pro-inflammatory factors (IL-1ß, TNF-α) as well as decreases the contents of anti-inflammatory factors (IL-4, IL-10) in HT22 cells. We also found that CORT increases the expressions of necroptosis-related proteins (p-RIP1/RIP1, p-RIP3/RIP3, and p-MLKL/MLKL) and decreases the cell viability in HT22 cells, indicating that CORT induces necroptosis in HT22 cells. Itaconate improves CORT-induced neuroinflammation and necroptosis. Furthermore, itaconate upregulates the expression of Menin in CORT-exposed HT22 cells. Importantly, silencing Menin abolishes the antagonistic effect of itaconate on CORT-induced necroptosis and neuroinflammation. In brief, these results indicated that itaconate protects HT22 cells against CORT-induced neuroinflammation and necroptosis via upregulating Menin.

Wearable mobile health device for monitoring postoperative ambulation among patients with colorectal cancer undergoing minimally invasive surgery: A prospective comparison study.

BACKGROUND: This study aimed to evaluate the feasibility of using mHealth devices for monitoring postoperative ambulation among patients with colorectal cancer undergoing minimally invasive surgery (MIS). METHODS: Patients with colorectal cancer undergoing MIS were prospectively recruited to wear mHealth devices for recording postoperative ambulation between October 2018 and January 2021. The primary outcome was the compliance by evaluating the weekly submission rate of step counts. The secondary outcome was the association of weekly step counts and postoperative length of stay. RESULTS: Of 107 eligible patients, 53 patients wore mHealth devices, whereas 54 patients did not. The average weekly submission rate was 72.6% for the first month after surgery. The total step counts <4000 or >10 000 in the postoperative week one were negatively associated with postoperative length of stay (ß = -2.874, p = 0.038). CONCLUSIONS: mHealth devices provide an objective assessment of postoperative ambulation among patients with colorectal cancer undergoing MIS. CLINICAL TRIAL REGISTRATION: NCT03277235.

Heterochronous multiple primary prostate cancer and lymphoma: A case report.

BACKGROUND: Multiple primary malignant tumors (MPMTs) are rare type of cancer, especially when solid tumors are the first and lymphoma is the second primary malignancy. We report a patient with heterochronous MPMTs consisting of prostate cancer and rectal diffuse large B-cell lymphoma (DLBCL). CASE SUMMARY: We report a 77-year-old male patient diagnosed with prostate cancer who was treated with radiation therapy and one year of endocrine therapy with bicalutamide (50 mg per day) and an extended-release implant of goserelin (1/28 d). Seven years later, rectal DLBCL with lung metastases was found. CONCLUSION: Although rare, the possibility of prostate cancer combined with a double primary cancer of DLBCL can provide a deeper understanding.

EGFR Oncogenic Mutations in NSCLC Impair Macrophage Phagocytosis and Mediate Innate Immune Evasion Through Up-Regulation of CD47.

INTRODUCTION: EGFR-mutated NSCLC is characterized by an immunosuppressive microenvironment that confers limited clinical effectiveness to anti-PD-1 or PD-L1 antibodies. Despite the discouraging outcomes of immunotherapy, novel immune checkpoints are constantly emerging, among which the specific vulnerability for therapeutic intervention in the context of EGFR-mutated NSCLC remains unresolved. METHODS: Data sets of patient- and cell line-levels were used for screening and mutual validation of association between EGFR mutation and a panel of immune checkpoint-related genes. Regulatory mechanism was elucidated through in vitro manipulation of EGFR signaling pathway and evaluated by immunoblot analysis, quantitative polymerase chain reaction, flow cytometry, immunofluorescence staining, and chromatin immunoprecipitation. In vivo investigation of different therapeutic strategies were conducted using both immunocompetent and immunodeficient mouse models. RESULTS: Among all screened immune checkpoints, CD47 emerged as the candidate most relevant to EGFR activation. Mechanistically, EGFR mutation constitutively activated downstream ERK and AKT pathways to respectively up-regulate the transcriptional factors c-Myc and NF-κB, both of which structurally bound to the promotor region of CD47 and actively transcribed this "don't eat me" signal. Impaired macrophage phagocytosis was observed on introduction of EGFR-sensitizing mutations in NSCLC cell line models, whereas CD47 blockade restored the phagocytic capacity and augmented tumor cell killing in both in vitro and in vivo models. Remarkably, the combination of anti-CD47 antibody with EGFR tyrosine kinase inhibitor revealed an additive antitumor activity compared with monotherapy of either antitumor agent in both immunocompetent and adaptive immunity-deficient mouse models. CONCLUSIONS: EGFR-sensitizing mutation facilitates NSCLC's escape from innate immune attack through up-regulating CD47. Combination therapy incorporating CD47 blockade holds substantial promise for clinical translation in developing more effective therapeutic approaches against EGFR-mutant NSCLC.

Hetero-Diatomic CoN4-NiN4 Site Pairs with Long-Range Coupling as Efficient Bifunctional Catalyst for Rechargeable Zn-Air Batteries.

In this study, Co/Ni-NC catalyst with hetero-diatomic Co/Ni active sites dispersed on nitrogen-doped carbon matrix is synthesized via the controlled pyrolysis of ZIF-8 containing Co2+ and Ni2+ compounds. Experimental characterizations and theoretical calculations reveal that Co and Ni are atomically and uniformly dispersed in pairs of CoN4-NiN4 with an intersite distance ≈0.41 nm, and there is long-range d-d coupling between Co and Ni with more electron delocalization for higher bifunctional activity. Besides, the in situ grown carbon nanotubes at the edges of the catalyst particles allow high electronic conductivity for electrocatalysis process. Electrochemical evaluations demonstrate the superior ORR and OER bifunctionality of Co/Ni-NC catalyst with a narrow potential gap of only 0.691 V and long-term durability, significantly prevailing over the single-atom Co-NC and Ni-NC catalysts and the benchmark Pt/C and RuO2 catalysts. Co/Ni-NC catalyzed Zn-air batteries achieve a high specific capacity of 771 mAh g-1 and a long continuous operation period up to 340 h with a small voltage gap of ≈0.65 V, also much superior to Pt/C-RuO2.