Indole-3-propionic acid alleviates sepsis-associated acute liver injury by activating pregnane X receptor.

BACKGROUND: The morbidity and mortality of sepsis are extremely high, which is a major problem plaguing human health. However, current drugs and measures for the prevention and treatment of sepsis have little effect. Sepsis-associated acute liver injury (SALI) is an independent risk factor for sepsis, which seriously affects the prognosis of sepsis. Studies have found that gut microbiota is closely related to SALI, and indole-3-propionic Acid (IPA) can activate Pregnane X receptor (PXR). However, the role of IPA and PXR in SALI has not been reported. METHODS: This study aimed to explore the association between IPA and SALI. The clinical data of SALI patients were collected and IPA level in feces was detected. The sepsis model was established in wild-type mice and PXR knockout mice to investigate the role of IPA and PXR signaling in SALI. RESULTS: We showed that the level of IPA in patients' feces is closely related to SALI, and the level of IPA in feces has a good ability to identify and diagnose SALI. IPA pretreatment significantly attenuated septic injury and SALI in wild-type mice, but not found in knockout PXR gene mice. CONCLUSIONS: IPA alleviates SALI by activating PXR, which reveals a new mechanism of SALI, and provides potentially effective drugs and targets for the prevention of SALI.

Featured immune characteristics of COVID-19 and systemic lupus erythematosus revealed by multidimensional integrated analyses.

BACKGROUND: Coronavirus disease 2019 (COVID-19) shares similar immune characteristics with autoimmune diseases like systemic lupus erythematosus (SLE). However, such associations have not yet been investigated at the single-cell level. METHODS: We integrated and analyzed RNA sequencing results from different patients and normal controls from the GEO database and identified subsets of immune cells that might involve in the pathogenesis of SLE and COVID- 19. We also disentangled the characteristic alterations in cell and molecular subset proportions as well as gene expression patterns in SLE patients compared with COVID-19 patients. RESULTS: Key immune characteristic genes (such as CXCL10 and RACK1) and multiple immune-related pathways (such as the coronavirus disease-COVID-19, T-cell receptor signaling, and MIF-related signaling pathways) were identified. We also highlighted the differences in peripheral blood mononuclear cells (PBMCs) between SLE and COVID-19 patients. Moreover, we provided an opportunity to comprehensively probe underlying B-cell‒cell communication with multiple ligand-receptor pairs (MIF-CD74+CXCR4, MIF-CD74+CD44) and the differentiation trajectory of B-cell clusters that is deemed to promote cell state transitions in COVID-19 and SLE. CONCLUSIONS: Our results demonstrate the immune response differences and immune characteristic similarities, such as the cytokine storm, between COVID-19 and SLE, which might pivotally function in the pathogenesis of the two diseases and provide potential intervention targets for both diseases.

HBx Protein Contributes to Liver Carcinogenesis by H3K4me3 Modification Through Stabilizing WD Repeat Domain 5 Protein.

BACKGROUND AND AIMS: Cancer is typically considered as a genetic and epigenetic disease. Although numerous studies have indicated that an aberrant structure, function, or expression level of epigenetic enzymes contribute to many tumor types, precisely how the epigenetic mechanisms are involved in the hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) remains unknown. APPROACH AND RESULTS: In this study, we found that the WD repeat domain 5 protein (WDR5)-a core subunit of histone H3 lysine 4 methyltransferase complexes, which catalyze the generation of histone H3 lysine 4 trimethylation (H3K4me3) modification-is highly expressed in HBV-related HCC and promotes HCC development. WDR5 plays a critical role in HBV-driven cell proliferation and tumor growth in mice, and the WDR5-0103 small-molecule inhibitor of WDR5 activity compromises HBV- and hepatitis B x protein (HBx)-driven tumor proliferation. The aberrantly high WDR5 protein level was found to involve HBx through its stabilization of the WDR5 protein by inhibiting the interaction between the damage-specific DNA-binding protein 1/cullin-4 and WDR5, causing decreased ubiquitination of the WDR5 protein. HBx was found to colocalize with WDR5 on chromatin genome wide and promotes genome-wide H3K4me3 modification by means of WDR5. Furthermore, the recruitment of HBx to promoters of target genes relied on its interaction with WDR5 through its α-helix domain. WDR5 was also found to promote HBV transcription through H3K4 modification of covalently closed circular DNA minichromosome, and WDR5-0103 was able to inhibit HBV transcription. Finally, the in vitro and in vivo data further proved that HBx exerted its tumor-promoting function in a WDR5-dependent manner. CONCLUSIONS: Our data reveals that WDR5 is a key epigenetic determinant of HBV-induced tumorigenesis and that the HBx-WDR5-H3K4me3 axis may be a potential therapeutic target in HBV-induced liver pathogenesis.

Prognostic Values of CD38+CD101+PD1+CD8+ T Cells in Pancreatic Cancer.

Programmed death-1 (PD-1), a key immune checkpoint molecule, has been developed as an oncotherapy target for various carcinomas. However, treatment with anti-PD-1 elicited only a minimal effect in pancreatic ductal adenocarcinoma (PDAC). Subsequent studies revealed the existence of a subset of PD-1+ T cells coexpressing CD38 and CD101, representing a fixed dysfunctional subpopulation that are not able to be rescued by anti-PD-1 immunotherapy. However, whether this subpopulation of PD-1 expressing CD8+ T cells could be useful in predicting PDAC stage or prognosing survival is unknown. In this study, we used flow cytometry and immunofluorescence assay to analyze the expression of CD38 and CD101 in 183 clinical PDAC samples, including 84 of peripheral blood and 99 of surgical tissues. High coexpression of CD38/CD101 on peripheral PD-1+CD8+ T cells or tumor-infiltrating lymphocytes (TILs) was found to be most significantly correlated with Tumor/Node/Metastasis (T/N/M) classification and clinical stage, in contrast PD-1+CD8+ T cells could not correlate with T classification. CD38/CD101 co-repression on TILs also correlated with the poor survival in these PDAC patient samples. Our data suggest that CD38/CD101 might represent a more helpful biomarker than PD-1 alone for diagnosis and prognosis of PDAC.

LncRNA MALAT1 Promotes Oxygen-Glucose Deprivation and Reoxygenation Induced Cardiomyocytes Injury Through Sponging miR-20b to Enhance beclin1-Mediated Autophagy.

BACKGROUND/AIMS: LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is reported to be highly expressed in myocardial I/R injury and closely related to autophagy. However, the exact biological role of MALAT1 and its underlying mechanism in myocardial I/R injury remain to be elucidated. METHODS: We established incultured H9C2 cardiomyocytes an oxygen-glucose deprivation and reoxygenation (OGD/R) model for 6 h and then reoxygen-glucose for 4 h. We measured cell damage and autophagy levels after OGD/R by real-time quantitative PCR and Western blot. The relationships between miR-20b and MALAT1, beclin1 were confirmed by luciferase reporter assay. RESULTS: We found that the expression of MALAT1 and beclin1, cell damage levels (lactate dehydrogenase (LDH) release, 222.4 ± 29.4 vs. 577.5 ± 27.4 U/L; creatine kinase MB isoenzyme (CK-MB), 1.0 ± 0.2 vs. 4.3 ± 0.4; cardiac troponin I (cTn-I), 1.0 ± 0.3 vs. 3.0 ± 0.3; p < 0.05), and autophagy levels were significantly increased after OGD/R model, while cell viability (100.0 vs. 54.2 ± 2.2%, p < 0.05) and the expression of miR-20b and P62 were reduced; the trend of all the above data was significantly reversed by MALAT1 siRNA. In addition, the luciferase reporter assay results confirmed that MALAT1 directly binds to miR-20b-5p and functions as a ceRNA for miR-20b-5p to regulate beclin1. As a result, MALAT1 overexpression antagonized while MALAT1 knockdown enhanced the inhibitory effects of miR-20b-5p on beclin1-related cardiomyocytes autophagy in OGD/R injury. CONCLUSION: LncRNA MALAT1 promotes OGD/R-induced cardiomyocytes injury through sponging miR-20b to enhance beclin1-mediated autophagy.

Central nervous system progression in advanced non-small cell lung cancer patients with EGFR mutations in response to first-line treatment with two EGFR-TKIs, gefitinib and erlotinib: a comparative study.

BACKGROUND: Central nervous system (CNS) brain metastasis of advanced non-small cell lung cancer (NSCLC) patients confers a worse quality of life and prognosis. The efficacy comparison of two first-generation epidermal growth factor receptor (EGFR) inhibitors erlotinib or gefitinib as first-line treatment for CNS metastasis NSCLC patients with EGFR-sensitizing mutations is yet to be elucidated. METHODS: A retrospective analysis was done on cerebral metastasis rate after erlotinib or gefitinib as first-line treatment for advanced NSCLC patients with EGFR-sensitizing mutations. Time to neurological progression (nTTP) and median progression-free survival (mPFS) were calculated. RESULTS: The study involved 279 patients (erlotinib group: 108, gefitinib group: 171). After a median follow-up of 22 months, 27 patients (25%) in the erlotinib group and 60 patients (35.1%) in the gefitinib group showed CNS progression. The HR of CNS progression for erlotinib versus gefitinib was 0.695 [95% confidence interval (CI), 0.406-1.190], suggesting a risk reduction of 30.5% although not achieving statistical significance. The 6-, 12- and 18-month cumulative CNS progression rates were 0.9, 3.7 and 12% for erlotinib compared with corresponding rates of 5.8, 9.4 and 17% for gefitinib (P = 0.181). However, for those patients with preexisting brain metastases prior to EGFR-TKI treatment, erlotinib as first line treatment significantly extended the median nTTP in comparison to gefitinib (30 months vs 15.8 months, p = 0.024). CONCLUSIONS: Our data show that nTTP can be effectively extended in preexisting brain metastases patients with EGFR-sensitizing mutations initially treated with erlotinib compared with gefitinib. If confirmed, our results indicate that erlotinib may play an important role in controlling CNS progression from EGFR mutation-positive NSCLC.

Melatonin regulates PARP1 to control the senescence-associated secretory phenotype (SASP) in human fetal lung fibroblast cells.

Cellular senescence is an important tumor-suppressive mechanism. However, acquisition of a senescence-associated secretory phenotype (SASP) in senescent cells has deleterious effects on the tissue microenvironment and, paradoxically, promotes tumor progression. In a drug screen, we identified melatonin as a novel SASP suppressor in human cells. Strikingly, melatonin blunts global SASP gene expression upon oncogene-induced senescence (OIS). Moreover, poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, was identified as a new melatonin-dependent regulator of SASP gene induction upon OIS. Here, we report two different but potentially coherent epigenetic strategies for melatonin regulation of SASP. The interaction between the telomeric repeat-containing RNA (TERRA) and PARP-1 stimulates the SASP, which was attenuated by 67.9% (illustrated by the case of IL8) by treatment with melatonin. Through binding to macroH2A1.1, PARP-1 recruits CREB-binding protein (CBP) to mediate acetylation of H2BK120, which positively regulates the expression of target SASP genes, and this process is interrupted by melatonin. Consequently, the findings provide novel insight into melatonin's epigenetic role via modulating PARP-1 in suppression of SASP gene expression in OIS-induced senescent cells. Our studies identify melatonin as a novel anti-SASP molecule, define PARP-1 as a new target by which melatonin regulates SASP, and establish a new epigenetic paradigm for a pharmacological mechanism by which melatonin interrupts PARP-1 interaction with the telomeric long noncoding RNA(lncRNA) or chromatin.

High expression of sphingosine kinase 1 is associated with poor prognosis in nasopharyngeal carcinoma.

It has been reported that sphingosine kinase 1 (SPHK1), an oncogenic enzyme, was involved in the development and progression of a number of human cancers. However, the role of SPHK1 in nasopharyngeal carcinoma (NPC) is largely unknown. The present study aimed to characterize the expression of SPHK1 in human NPC and evaluate its clinical significance. Real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and Western blot analyses showed that the expression of SPHK1 mRNA and protein in NPC specimens was significantly higher than that in non-tumorous nasopharyngeal mucosa biopsies. Immunohistochemistry (IHC) was conducted to characterize the expression pattern of SPHK1 in 142 archived paraffin-embedded NPC specimens. Statistical analyses revealed that high levels of SPHK1 expression were associated with the clinical stages, locoregional recurrence and distant metastasis of NPC. NPC patients with high levels of SPHK1 expression had shorter survival time, whereas those with lower levels of SPHK1 expression survived longer. Moreover, multivariate analysis suggested that SPHK1 up-regulation was an independent prognostic factor for NPC. Our results suggest for the first time that SPHK1 is involved in the development and progression of NPC, which can be used as a useful prognostic marker for NPC patients and may be an effective target for treating NPC.

Marked anti-tumor effects of CD8(+)CD62L(+) T cells from melanoma-bearing mice.

CD8(+)CD62L(+) T cells have been shown to play pivotal roles in anti-viral immunity, chronic myeloid leukemia and renal cell carcinoma. Recently, CD8(+)CD62L(+) T cells from naïve mice (nCD8(+)CD62L(+) T cells) have shown superior anti-tumor properties in melanoma-bearing mice. Considering that antigen-specific memory T cells have shown to possess more potent immunity than non-specific memory T cells, we hypothesized that CD8(+)CD62L(+) T cells from tumor-bearing individuals (mCD8(+)CD62L(+) T cells) might have superior anti-tumor effect than nCD8(+)CD62L(+) T cells. Therefore, we investigated phenotypes, functions and the in vivo distribution of mCD8(+)CD62L(+) T cells in tumor-bearing mice. We found that, while keeping the features of central memory T cells, the frequency of mCD8(+)CD62L(+) T cell in the spleen of tumor-bearing mice was significantly higher than that the one of nCD8(+)CD62L(+) T cell in naive mice. Moreover, we demonstrated that mCD8(+)CD62L(+) T cells had higher proliferation rate and IFN-γ production than nCD8(+)CD62L(+) T cells, in vitro. We performed adoptive transfer of mCD8(+)CD62L(+) T cells into melanoma-bearing mice and tracked them in spleen, lymph nodes and in melanoma tissues. Our results show that mCD8(+)CD62L(+) T cells had stronger in vivo anti-tumoral activity than nCD8(+)CD62L(+) T cells. This study highlights the therapeutic potential of mCD8(+)CD62L(+) T cells in the immunotherapy of melanoma and possibly other tumors.

Patients with single brain metastasis from non-small cell lung cancer equally benefit from stereotactic radiosurgery and surgery: a systematic review.

BACKGROUND: The appropriate treatment of non-small cell lung cancer (NSCLC) with single brain metastasis (SBM) is still controversial. A systematic review was designed to evaluate the effectiveness of neurosurgery and stereotactic radiosurgery (SRS) in patients with SBM from NSCLC. MATERIAL/METHODS: PUBMED, EMBASE, the Cochrane Library, Web of Knowledge, Current Controlled Trials, Clinical Trials, and 2 conference websites were searched to select NSCLC patients with only SBM who received brain surgery or SRS. SPSS 18.0 software was used to analyze the mean median survival time (MST) and Stata 11.0 software was used to calculate the overall survival (OS). RESULTS: A total of 18 trials including 713 patients were systematically reviewed. The MST of the patients was 12.7 months in surgery group and 14.85 months in SRS group, respectively. The 1, 2, and 5 years OS of the patients were 59%, 33%, and 19% in surgery group, and 62%, 33%, and 14% in SRS group, respectively. Furthermore, in the surgery group, the 1 and 3 years OS were 68% and 15% in patients with controlled primary tumors, and 50% and 13% in the other patients with uncontrolled primary tumors, respectively. Interestingly, the 5-year OS was up to 21% in patients with controlled primary tumors. CONCLUSIONS: There was no significant difference in MST or OS between patients treated with neurosurgery and SRS. Patients with resectable lung tumors and SBM may benefit from the resection of both primary lesions and metastasis.

VSIG4 expression on macrophages facilitates lung cancer development.

Tumor-associated macrophages are a prominent component of lung cancer stroma and contribute to tumor progression. The protein V-set and Ig domain-containing 4 (VSIG4), a novel B7 family-related macrophage protein that has the capacity to inhibit T-cell activation, has a potential role in the development of lung cancer. In this study, 10 human non-small-cell lung cancer specimens were collected and immunohistochemically analyzed for VSIG4 expression. Results showed massive VSIG4(+) cell infiltration throughout the samples. Immunofluorescent double staining showed that VSIG4 was present on CD68(+) macrophages, but absent from CD3(+) T cells, CD31(+) endothelial cells, and CK-18(+) epithelial cells. Moreover, VSIG4 was coexpressed on B7-H1(+) and B7-H3(+) cells in these tumor specimens. Transfection of the VSIG4 gene into 293FT cells demonstrated that the VSIG4 signal could inhibit cocultured CD4(+) and CD8(+) T-cell proliferation and cytokine (IL-2 and IFN-γ) production in vitro. Interestingly, in a murine tumor model induced by Lewis lung carcinoma cell line, we found that tumors grown in VSIG4-deficient (VSIG4(-/-)) mice were significantly smaller than those found in wild-type littermates. All of these results demonstrate that macrophage-associated VSIG4 is an activator that facilitates lung carcinoma development. Specific targeting of VSIG4 may prove to be a novel, efficacious strategy for the treatment of this carcinoma.

Nedaplatin or oxaliplatin combined with paclitaxel and docetaxel as first-line treatment for patients with advanced non-small cell lung cancer.

BACKGROUND: Both nedaplatin and oxaliplatin combined with paclitaxel or docetaxel have demonstrated potent activity in advanced non-small cell lung cancer (NSCLC) patients, but there is no study comparing the difference between these 2 chemotherapy regimens. The aim of this study was to evaluate and compare the efficacy and safety between the combination chemotherapy of nedaplatin or oxaliplatin plus paclitaxel and docetaxel in patients with advanced NSCLC. MATERIAL AND METHODS: We retrospectively reviewed patients with stage III-IV unresectable NSCLC from 1 January 2010 to 31 December 2013 at Southwest Hospital. They all received nedaplatin (80 mg/m2, nedaplatin group) or oxaliplatin (130 mg/m2, oxaliplatin group) combined with paclitaxel (175 mg/m2) or docetaxel (75 mg/m2) as first-line treatment. RESULTS: There are 174 patients enrolled - 123 patients in the nedaplatin group and 51 patients in the oxaliplatin group. The objective response rates were 47.3% and 34.1% and the disease control rates were 87.5% and 79.5% in nedaplatin and oxaliplatin groups, respectively. The progression-free survival time was 10.4 months and 9.6 months (p=0.722) and the overall survival time was 18.5 months and 25.5 months in the nedaplatin and oxaliplatin groups, respectively (p=0.09). Total toxicity was greater in the oxaliplatin group (p=0.008), but there is no significant difference among ¾ grade adverse events between the 2 groups (P=0.595). CONCLUSIONS: The effect of nedaplatin plus paclitaxel and docetaxel is the same as oxaliplatin plus paclitaxel and docetaxel, and the toxicity of nedaplatin is well tolerate as first-line treatment for patients with advanced NSCLC.

MS4A6D Promotes carrageenan-induced footpad swelling in mice through enhancing macrophages-derived inflammation.

Our previous work has demonstrated that the tetraspan MS4A6D interacts with MHC-II to be a complex that promotes macrophage activation (Mol Immunol. 2023; 160: 121-132), however, the exact role of MS4A6D in controlling macrophage-derived inflammation is still poorly understood. Here, we showed that Ms4a6d-deficient (Ms4a6d-/-) mice manifested a lower level of footpad swelling induced by subcutaneous injection of 100 µL of 1% Carrageenan (CGN, w/v) plus CaCl2 (50 mM), a phenomenon that is similar to Nlrp3-/-, Casp-1-/-, and Ilr1-/- mice. Mechanistically, F4/80+ macrophages infiltrated in the footpad tissues of the Ms4A6d-/- mice was significantly lower than that of the WT littermates, leading to dramatically lower levels of proIL-1ß in vivo. Moreover, macrophages from Ms4a6d-/- mice also showed a dramatical reduction of Il-1ß secretion following NLRP3 inflammsome activation in vitro. Interestingly, both Ms4a6dC237G mutant (Interruption of MS4A6D homodimerization) and Ms4a6dY241G mutant (deletion of heITAM motif) mice also significantly inhibited CGN-induced footpad swelling due to lower levels of Il-1ß secretion in vivo. Collectively, MS4A6D aggravates CGN-induced footpad swelling in mice by enhancing NLRP3 inflammasome in macrophages and inducing the release of IL-1ß, indicating that MS4A6D promotes the progression of acute inflammation.

Dock4 contributes to neuropathic pain by regulating spinal synaptic plasticity in mice.

Introduction: Neuropathic pain (NP) conditions arising from injuries to the nervous system due to trauma, disease, or neurotoxins are chronic, severe, debilitating, and exceedingly difficult to treat. However, the mechanisms of NP are not yet clear. Here we explored the role of Dock4, an atypical Rac1 GEF, in the development of NP. Methods: Mechanical allodynia was assessed as paw withdrawal threshold by a dynamic plantar aesthesiometer. Immunofluorescence staining was conducted to investigate the expression and localization of Dock4, Rac1 and GluN2B. Quantitative analysis of Dock4, Rac1 and GluN2B were determined by qRT-PCR and Western blot assay. Spontaneous excitatory and inhibitory postsynaptic currents in spinal cord slices were examined using whole cell patch clam. Dendritic spine remodeling and synaptogenesis were detected in cultured dorsal spinal neurons. Results and discussion: We found that SNL caused markedly mechanical allodynia accompanied by increase of Dock4, GTP-Rac1and GluN2B, which was prevented by knockdown of Dock4. Electrophysiological tests showed that SNL facilitated excitatory synaptic transmission, however, this was also inhibited by Dock RNAi-LV. Moreover, knockdown of Dock4 prevented dendritic growth and synaptogenesis. Conclusion: In summary, our data indicated that Dock4 facilitated excitatory synaptic transmission by promoting the expression of GluN2B at the synaptic site and synaptogenesis, leading to the occurrence of NP.

Simultaneous Differential Detection of H5, H7, H9 and Nine NA Subtypes of Avian Influenza Viruses via a GeXP Assay.

H5, H7 and H9 are the most important subtypes of avian influenza viruses (AIVs), and nine neuraminidase (NA) subtypes (N1-N9) of AIVs have been identified in poultry. A method that can simultaneously detect H5, H7, H9 and the nine NA subtypes of AIVs would save time and effort. In this study, 13 pairs of primers, including 12 pairs of subtype-specific primers for detecting particular subtypes (H5, H7, H9 and N1-N9) and one pair of universal primers for detecting all subtypes of AIVs, were designed and screened. The 13 pairs of primers were mixed in the same reaction, and the 13 target genes were simultaneously detected. A GeXP assay using all 13 pairs of primers to simultaneously detect H5, H7, H9 and the nine NA subtypes of AIVs was developed. The GeXP assay showed specific binding to the corresponding target genes for singlet and multiplex templates, and no cross-reactivity was observed between AIV subtypes and other related avian pathogens. Detection was observed even when only 102 copies of the 13 target genes were present. This study provides a high-throughput, rapid and labor-saving GeXP assay for the simultaneous rapid identification of three HA subtypes (H5, H7 and N9) and nine NA subtypes (N1-N9) of AIVs.

Tetraspan MS4A6D is a coreceptor of MHC class II antigen (MHC-II) that promotes macrophages-derived inflammation.

Our previous research demonstrated that the tetraspan MS4A6D is an adapter of VSIG4 that controls NLRP3 inflammasome activation (Sci Adv. 2019: eaau7426); however, the expression, distribution and biofunction of MS4A6D are still poorly understood. Here, we showed that MS4A6D is restricted to mononuclear phagocytes and that its gene transcript is controlled by the transcription factor NK2 homeobox-1 (NKX2-1). Ms4a6d-deficient (Ms4a6d-/-) mice showed normal macrophage development but manifested a greater survival advantage against endotoxin (lipopolysaccharide) challenge. Mechanistically, MS4A6D homodimers crosslinked with MHC class II antigen (MHC-II) to form a surface signaling complex under acute inflammatory conditions. MHC-II occupancy triggered Tyr241 phosphorylation in MS4A6D, leading to activation of SYK-CREB signaling cascades, further resulting in augmenting the transcription of proinflammatory genes (Il1b, Il6 and Tnfa) and amplifying the secretion of mitochondrial reactive oxygen species (mtROS). Deletion of Tyr241 or interruption of Cys237-mediated MS4A6D homodimerization in macrophages alleviated inflammation. Importantly, both Ms4a6dC237G and Ms4a6dY241G mutation mice phenocopied Ms4a6d-/- animals to prevent endotoxin lethality, highlighting MS4A6D as a novel target for treating macrophage-associated disorders.

Pathogenicity and molecular characteristics of fowl adenovirus serotype 4 with moderate virulence in Guangxi Province, China.

The GX2020-019 strain of fowl adenovirus serotype 4 (FAdV-4) was isolated from the liver of chickens with hydropericardium hepatitis syndrome in Guangxi Province, China, and was purified by plaque assay three times. Pathogenicity studies showed that GX2020-019 can cause typical FAdV-4 pathology, such as hydropericardium syndrome and liver yellowing and swelling. Four-week-old specific pathogen-free (SPF) chickens inoculated with the virus at doses of 103 median tissue culture infectious dose (TCID50), 104 TCID50, 105 TCID50, 106 TCID50, and 107 TCID50 had mortality rates of 0, 20, 60, 100, and 100%, respectively, which were lower than those of chickens inoculated with other highly pathogenic Chinese isolates, indicating that GX2020-019 is a moderately virulent strain. Persistent shedding occurred through the oral and cloacal routes for up to 35 days postinfection. The viral infection caused severe pathological damage to the liver, kidney, lung, bursa of Fabricius, thymus, and spleen. The damage to the liver and immune organs could not be fully restored 21 days after infection, which continued to affect the immune function of chickens. Whole genome analysis indicated that the strain belonged to the FAdV-C group, serotype 4, and had 99.7-100% homology with recent FAdV-4 strains isolated from China. However, the amino acid sequences encoded by ORF30 and ORF49 are identical to the sequences found in nonpathogenic strains, and none of the 32 amino acid mutation sites that appeared in other Chinese isolates were found. Our research expands understanding of the pathogenicity of FAdV-4 and provides a reference for further studies.

Anti-PD-1 therapy achieves favorable outcomes in HBV-positive non-liver cancer.

Anti-PD-1 therapy has shown promising outcomes in the treatment of different types of cancer. It is of fundamental interest to analyze the efficacy of anti-PD-1 therapy in cancer patients infected with hepatitis B virus (HBV) since the comorbidity of HBV and cancer is widely documented. We designed a multicenter retrospective study to evaluate the efficacy of anti-PD-1 therapy on non-liver cancer patients infected with HBV. We found anti-PD-1 therapy achieved much better outcomes in HBV+ non-liver cancer patients than their HBV- counterparts. We performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) from esophageal squamous cell carcinoma (ESCC) patients. We found both cytotoxicity score of T cells and MHC score of B cells significantly increased after anti-PD-1 therapy in HBV+ ESCC patients. We also identified CX3CR1high TEFF, a subset of CD8+ TEFF, associated with better clinical outcome in HBV+ ESCC patients. Lastly, we found CD8+ TEFF from HBV+ ESCC patients showing higher fraction of Exhaustionhi T than their HBV- counterpart. In summary, anti-PD-1 therapy on HBV+ non-liver cancer patients is safe and achieves better outcomes than that on HBV- non-liver cancer patients, potentially because HBV+ patients had higher fraction of Exhaustionhi T, which made them more efficiently respond to anti-PD-1 therapy.

The characteristic expression of B7-H3 and B7-H4 in liver biopsies from patients with HBV-related acute-on-chronic liver failure.

Hepatitis B virus (HBV) is a major public health problem, and HBV-related acute-on-chronic liver failure (HBV-ACLF) has an extremely poor prognosis due to a lack of effective treatments. B7-H3 and B7-H4 are two novel members of the B7 superfamily that are actively involved in regulating the pathogenesis of infectious diseases. However, the intrahepatic expression of both members in HBV-ACLF patients has yet to be described. In this study, we analyzed the expression of B7-H3 and B7-H4 in HBV-ACLF biopsies by immunohistochemistry. Our results showed that both members were observed in all HBV-ACLF samples, and their expression was chiefly observed on infiltrating inflammatory cells and the damaged bile ducts. Immunofluorescence double staining showed that B7-H4 was expressed chiefly on CD3(+) T cells, CD68(+) macrophages, CK-18(+) bile ducts, and CD31(+) endothelial cells, while B7-H3 was found on all cell types detected. The expression of the programmed death (PD)-1 ligands, PD-L1 and PD-L2, was also detected in these liver tissues and they were found to be co-expressed with B7-H3 and B7-H4. These results suggest that the B7-family signaling is most likely to affect the pathogenesis of this disease, and a clear understanding of their functional roles may further elucidate the disease process.

INPP4B inhibits glioma cell proliferation and immune escape via inhibition of the PI3K/AKT signaling pathway.

INPP4B (Inositol polyphosphate 4-phosphatase type II) has been regarded as a suppressor of several human tumors, but its biological function, expression, and clinical significance in glioma tissues and cell lines are unclear. Notably, whether INPP4B participates in immune escape of glioma deserves urgent attention. Here, we confirmed that INPP4B expression is often downregulated in low- and high-grade human glioma tissues, in tissues from an orthotopic mouse model of brain glioma and in glioma cells. We found that INPP4B overexpression restrained the proliferation, migration, apoptosis resistance, PD-L1 expression, and T cell suppression by glioma cells, whereas INPP4B silencing had the opposite effects. Moreover, we showed that INPP4B inhibited glioma cell proliferation, migration, and PD-L1 expression by downregulating PI3K/AKT signaling. Collectively, these data support that INPP4B may inhibit glioma progression, and particularly, glioma's immune escape. Thus, INPP4B may constitute a valuable target for glioma treatment.