Disrupted cognitive and affective empathy network interactions in autistic children viewing social animation.

Empathy can be divided into two core components, cognitive empathy (CE) and affective empathy (AE), mediated by distinct neural networks. Deficient empathy is a central feature of autism spectrum conditions (ASCs), but it is unclear if this deficit results from disruption solely within empathy networks or from disrupted functional integration between CE and AE networks. To address this issue, we measured functional connectivity (FC) patterns both within and between empathy networks in autistic children (4-8 years, n = 31) and matched typically developing (TD) children (n = 26) using near-infrared spectroscopy during the presentation of an animated story evoking CE and AE. Empathy and social communication ability were also assessed using the Empathy Quotient/Systemizing Quotient (EQ/SQ) and Social Responsiveness Scale, respectively. The results showed that the FC in the AE network of autistic children did not differ from the TD group across conditions; however, the ASC group showed weaker FC in the CE network under the CE condition and weaker FC between networks when processing AE information, the latter of which was negatively correlated with EQ scores in ASC. The empathy defect in ASC may involve abnormal integration of CE and AE network activities under AE conditions.

An estrogen-regulated long non-coding RNA NCALD promotes luminal breast cancer proliferation by activating GRHL2.

PURPOSE: Luminal breast cancer (BC) is a prevalent subtype associated with an increased risk of late disease recurrence and mortality. Long noncoding RNAs (lncRNAs) likely play significant roles in regulating tissue-specific gene expression during tumorigenesis. However, the biological function and underlying mechanisms of specific dysregulated lncRNAs in luminal BC remain largely unknown, which has drawn our attention. METHODS: The expression pattern of lncRNA NCALD in luminal BC was predicted and validated in collected tissue samples. Following cell transfection with knockdown of lncRNA NCALD and ESR1 and overexpression of GRHL2 and ESR1, we investigated the interactions among lncRNA NCALD, ESR1, and GRHL2. Additionally, their regulatory functions in luminal BC cell biological processes were studied. Subsequently, a xenograft tumor model was prepared for validation. RESULTS: Our study identified a specific overexpression of the lncRNA NCALD in luminal BC, which correlated with an unfavorable prognosis. Suppression of lncRNA NCALD or ESR1 led to inhibition of GRHL2 expression, while concurrent overexpression of ESR1 and lncRNA NCALD potentially elevated GRHL2 expression. Mechanistically, ERα may drive the expression of lncRNA NCALD. Furthermore, the 1-151 nt fragment of lncRNA NCALD was found to recruit ERα and interact with its oest-Recep domain located in the promoter region of GRHL2, ultimately inducing GRHL2 transcription. CONCLUSIONS: These findings reveal the involvement of lncRNA NCALD and its specific expression pattern in luminal BC. Targeting lncRNA NCALD could be a potential therapeutic strategy for delaying the progression of BC.

Comparative single-cell analysis reveals heterogeneous immune landscapes in adenocarcinoma of the esophagogastric junction and gastric adenocarcinoma.

Adenocarcinoma of the esophagogastric junction (AEG) is a type of tumor that arises at the anatomical junction of the esophagus and stomach. Although AEG is commonly classified as a subtype of gastric adenocarcinoma (GAC), the tumor microenvironment (TME) of AEG remains poorly understood. To address this issue, we conducted single-cell RNA sequencing (scRNA-seq) on tumor and adjacent normal tissues from four AEG patients and performed integrated analysis with publicly available GAC single-cell datasets. Our study for the first time comprehensively deciphered the TME landscape of AEG, where heterogeneous AEG malignant cells were identified with diverse biological functions and intrinsic malignant nature. We also depicted transcriptional signatures and T cell receptor (TCR) repertoires for T cell subclusters, revealing enhanced exhaustion and reduced clone expansion along the developmental trajectory of tumor-infiltrating T cells within AEG. Notably, we observed prominent enrichment of tumorigenic cancer-associated fibroblasts (CAFs) in the AEG TME compared to GAC. These CAFs played a critical regulatory role in the intercellular communication network with other cell types in the AEG TME. Furthermore, we identified that the accumulation of CAFs in AEG might be induced by malignant cells through FGF-FGFR axes. Our findings provide a comprehensive depiction of the AEG TME, which underlies potential therapeutic targets for AEG patient treatment.

Local structural and functional MRI markers of compulsive behaviors and obsessive-compulsive disorder diagnosis within striatum-based circuits.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a classic disorder on the compulsivity spectrum, with diverse comorbidities. In the current study, we sought to understand OCD from a dimensional perspective by identifying multimodal neuroimaging patterns correlated with multiple phenotypic characteristics within the striatum-based circuits known to be affected by OCD. METHODS: Neuroimaging measurements of local functional and structural features and clinical information were collected from 110 subjects, including 51 patients with OCD and 59 healthy control subjects. Linked independent component analysis (LICA) and correlation analysis were applied to identify associations between local neuroimaging patterns across modalities (including gray matter volume, white matter integrity, and spontaneous functional activity) and clinical factors. RESULTS: LICA identified eight multimodal neuroimaging patterns related to phenotypic variations, including three related to symptoms and diagnosis. One imaging pattern (IC9) that included both the amplitude of low-frequency fluctuation measure of spontaneous functional activity and white matter integrity measures correlated negatively with OCD diagnosis and diagnostic scales. Two imaging patterns (IC10 and IC27) correlated with compulsion symptoms: IC10 included primarily anatomical measures and IC27 included primarily functional measures. In addition, we identified imaging patterns associated with age, gender, and emotional expression across subjects. CONCLUSIONS: We established that data fusion techniques can identify local multimodal neuroimaging patterns associated with OCD phenotypes. The results inform our understanding of the neurobiological underpinnings of compulsive behaviors and OCD diagnosis.

Extranodal NK/T-Cell Lymphoma Predominantly Composed of Anaplastic Cells: A Frequently Misdiagnosed and Highly Aggressive Variant.

Extranodal NK/T-cell lymphoma (ENKTL) is a non-Hodgkin lymphoma associated with the Epstein-Barr virus that primarily affects individuals in East Asia and indigenous populations in Central and South America. Morphologically, ENKTL typically consists of medium-sized cells or a combination of small and large cells. This report presents 10 cases characterized by predominantly anaplastic cells with diffuse expression of CD30, resembling anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK-negative ALCL) and demonstrating highly aggressive behavior. The cohort included 9 males and 1 female, ranging in age from 29 to 65 years (median age: 47 y). Eight patients presented with nasal disease, while 2 had non-nasal disease. Five patients had stage I/II disease, and the remaining 5 had stage III/IV disease. Morphologically, necrosis was observed in 9 cases, angiocentric-angiodestructive growth in 3 cases, and pseudoepitheliomatous hyperplasia in 2 cases. Anaplastic cells predominated in all cases, with some displaying eccentric, horseshoe-shaped, or kidney-shaped nuclei (referred to as "Hallmark" cells). The morphology profile was monomorphic in 3 cases and polymorphic in 7 cases. Immunohistochemically, all cases tested positive for cytotoxic granule markers (TIA1 and granzymeB) and Epstein-Barr virus-encoded RNA. Cytoplasmic expression of CD3ε and CD56 was observed in 9 of 10 cases. Interestingly, most cases (7 of 8) exhibited variable expression of MuM1, ranging from 10% to 90%. All cases showed diffuse positivity for CD30 but were negative for ALK, resulting in 3 cases being initially misdiagnosed as ALK-negative ALCL. Compared with nonanaplastic cases, anaplastic cells predominant ENKTL had a significantly higher frequency of "B" symptoms, bone marrow involvement, hemophagocytic lymphohistiocytosis, and higher Ki67 proliferative index. These findings provide valuable information for pathologists, expanding their understanding of the cytologic spectrum of ENKTL. This rare variant of ENKTL, characterized by the predominance of anaplastic cells and diffuse CD30 expression, exhibits high aggressiveness and should be differentiated from ALK-negative ALCL. Awareness of this uncommon variant is crucial in preventing misdiagnosis and ensuring the timely initiation of therapy.

Tumor cell-derived exosomes mediating hsa_circ_0001739/lncRNA AC159540.1 facilitate liver metastasis in colorectal cancer.

BACKGROUND: The current study probed into how tumor cell-derived exosomes (Exos) mediated hsa_circ_0001739/lncRNA AC159540.1 to manipulate microRNA (miR)-218-5p/FTO-N6-methyladenosine (m6A)/MYC signal axis in liver metastasis in colorectal cancer (CRC). METHODS: hsa_circ_0001739 and lncRNA AC159540.1 were identified as the upstream regulator of miR-218-5p using ENCORI and LncBase databases. Expression patterns of miR-218-5p, hsa_circ_0001739, lncRNA AC159540.1, FTO, and MYC were detected, accompanied by loss-and-gain-of function assays to examine their effects on CRC cell biological functions. SW480 cells-derived Exos were purified, followed by in vitro studies to uncover the effect of hsa_circ_0001739/lncRNA AC159540. RESULTS: miR-218-5p was downregulated while hsa_circ_0001739/lncRNA AC159540.1 was upregulated in CRC tissues and cells. Silencing of hsa_circ_0001739/lncRNA AC159540.1 restrained the malignant phenotypes of CRC cells. Exos-mediated hsa_circ_0001739/lncRNA AC159540.1 competitively inhibited miR-218-5p to elevate FTO and MYC. The inducing role of Exos-mediated hsa_circ_0001739/lncRNA AC159540.1 in CRC was also validated in vivo. CONCLUSION: Conclusively, Exos-mediated circ_0001739/lncRNA AC159540.1 regulatory network is critical for CRC, offering a theoretical basis for CRC treatment.

Prednisolone Accelerates Embryonic Development of Zebrafish via Glucocorticoid Receptor Signaling at Low Concentrations.

Synthetic glucocorticoids have been widely detected in aquatic ecosystems and may pose a toxicological risk to fish. In the present study, we described multiple end point responses of zebrafish to a commonly prescribed glucocorticoid, prednisolone (PREL), at concentrations between 0.001 and 9.26 µg/L. Of 23 end points monitored, 7 were affected significantly. Significant increases in the frequency of yolk extension formation, spontaneous contraction, heart rate, and ocular melanin density and significant decreases of ear-eye distance at PREL concentrations of 0.001 µg/L and above clearly pointed to the acceleration of embryonic development of zebrafish by PREL. Further confirmation came from the alterations in somite numbers, head-trunk angle, and yolk sac size, as well as outcomes obtained via RNA sequencing, in which signaling pathways involved in tissue/organ growth and development were highly enriched in embryos upon PREL exposure. In addition, the crucial role of glucocorticoid receptor (GR) for PREL-induced effects was confirmed by both, the coexposure to antagonist mifepristone (RU486) and GR-/- mutant zebrafish experiments. We further demonstrated similar accelerations of embryonic development of zebrafish upon exposure to 11 additional glucocorticoids, indicating generic adverse effect characteristics. Overall, our results revealed developmental alterations of PREL in fish embryos at low concentrations and thus provided novel insights into the understanding of the potential environmental risks of glucocorticoids.

Systematic analysis of circadian disrupting substances with a high-throughput zebrafish circadian behavior screening approach.

Circadian rhythm aligns numerous biological functions in majority of animals. Aside from well-known external factors such as the light-dark cycle and temperature, circadian rhythm can also be regulated by rarely explored factors such as synthetic substances. Here, we established a circadian behavior screening approach utilizing zebrafish larvae model, which integrated high-throughput capabilities with automated batch processing. With this approach, we systematically analyzed the circadian disruptive effects of >60 synthetic substances commonly detected in aquatic environment by assessing both the circadian period length and amplitude of circadian behavior, with an exposure concentration set at 100 µg/L. Among tested substances, a series of circadian disrupting compounds (circadian disruptors) were identified. Several categories of the hit compounds can be recognized, such as phthalate (diisopentyl phthalate (DIPP), with 10.1 % and 49.6 % increases for circadian period length and amplitude, respectively), neuroactive substance (mirtazapine, with 10.6 % and 63.1 % increases, respectively), and biocides (thiamethoxam, with 100.3 % increase for amplitude). Among these compounds, DIPP increased circadian period length and amplitude with a high degree. Aside from DIPP, we further examined eleven other phthalates and demonstrated that benzyl butyl phthalate, diisobutyl phthalate and diisohexyl phthalate could also significantly increase the zebrafish circadian period length by 7.9 %, 3.7 % and 8.5 %, respectively. Collectively, the present findings substantiated the feasibility of this high throughput screening strategy for circadian disruptor's discovery and provided novel insights into understanding of the potential risks of synthetic substances.

Dopamine Receptor 1 Impedes ILC2-Mediated Antitumor Immunity.

Ever-growing evidence has revealed that group 2 innate lymphoid cells (ILC2s) exhibit pleiotropic effects in antihelminth immunity, allergy, tissue protection, and cancer. Currently, the role of ILC2s in cancer is highly controversial regarding the intricate tumor microenvironment (TME), and the tumor-promoting or antitumor immunological mechanisms of ILC2s remain largely unknown. In this study, we report that dopamine receptor 1 (DRD1) restrains ILC2 activity in the TME. DRD1 deficiency promotes ILC2 activation, which irritates eosinophil recruitment and cytotoxic CD8+ T cell expansion during ongoing malignancy. Consequently, DRD1-deficient mice exhibit delayed tumor growth and reduced tumor progression. Furthermore, fenoldopam, a selective DRD1 agonist, restrains the ILC2 response in the TME and aggravates tumor burden in mice. Taken together, our data elaborate that the DRD1 signal acts as an excitatory rheostat in regulating ILC2-dependent antitumor immunity.

Social visual preference mediates the effect of cortical thickness on symptom severity in children with autism spectrum disorder.

Background: Evidence suggests that there is a robust relationship between altered neuroanatomy and autistic symptoms in individuals with autism spectrum disorder (ASD). Social visual preference, which is regulated by specific brain regions, is also related to symptom severity. However, there were a few studies explored the potential relationships among brain structure, symptom severity, and social visual preference. Methods: The current study investigated relationships among brain structure, social visual preference, and symptom severity in 43 children with ASD and 26 typically developing (TD) children (aged 2-6 years). Results: Significant differences were found in social visual preference and cortical morphometry between the two groups. Decreased percentage of fixation time in digital social images (%DSI) was negatively related to not only the thickness of the left fusiform gyrus (FG) and right insula, but also the Calibrated Severity Scores for the Autism Diagnostic Observation Schedule-Social Affect (ADOS-SA-CSS). Mediation analysis showed that %DSI partially mediated the relationship between neuroanatomical alterations (specifically, thickness of the left FG and right insula) and symptom severity. Conclusion: These findings offer initial evidence that atypical neuroanatomical alterations may not only result in direct effects on symptom severity but also lead to indirect effects on symptom severity through social visual preference. This finding enhances our understanding of the multiple neural mechanisms implicated in ASD.

Human umbilical cord mesenchymal stem cell-derived exosomes carrying miR-1827 downregulate SUCNR1 to inhibit macrophage M2 polarization and prevent colorectal liver metastasis.

microRNA-1827 (miR-1827) is proposed to be enriched in exosomes from mesenchymal stem cells (MSCs-Exos). A recent study has addressed the suppressive effect of exosomes from human umbilical cord mesenchymal stem cells (hUC-MSCs-Exos) on colorectal cancer (CRC) metastasis. Hence, our study aims at investigating whether hUC-MSCs-Exos can modulate the liver metastasis in CRC by mediating miR-1827. Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were used to identify hUC-MSCs-Exos. Using gain- and loss-of-function approaches, the expression of miR-1827 and succinate receptor 1 (SUCNR1) was altered. Consequently, the biological functions of CRC cells were assessed by CCK-8 and Transwell assays and macrophage M2 polarization was assayed by flow cytometry. Dual-luciferase reporter assay was applied to clarify interaction between miR-1827 and SUCNR1. CRC cells were incubated with hUC-MSCs-Exos and tumor-bearing mice were injected with hUC-MSCs-Exos to examine the effects on CRC cell growth and metastasis. SUCNR1, lowly expressed in CRC, could promote CRC cell growth and macrophage M2 polarization. miR-1827 could target SUCNR1 and hence suppress the progression and metastasis of CRC. hUC-MSCs-Exos carried miR-1827 to inhibit M2 macrophage polarization by downregulating SUCNR1 expression, and inhibited proliferating, migrating and invading properties of CRC cells. Furthermore, hUC-MSCs-Exos carrying miR-1827 blocked CRC liver metastasis in vivo. These findings indicate hUC-MSCs-Exos as an inhibitor of M2 macrophage polarization and liver metastasis in CRC through inducing miR-1827-targeted inhibition of SUCNR1. This provides a theoretical basis for understanding the mechanisms underlying Exos-based target therapy for CRC.

Body mass index, as a novel predictor of hepatocellular carcinoma patients treated with Anti-PD-1 immunotherapy.

Immunocheckpoint inhibitors have shown significant efficacy in the treatment of hepatocellular carcinoma (HCC), but there are individual differences. The aim of this study was to explore body mass index (BMI) as a predictor of anti-PD-1 efficacy in patients with HCC. We retrospectively analyzed 101 HCC patients who treated with anti-PD-1 at Sun Yat-sen University Cancer Center from July 2018 to November 2019 and divided them into overweight (BMI > 24.9) and non-overweight (BMI ≤ 24.9) groups based on baseline BMI levels. BMI > 24.9 accounted for 22 cases (21.8%) and BMI ≤ 24.9 accounted for 79 cases (78.2%) in the study cohort. Overweight patients had higher disease control rates than non-overweight patients (P = 0.019, respectively). The mean progression-free survival (PFS) in overweight patients (10.23 months) was significantly longer than that of non-overweight patients (6.85 months; P = 0.027). Among patients with immune-related adverse events (irAEs), the mean PFS was also significantly longer in overweight patients (7.72 months) than in non-overweight patients (5.31 months, P = 0.034). Multivariate analysis showed that BMI was an independent prognostic factor for PFS in HCC patients treated with anti-PD-1 (hazard ratio: 0.47, P = 0.044). Thus, higher BMI predicts a better prognosis among HCC patients treated with anti-PD-1. In clinical practice, patients' BMI can provide a useful tool for predicting the efficacy of anti-PD-1 therapy.

HDAC8 Promotes Liver Metastasis of Colorectal Cancer via Inhibition of IRF1 and Upregulation of SUCNR1.

Histone deacetylases (HDACs) are well-characterized for their involvement in tumor progression. Herein, the current study set out to unravel the association of HDAC8 with colorectal cancer (CRC). Bioinformatics analyses were carried out to retrieve the expression patterns of HDAC8 in CRC and the underlying mechanism. Following expression determination, the specific roles of HDAC8, IRF1, and SUCNR1 in CRC cell functions were analyzed following different interventions. Additionally, tumor formation and liver metastasis in nude mice were operated to verify the fore experiment. Bioinformatics analyses predicted the involvement of the HDAC8/IRF1/SUCNR1 axis in CRC. In vitro cell experiments showed that HDAC8 induced the CRC cell growth by reducing IRF1 expression. Meanwhile, IRF1 limited SUCNR1 expression by binding to its promoter. SUCNR1 triggered the growth and metastasis of CRC by inhibiting cell autophagy. HDAC8 blocked IRF1-mediated SUCNR1 inhibition and thereby inhibited autophagy, accelerating CRC cell growth. Lastly, HDAC8 facilitated the development of CRC and liver metastasis by regulating the IRF1/SUCNR1 axis in vivo. Taken together, our findings highlighted the critical role for the HDAC8/IRF1/SUCNR1 axis in the regulation of autophagy and the resultant liver metastasis in CRC.

Identification of prognostic stemness biomarkers in colon adenocarcinoma drug resistance.

BACKGROUND: Colon adenocarcinoma (COAD) is one of the leading causes of death worldwide. Cancer stem cells (CSCs) are vital for COAD chemoresistance and recurrence, however little is known about stem cell-related biomarkers in drug resistance and COAD prognosis prediction. METHODS: To uncover the roles of CSC in COAD tumorigenesis, chemoresistance, and prognosis, we retrieved COAD patients' RNAseq data from TCGA (The Cancer Genome Atlas). We further performed analysis of differentially expressed genes (DEGs) and mRNA expression-based stemness index (mRNAsi) to identify stemness-related COAD biomarkers. We then evaluated the roles of mRNAsi in tumorigenesis, clinical-stage, overall survival (OS), and chemoresistance. Afterward, we used identified prognostic stemness-related genes (PSRGs) to construct a prediction model. After constructing the prediction model, we used elastic Net regression and area under the curve (AUC) to explore the prediction value of PSRGs based on risk scores and the receiver operator characteristic (ROC) curve. To elucidate the underlying interconnected systems, we examined relationships between the levels of TFs, PSRGs, and 50 cancer hallmarks by a Pearson correlation analysis. RESULTS: Twelve thousand one hundred eight DEGs were identified by comparing 456 primary COADs and 41 normal solid tissue samples. Furthermore, we identified 4351 clinical stage-related DEGs, 16,516 stemness-associated DEGs, and 54 chemoresistance-related DEGs from cancer stages: mRNAsi, and COAD chemoresistance. Compared to normal tissue samples, mRNAsi in COAD patients were marked on an elevation and involved in prognosis (p = 0.027), stemness-related DEGs based on chemoresistance (OR = 3.28, p ≤ 0.001) and AJCC clinical stage relating (OR = 4.02, p ≤ 0.001) to COAD patients. The prediction model of prognosis were constructed using the 6 PSRGs with high accuracy (AUC: 0.659). The model identified universal correlation between NRIP2 and FDFT1 (key PRSGs), and some cancer related transcription factors (TFs) and trademarks of cancer gene were in the regulatory network. CONCLUSION: We found that mRNAsi is a reliable predictive biomarker of tumorigenesis and COAD prognosis. Our established prediction model of COAD chemoresistance, which includes the six PSRGs, is effective, as the model provides promising therapeutic targets in the COAD.

A genomic-augmented multivariate prognostic model for the survival of natural-killer/T-cell lymphoma patients from an international cohort.

With lowering costs of sequencing and genetic profiling techniques, genetic drivers can now be detected readily in tumors but current prognostic models for Natural-killer/T cell lymphoma (NKTCL) have yet to fully leverage on them for prognosticating patients. Here, we used next-generation sequencing to sequence 260 NKTCL tumors, and trained a genomic prognostic model (GPM) with the genomic mutations and survival data from this retrospective cohort of patients using LASSO Cox regression. The GPM is defined by the mutational status of 13 prognostic genes and is weakly correlated with the risk-features in International Prognostic Index (IPI), Prognostic Index for Natural-Killer cell lymphoma (PINK), and PINK-Epstein-Barr virus (PINK-E). Cox-proportional hazard multivariate regression also showed that the new GPM is independent and significant for both progression-free survival (PFS, HR: 3.73, 95% CI 2.07-6.73; p < .001) and overall survival (OS, HR: 5.23, 95% CI 2.57-10.65; p = .001) with known risk-features of these indices. When we assign an additional risk-score to samples, which are mutant for the GPM, the Harrell's C-indices of GPM-augmented IPI, PINK, and PINK-E improved significantly (p < .001, χ2 test) for both PFS and OS. Thus, we report on how genomic mutational information could steer toward better prognostication of NKTCL patients.

Imbalance between the caudate and putamen connectivity in obsessive-compulsive disorder.

BACKGROUND: Compulsive behaviors in obsessive-compulsive disorder (OCD) have been suggested to result from an imbalance in cortico-striatal connectivity. However, the nature of this impairment, the relative involvement of different striatal areas, their imbalance in genetically related but unimpaired individuals, and their relationship with cognitive dysfunction in OCD patients, remain unknown. METHODS: In the current study, striatal (i.e., caudate and putamen) whole-brain connectivity was computed in a sample of OCD patients (OCD, n = 62), unaffected first-degree relatives (UFDR, n = 53) and healthy controls (HC, n = 73) by ROI-based resting-state functional magnetic resonance imaging (rs-fMRI). A behavioral task switch paradigm outside of the scanner was also performed to measure cognitive flexibility in OCD patients. RESULTS: There were significantly increased strengths (Z-transformed Pearson correlation coefficient) in caudate connectivity in OCD patients. A significant correlation between the two types of connectivity strengths in the relevant regions was observed only in the OCD patient group. Furthermore, the caudate connectivity of patients was negatively associated with their task-switch performance. CONCLUSIONS: The imbalance between the caudate and putamen connectivity, arising from the abnormal increase of caudate activity, may serve as a clinical characteristic for obsessive-compulsive disorder.

Nasopharyngeal cancer cell-derived exosomal PD-L1 inhibits CD8+ T-cell activity and promotes immune escape.

Programmed cell death ligand 1 (PD-L1) is an immune surface protein that binds to programmed cell death 1 (PD-1) and allows tumors to evade T-cell immunity. This study aims to define the role of PD-L1 shuttled by tumor cell-derived exosomes in the immune escape of nasopharyngeal carcinoma (NPC). PD-L1 expression was determined in the exosomes isolated from the plasma of NPC patients or from NPC cells. It was found that PD-L1 was highly expressed in the exosomes from the plasma of NPC patients and also in the exosomes from NPC cells. PD-L1/PD-1 binding was identified in the presence or absence of interferon-gamma (IFN-γ) or anti-PD-L1 antibody. PD-L1 expression was elevated following IFN-γ treatment. Binding of PD-L1 to PD-1 was augmented by IFN-γ and blocked by anti-PD-L1 antibody. Following this, CD8+ T cells were sorted out from peripheral blood samples to assess the binding between exosomal PD-L1 and PD-1 on the CD8+ T-cell surface, and to measure the percentage of Ki-67-positive T cells. The results indicated that exosomal PD-L1 bound to the PD-1 on CD8+ T-cell surface, leading to a reduced percentage of Ki-67-positive CD8+ T cells and downregulated production of cytokines. In vivo data confirmed that exosomal PD-L1 promoted NPC tumor growth in mice by suppressing CD8+ T-cell activity. In conclusion, NPC cell-derived exosomes deliver PD-L1 to bind to PD-1 on the CD8+ T-cell surface, through which cytotoxic CD8+ T-cell function was attenuated and the immune escape was thus promoted in NPC.

Controlled PAH-mediated method with enhanced optical properties for simple, stable immunochromatographic assays.

Despite their potential for signal amplification in immunochromatographic assays (ICAs) with Au nanoparticles (AuNPs) as probes, metal growth methods are of limited practical applicability given their complex non-specificity and lack of robust growth schemes. Here, we propose a novel method of polyallylamine hydrochloride (PAH)-mediated metal growth for the detection of Escherichia coli O157:H7 by AuNP-ICA. The developed method relies on the highly controlled growth of Cu shells on the AuNP core and allows one to achieve highly enhanced colorimetric signals by controlling PAH as the growth framework. The introduction of PAH eliminates the non-specific adsorption of Cu ions on the nitrocellulose membrane and thus provides maximized and effective signal-to-noise ratios to achieve a detection limit of 9.8 CFU/mL for E. coli O157:H7. Moreover, the newly developed detection method exhibits good reproducibility (coefficient of variation <13%), remarkable stability, and practical applicability. The PAH-mediated signal enhancement system paves the way to the realization of stable metal growth methods based on Au, Ag, and other metals and is well suited for the rapid, stable, and sensitive detection of food-borne pathogens using the AuNP-ICA platform.

Ferroptosis-related gene SLC1A5 is a novel prognostic biomarker and correlates with immune infiltrates in stomach adenocarcinoma.

BACKGROUND: Stomach adenocarcinoma (STAD) is associated with high morbidity and mortality rates. Ferroptosis is an iron-dependent form of cell death, which plays an important role in the development of many cancers. Tumor-associated competing endogenous RNAs (ceRNAs) regulate tumorigenesis and development. Our study aimed to construct ceRNA networks and explore the relationship between ferroptosis-related genes in the ceRNA network and immune infiltration in STAD. METHODS: Based on the interactions among long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs), a ceRNA network was constructed to illustrate the relationships among lncRNAs, miRNAs, and mRNAs. Subsequently, gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) functional enrichment analyses were carried out to explore the functions and interactions of the differentially expressed (DE) mRNAs related to the ceRNA network. Differential expression and prognostic analysis of ferroptosis-related genes in the ceRNA network were performed using the R package "limma" and "survminer." The correlation between ferroptosis-related genes and tumor-infiltrating immune cells was analyzed using Spearman correlation analysis and CIBERSORT. Quantitative real-time PCR (qRT-PCR) was used to validate the expression of ferroptosis-related genes in STAD cells lines. RESULTS: A ceRNA network consisting of 29 DElncRNAs, 31 DEmiRNAs, and 182 DEmRNAs was constructed. These DEmRNAs were significantly enriched in pathways related to the occurrence and development of STAD. The ferroptosis-related gene SLC1A5 was upregulated in STAD (P < 0.001) and was associated with better prognosis (P = 0.049). The CIBERSORT database and Spearman correlation analysis indicated that SLC1A5 was correlated with eight types of tumor-infiltrating immune cells and immune checkpoints, including PD-L1(CD-274) and PD-1(PDCD1). The SLC1A5 mRNA was found to be highly expressed in STAD cells lines. CONCLUSIONS: Our study provides insights into the function of ceRNAs in STAD and identifies biomarkers for the development of therapies for STAD. The ferroptosis-related gene SLC1A5 in the ceRNA network was associated with both tumor-infiltrating immune cells and immune checkpoints in the tumor microenvironment, suggesting that SLC1A5 may be a novel prognostic marker and a potential target for STAD immunotherapy in the future.

Combining serum inflammation indexes at baseline and post treatment could predict pathological efficacy to anti­PD­1 combined with neoadjuvant chemotherapy in esophageal squamous cell carcinoma.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) have been used to predict therapeutic response in different tumors. However, no assessments of their usefulness have been performed in esophageal squamous cell carcinoma (ESCC) patients receiving anti­PD­1 combined with neoadjuvant chemotherapy. METHODS: The respective data of 64 ESCC patients receiving anti­PD­1 combined with neoadjuvant chemotherapy were analyzed. Whether NLR, LMR, PLR, and SII at baseline and post-treatment might predict pathological response to anti­PD­1 plus neoadjuvant chemotherapy, and cutoff values of these parameters were all determined by ROC curve analysis. RESULTS: NLR (cutoff = 3.173, AUC = 0.644, 95% CI 0.500-0.788, P = 0.124, sensitivity = 1.000, specificity = 0.373), LMR (cutoff = 1.622, AUC = 0.631, 95% CI 0.477-0.784, P = 0.161, sensitivity = 0.917, specificity = 0.137), PLR (cutoff = 71.108, AUC = 0.712, 95% CI 0.575-0.849, P = 0.023, sensitivity = 1.000, specificity = 0.059), and SII at baseline (cutoff = 559.266, AUC = 0.681, 95% CI 0.533-0.830, P = 0.052, sensitivity = 0.373, specificity = 1.000) seemed to be a useful predictor for distinguishing responders from non-responders. Combining NLR with SII at baseline (AUC = 0.729, 95% CI 0.600-0.858, P = 0.014, sensitivity = 0.917, specificity = 0.510), LMR and SII at baseline (AUC = 0.735, 95% CI 0.609-0.861, P = 0.012, sensitivity = 1.000 specificity = 0.471), PLR and SII at baseline (AUC = 0.716, 95% CI 0.584-0.847, P = 0.021, sensitivity = 1.000 specificity = 0.431), and LMR and PLR at post-treatment in the third period (AUC = 0.761, 95% CI 0.605-0.917, P = 0.010, sensitivity = 0.800, specificity = 0.696) might slightly increase the prediction ability to determine patients who have response or no response. Finally, combining LMR at baseline, SII at post-treatment in the second period with PLR at post-treatment in the third period could be considered a better predictor for discriminating responders and non-responders than single or dual biomarkers (AUC = 0.879, 95% CI 0.788-0.969, P = 0.0001, sensitivity = 0.909, specificity = 0.800). CONCLUSIONS: The models we constructed allowed for the accurate and efficient stratification of ESCC patients receiving anti-PD-1 plus chemotherapy and are easily applicable for clinical practice at no additional cost.