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1.
Respiration ; 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38663359

RESUMO

INTRODUCTION: Although long-term macrolide antibiotics could reduce the recurrent exacerbation of chronic obstructive pulmonary disease (COPD), the side effect of bacterial resistance and the impact on the microbiota remain concerning. We investigated the influence of long-term erythromycin treatment on the airway and gut microbiota in mice with emphysema and patients with COPD. METHODS: We conducted 16S rRNA gene sequencing to explore the effect of erythromycin treatment on the lung and gut microbiota in mice with emphysema. Liquid chromatography-mass spectrometry was used for lung metabolomics. A randomized controlled trial was performed to investigate the effect of 48-week erythromycin treatment on the airway and gut microbiota in COPD patients. RESULTS: The mouse lung and gut microbiota were disrupted after cigarette smoke exposure. Erythromycin treatment depleted harmful bacteria and altered lung metabolism. Erythromycin treatment did not alter airway or gut microbial diversity in COPD patients. It reduced the abundance of pathogens, such as Burkholderia, in the airway of COPD patients and increased levels of symbiotic bacteria, such as Prevotella and Veillonella. The proportions of Blautia, Ruminococcus and Lachnospiraceae in the gut were increased in COPD patients after erythromycin treatment. The time to the first exacerbation following treatment was significantly longer in the erythromycin-treatment group than in the COPD group. CONCLUSION: Long-term erythromycin treatment reduces airway and gut microbe abundance in COPD patients but does not affect microbial diversity and restores microbiota balance in COPD patients by reducing the abundance of pathogenic bacteria.

2.
Int J Cardiol ; 407: 132065, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38642720

RESUMO

BACKGROUND: Accurate assessment and timely intervention play a crucial role in ameliorating poor short-term prognosis of acute pulmonary embolism (APE) patients. The currently employed scoring models exhibit a degree of complexity, and some models may not comprehensively incorporate relevant indicators, thereby imposing limitations on the evaluative efficacy. Our study aimed to construct and externally validate a nomogram that predicts 30-day all-cause mortality risk in APE patients. METHODS: Clinical data from APE patients in Intensive Care-IV database was included as a training cohort. Additionally, we utilized our hospital's APE database as an external validation cohort. The nomogram was developed, and its predictive ability was evaluated using receiver operating characteristic (ROC) curves, calibration plots and decision curve analysis. RESULTS: A collective of 1332 patients and 336 patients were respectively enrolled as the training cohort and the validation cohort in this study. Five variables including age, malignancy, oxygen saturation, blood glucose, and the use of vasopressor, were identified based on the results of the multivariate Cox regression model. The ROC value for the nomogram in the training cohort yielded 0.765, whereas in the validation group, it reached 0.907. Notably, these values surpassed the corresponding ROC values for the Pulmonary Embolism Severity Index, which were 0.713 in the training cohort and 0.754 in the validation cohort. CONCLUSIONS: The nomogram including five indicators had a good performance in predicting short-term prognosis in patients with APE, which was easier to apply and provided better recommendations for clinical decision-making.


Assuntos
Nomogramas , Embolia Pulmonar , Humanos , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/mortalidade , Masculino , Feminino , Prognóstico , Pessoa de Meia-Idade , Idoso , Doença Aguda , Valor Preditivo dos Testes , Estudos de Coortes , Estudos Retrospectivos , Fatores de Tempo
4.
Life Sci Alliance ; 7(4)2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38316463

RESUMO

Radiation therapy (RT) is one of the most commonly used anticancer therapies. However, the landscape of cellular response to irradiation, especially to a single high-dose irradiation, remains largely unknown. In this study, we performed a whole-genome CRISPR loss-of-function screen and revealed temporal inherent and acquired responses to RT. Specifically, we found that loss of the IL1R1 pathway led to cellular resistance to RT. This is in part because of the involvement of radiation-induced IL1R1-dependent transcriptional regulation, which relies on the NF-κB pathway. Moreover, the mitochondrial anti-apoptotic pathway, particularly the BCL2L1 gene, is crucially important for cell survival after radiation. BCL2L1 inhibition combined with RT dramatically impeded tumor growth in several breast cancer cell lines and syngeneic models. Taken together, our results suggest that the combination of an apoptosis inhibitor such as a BCL2L1 inhibitor with RT may represent a promising anticancer strategy for solid cancers including breast cancer.


Assuntos
Neoplasias da Mama , Mutações Sintéticas Letais , Proteína bcl-X , Feminino , Humanos , Proteína bcl-X/genética , Proteína bcl-X/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/radioterapia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Mutações Sintéticas Letais/genética
5.
Nature ; 627(8004): 656-663, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38418883

RESUMO

Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Kras mutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8+ cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation. This study provides new insights into epithelial cell states at the root of LUAD development, and such states could harbour potential targets for prevention or intervention.


Assuntos
Adenocarcinoma de Pulmão , Diferenciação Celular , Células Epiteliais , Neoplasias Pulmonares , Animais , Humanos , Camundongos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Aneuploidia , Carcinógenos/toxicidade , Células Epiteliais/classificação , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Organoides/efeitos dos fármacos , Organoides/metabolismo , Lesões Pré-Cancerosas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Taxa de Sobrevida , Produtos do Tabaco/efeitos adversos , Produtos do Tabaco/toxicidade
6.
Cancer Cell ; 41(8): 1407-1426.e9, 2023 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-37419119

RESUMO

Understanding tumor microenvironment (TME) reprogramming in gastric adenocarcinoma (GAC) progression may uncover novel therapeutic targets. Here, we performed single-cell profiling of precancerous lesions, localized and metastatic GACs, identifying alterations in TME cell states and compositions as GAC progresses. Abundant IgA+ plasma cells exist in the premalignant microenvironment, whereas immunosuppressive myeloid and stromal subsets dominate late-stage GACs. We identified six TME ecotypes (EC1-6). EC1 is exclusive to blood, while EC4, EC5, and EC2 are highly enriched in uninvolved tissues, premalignant lesions, and metastases, respectively. EC3 and EC6, two distinct ecotypes in primary GACs, associate with histopathological and genomic characteristics, and survival outcomes. Extensive stromal remodeling occurs in GAC progression. High SDC2 expression in cancer-associated fibroblasts (CAFs) is linked to aggressive phenotypes and poor survival, and SDC2 overexpression in CAFs contributes to tumor growth. Our study provides a high-resolution GAC TME atlas and underscores potential targets for further investigation.


Assuntos
Adenocarcinoma , Fibroblastos Associados a Câncer , Lesões Pré-Cancerosas , Neoplasias Gástricas , Humanos , Ecótipo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Adenocarcinoma/patologia , Fibroblastos Associados a Câncer/patologia , Lesões Pré-Cancerosas/patologia , Células Estromais/patologia , Microambiente Tumoral
7.
Nat Med ; 29(6): 1550-1562, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37248301

RESUMO

Tumor-infiltrating T cells offer a promising avenue for cancer treatment, yet their states remain to be fully characterized. Here we present a single-cell atlas of T cells from 308,048 transcriptomes across 16 cancer types, uncovering previously undescribed T cell states and heterogeneous subpopulations of follicular helper, regulatory and proliferative T cells. We identified a unique stress response state, TSTR, characterized by heat shock gene expression. TSTR cells are detectable in situ in the tumor microenvironment across various cancer types, mostly within lymphocyte aggregates or potential tertiary lymphoid structures in tumor beds or surrounding tumor edges. T cell states/compositions correlated with genomic, pathological and clinical features in 375 patients from 23 cohorts, including 171 patients who received immune checkpoint blockade therapy. We also found significantly upregulated heat shock gene expression in intratumoral CD4/CD8+ cells following immune checkpoint blockade treatment, particularly in nonresponsive tumors, suggesting a potential role of TSTR cells in immunotherapy resistance. Our well-annotated T cell reference maps, web portal and automatic alignment/annotation tool could provide valuable resources for T cell therapy optimization and biomarker discovery.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Linfócitos do Interstício Tumoral , Neoplasias/genética , Neoplasias/terapia , Neoplasias/metabolismo , Imunoterapia , Microambiente Tumoral
8.
Mol Ther Oncolytics ; 29: 30-41, 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-37114074

RESUMO

Longstanding evidence implicate glioma stem-like cells as the main drivers contributing toward glioblastoma (GBM) therapy resistance and tumor recurrence. Although oncolytic herpes simplex virus (oHSV) viral therapy is a promising biological therapy recently approved for melanoma (in the United States and Europe) and GBM (in Japan); however, the impact of this therapy on GBM stem-like cells (GSCs) is understudied. Here we show that post-oHSV virotherapy activated AKT signaling results in an enrichment of GSC signatures in glioma, which mimics the enrichment in GSC observed after radiation treatment. We also uncovered that a second-generation oncolytic virus armed with PTEN-L (oHSV-P10) decreases this by moderating IL6/JAK/STAT3 signaling. This ability was retained in the presence of radiation treatment and oHSV-P10-sensitized intracranial GBM to radiotherapy. Collectively, our findings uncover potential mechanisms to overcome GSC-mediated radiation resistance via oHSV-P10.

9.
J Immunother Cancer ; 11(2)2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36796878

RESUMO

BACKGROUND: Mammalian cells have developed multiple intracellular mechanisms to defend against viral infections. These include RNA-activated protein kinase (PKR), cyclic GMP-AMP synthase and stimulation of interferon genes (cGAS-STING) and toll-like receptor-myeloid differentiation primary response 88 (TLR-MyD88). Among these, we identified that PKR presents the most formidable barrier to oncolytic herpes simplex virus (oHSV) replication in vitro. METHODS: To elucidate the impact of PKR on host responses to oncolytic therapy, we generated a novel oncolytic virus (oHSV-shPKR) which disables tumor intrinsic PKR signaling in infected tumor cells. RESULTS: As anticipated, oHSV-shPKR resulted in suppression of innate antiviral immunity and improves virus spread and tumor cell lysis both in vitro and in vivo. Single cell RNA sequencing combined with cell-cell communication analysis uncovered a strong correlation between PKR activation and transforming growth factor beta (TGF-ß) immune suppressive signaling in both human and preclinical models. Using a murine PKR targeting oHSV, we found that in immune-competent mice this virus could rewire the tumor immune microenvironment to increase the activation of antigen presentation and enhance tumor antigen-specific CD8 T cell expansion and activity. Further, a single intratumoral injection of oHSV-shPKR significantly improved the survival of mice bearing orthotopic glioblastoma. To our knowledge, this is the first report to identify dual and opposing roles of PKR wherein PKR activates antivirus innate immunity and induces TGF-ß signaling to inhibit antitumor adaptive immune responses. CONCLUSIONS: Thus, PKR represents the Achilles heel of oHSV therapy, restricting both viral replication and antitumor immunity, and an oncolytic virus that can target this pathway significantly improves response to virotherapy.


Assuntos
Neoplasias Encefálicas , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Humanos , Camundongos , Neoplasias Encefálicas/patologia , Terapia Viral Oncolítica/métodos , Simplexvirus , Fator de Crescimento Transformador beta , Microambiente Tumoral , eIF-2 Quinase/metabolismo
10.
Mol Oncol ; 17(4): 564-581, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36495164

RESUMO

The incidence of bladder cancer and patient survival vary greatly among different populations, but the influence of the associated molecular features and evolutionary processes on its clinical treatment and prognostication remains unknown. Here, we analyze the genomic architectures of 505 bladder cancer patients from Asian/Black/White populations. We identify a previously unknown association between AHNAK mutations and activity of the APOBEC-a mutational signature, the activity of which varied substantially across populations. All significantly mutated genes but only half of arm-level somatic copy number alterations (SCNAs) are enriched with clonal events, indicating large-scale SCNAs as rich sources of bladder cancer clonal diversities. The prevalence of TP53 and ATM clonal mutations as well as the associated burden of SCNAs is significantly higher in Whites/Blacks than in Asians. We identify a trans-ancestry prognostic subtype of bladder cancer characterized by enrichment of non-muscle-invasive patients and muscle-invasive patients with good prognosis, increased CREBBP/FGFR3/HRAS/NFE2L2 mutations, decreased intra-tumor heterogeneity and genome instability, and an activated tumor microenvironment.


Assuntos
Neoplasias da Bexiga Urinária , Humanos , Prognóstico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Mutação/genética , Instabilidade Genômica , Genômica , Microambiente Tumoral
11.
FASEB J ; 37(2): e22727, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36583689

RESUMO

Transcriptional determinants in the skeletal muscle that govern exercise capacity, while poorly defined, could provide molecular insights into how exercise improves fitness. Here, we have elucidated the role of nuclear receptors, estrogen-related receptor alpha and gamma (ERRα/γ) in regulating myofibrillar composition, contractility, and exercise capacity in skeletal muscle. We used muscle-specific single or double (DKO) ERRα/γ knockout mice to investigate the effect of ERRα/γ deletion on muscle and exercise parameters. Individual knockout of ERRα/γ did not have a significant impact on the skeletal muscle. On the other hand, DKO mice exhibit pale muscles compared to wild-type (WT) littermates. RNA-seq analysis revealed a predominant decrease in expression of genes linked to mitochondrial and oxidative metabolism in DKO versus WT muscles. DKO muscles exhibit marked repression of oxidative enzymatic capacity, as well as mitochondrial number and size compared to WT muscles. Mitochondrial function is also impaired in single myofibers isolated from DKO versus WT muscles. In addition, mutant muscles exhibit reduced angiogenic gene expression and decreased capillarity. Consequently, DKO mice have a significantly reduced exercise capacity, further reflected in poor fatigue resistance of DKO mice in in vivo contraction assays. These results show that ERRα and ERRγ together are a critical link between muscle aerobic capacity and exercise tolerance. The ERRα/γ mutant mice could be valuable for understanding the long-term impact of impaired mitochondria and vascular supply on the pathogenesis of muscle-linked disorders.


Assuntos
Mitocôndrias , Músculo Esquelético , Camundongos , Animais , Músculo Esquelético/metabolismo , Camundongos Knockout , Mitocôndrias/metabolismo , Oxirredução , Estrogênios/metabolismo
12.
Genes Dev ; 36(17-18): 1016-1030, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36302555

RESUMO

Deubiquitylating enzymes (DUBs) remove ubiquitin chains from proteins and regulate protein stability and function. USP7 is one of the most extensively studied DUBs, since USP7 has several well-known substrates important for cancer progression, such as MDM2, N-MYC, and PTEN. Thus, USP7 is a promising drug target. However, systematic identification of USP7 substrates has not yet been performed. In this study, we carried out proteome profiling with label-free quantification in control and single/double-KO cells of USP7and its closest homolog, USP47 Our proteome profiling for the first time revealed the proteome changes caused by USP7 and/or USP47 depletion. Combining protein profiling, transcriptome analysis, and tandem affinity purification of USP7-associated proteins, we compiled a list of 20 high-confidence USP7 substrates that includes known and novel USP7 substrates. We experimentally validated MGA and PHIP as new substrates of USP7. We further showed that MGA deletion reduced cell proliferation, similar to what was observed in cells with USP7 deletion. In conclusion, our proteome-wide analysis uncovered potential USP7 substrates, providing a resource for further functional studies.


Assuntos
Proteômica , Ubiquitina Tiolesterase , Peptidase 7 Específica de Ubiquitina/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Proteoma , Ubiquitina/metabolismo , Ubiquitinação
13.
Sci Adv ; 8(19): eabm6638, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35559673

RESUMO

Exploiting cancer vulnerabilities is critical for the discovery of anticancer drugs. However, tumor suppressors cannot be directly targeted because of their loss of function. To uncover specific vulnerabilities for cells with deficiency in any given tumor suppressor(s), we performed genome-scale CRISPR loss-of-function screens using a panel of isogenic knockout cells we generated for 12 common tumor suppressors. Here, we provide a comprehensive and comparative dataset for genetic interactions between the whole-genome protein-coding genes and a panel of tumor suppressor genes, which allows us to uncover known and new high-confidence synthetic lethal interactions. Mining this dataset, we uncover essential paralog gene pairs, which could be a common mechanism for interpreting synthetic lethality. Moreover, we propose that some tumor suppressors could be targeted to suppress proliferation of cells with deficiency in other tumor suppressors. This dataset provides valuable information that can be further exploited for targeted cancer therapy.


Assuntos
Antineoplásicos , Neoplasias , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Genes Supressores de Tumor , Humanos , Neoplasias/genética , Mutações Sintéticas Letais
14.
Development ; 149(11)2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35451016

RESUMO

It has been established in the mouse model that during embryogenesis joint cartilage is generated from a specialized progenitor cell type, distinct from that responsible for the formation of growth plate cartilage. We recently found that mesodermal progeny of human pluripotent stem cells gave rise to two types of chondrogenic mesenchymal cells in culture: SOX9+ and GDF5+ cells. The fast-growing SOX9+ cells formed in vitro cartilage that expressed chondrocyte hypertrophy markers and readily underwent mineralization after ectopic transplantation. In contrast, the slowly growing GDF5+ cells derived from SOX9+ cells formed cartilage that tended to express low to undetectable levels of chondrocyte hypertrophy markers, but expressed PRG4, a marker of embryonic articular chondrocytes. The GDF5+-derived cartilage remained largely unmineralized in vivo. Interestingly, chondrocytes derived from the GDF5+ cells seemed to elicit these activities via non-cell-autonomous mechanisms. Genome-wide transcriptomic analyses suggested that GDF5+ cells might contain a teno/ligamento-genic potential, whereas SOX9+ cells resembled neural crest-like progeny-derived chondroprogenitors. Thus, human pluripotent stem cell-derived GDF5+ cells specified to generate permanent-like cartilage seem to emerge coincidentally with the commitment of the SOX9+ progeny to the tendon/ligament lineage.


Assuntos
Cartilagem Articular , Condrócitos , Células-Tronco Pluripotentes , Animais , Cartilagem Articular/citologia , Cartilagem Articular/metabolismo , Diferenciação Celular , Condrócitos/citologia , Condrócitos/metabolismo , Condrócitos/patologia , Condrogênese , Fator 5 de Diferenciação de Crescimento/metabolismo , Humanos , Hipertrofia , Camundongos , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo
15.
Clin Cancer Res ; 28(7): 1460-1473, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35022322

RESUMO

PURPOSE: Oncolytic herpes simplex virus-1 (oHSV) infection of brain tumors activates NOTCH, however the consequences of NOTCH on oHSV-induced immunotherapy is largely unknown. Here we evaluated the impact of NOTCH blockade on virus-induced immunotherapy. EXPERIMENTAL DESIGN: RNA sequencing (RNA-seq), TCGA data analysis, flow cytometry, Luminex- and ELISA-based assays, brain tumor animal models, and serum analysis of patients with recurrent glioblastoma (GBM) treated with oHSV was used to evaluate the effect of NOTCH signaling on virus-induced immunotherapy. RESULTS: TCGA data analysis of patients with grade IV glioma and oHSV treatment of experimental brain tumors in mice showed that NOTCH signaling significantly correlated with a higher myeloid cell infiltration. Immunofluorescence staining and RNA-seq uncovered a significant induction of Jag1 (NOTCH ligand) expression in infiltrating myeloid cells upon oHSV infection. Jag1-expressing macrophages further spread NOTCH activation in the tumor microenvironment (TME). NOTCH-activated macrophages increased the secretion of CCL2, which further amplified myeloid-derived suppressor cells. CCL2 and IL10 induction was also observed in serum of patients with recurrent GBM treated with oHSV (rQnestin34.5; NCT03152318). Pharmacologic blockade of NOTCH signaling rescued the oHSV-induced immunosuppressive TME and activated a CD8-dependent antitumor memory response, resulting in a therapeutic benefit. CONCLUSIONS: NOTCH-induced immunosuppressive myeloid cell recruitment limited antitumor immunity. Translationally, these findings support the use of NOTCH inhibition in conjunction with oHSV therapy.


Assuntos
Glioblastoma , Células Supressoras Mieloides , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Linhagem Celular Tumoral , Glioblastoma/patologia , Humanos , Imunoterapia , Camundongos , Células Supressoras Mieloides/metabolismo , Recidiva Local de Neoplasia/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Simplexvirus , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Cancer Immunol Immunother ; 71(6): 1479-1495, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34716463

RESUMO

An important mechanism of oncolytic virotherapy in ameliorating cancer immunotherapy is by inducing significant changes in the immune landscape in the tumor microenvironment (TME). Despite this notion and the potential therapeutic implications, a comprehensive analysis of the immune changes in carcinomas induced by virotherapy has not yet been elucidated. We conducted single-cell RNA sequencing analysis on carcinomas treated with an HSV-2-based oncolytic virus to characterize the immunogenic changes in the TME. We specifically analyzed and compared the immune cell composition between viral treated and untreated tumors. We also applied CellChat to analyze the complex interactions among the infiltrated immune cells. Our data revealed significant infiltration of B cells in addition to other important immune cells, including CD4+, CD8+, and NK cells following virotherapy. Further analysis identified distinct subset compositions of the infiltrated immune cells and their activation status upon virotherapy. The intensive interactions among the infiltrated immune cells as revealed by CellChat analysis may further shape the immune landscape in favor of generating antitumor immunity. Our findings will facilitate the design of new strategies in incorporating immunotherapy into virotherapy for clinical translation. Moreover, the significant infiltration of B cells makes it suitable for combining virotherapy with immune checkpoint inhibitors.


Assuntos
Carcinoma , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Imunoterapia , Vírus Oncolíticos/genética , Análise de Sequência de RNA , Microambiente Tumoral
17.
Mol Ther Oncolytics ; 23: 330-341, 2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34786476

RESUMO

The oncolytic effect of virotherapy derives from the intrinsic capability of the applied virus in selectively infecting and killing tumor cells. Although oncolytic viruses of various constructions have been shown to efficiently infect and kill tumor cells in vitro, the efficiency of these viruses to exert the same effect on tumor cells within tumor tissues in vivo has not been extensively investigated. Here we report our studies using single-cell RNA sequencing to comprehensively analyze the gene expression profile of tumor tissues following herpes simplex virus 2-based oncolytic virotherapy. Our data revealed the extent and cell types within the tumor microenvironment that could be infected by the virus. Moreover, we observed changes in the expression of cellular genes, including antiviral genes, in response to viral infection. One notable gene found to be upregulated significantly in oncolytic virus-infected tumor cells was Gadd45g, which is desirable for optimal virus replication. These results not only help reveal the precise infection status of the oncolytic virus in vivo but also provide insight that may lead to the development of new strategies to further enhance the therapeutic efficacy of oncolytic virotherapy.

19.
Front Pharmacol ; 12: 672065, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34707493

RESUMO

Background and Objective: Corticosteroid resistance is a major barrier to chronic obstructive pulmonary disease (COPD), but the exact mechanism of corticosteroid resistance in COPD has been less well studied. Methods: The microarray dataset GSE11906, which includes genomic and clinical data on COPD, was downloaded from the Gene Expression Omnibus (GEO) database, and the differentially expressed genes (DEGs) were identified using R software. Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes (KEGG) were utilized to enrich and analyze the gene cohort related to the response to steroid hormones, respectively. The Connectivity Map (CMap) database was used to screen corticosteroid resistance-related drugs that might exert a potential therapeutic effect. STRING was used to construct a protein-protein interaction (PPI) network of the gene cohort, and the CytoHubba plug-in of Cytoscape was used to screen the hub genes in the PPI network. The expression levels of hub genes in cigarette smoke extract (CSE)-stimulated bronchial epithelial cells were assayed by quantitative real-time PCR and western blotting. Results: Twenty-one genes were found to be correlated with the response to steroid hormones. In the CMap database, 32 small-molecule compounds that might exert a therapeutic effect on corticosteroid resistance in COPD were identified. Nine hub genes were extracted from the PPI network. The expression levels of the BMP4, FOS, FN1, EGFR, and SPP1 proteins were consistent with the microarray data obtained from molecular biology experiments. Scopoletin significantly restrained the increases in the levels of AKR1C3, ALDH3A1, FN1 and reversed the decreases of phosphorylated GR and HDAC2 caused by CSE exposure. Conclusion: The BMP4, FOS, FN1, EGFR, and SPP1 genes are closely correlated with CSE-induced glucocorticoid resistance in airway epithelial cells. Scopoletin may be a potential drug for the treatment of glucocorticoid resistance caused by CSE.

20.
Cancers (Basel) ; 13(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34359773

RESUMO

Although cisplatin is very effective as a treatment strategy in triple-negative breast cancer (TNBC), it has unwarranted outcomes owing to recurrence, chemoresistance and neurotoxicity. There is critically important to find new, effective and safe therapeutics for TNBC. We determined if SP-receptor antagonism in combination with cisplatin may serve as a novel, more efficacious and safer therapeutic option than existing therapies for TNBC. We used a neuronal cell line (PC12) and two TNBC cell lines (Sum 185 and Sum 159) for these studies. We determined that the levels of cells expressing the high-affinity SP-receptor (neurokinin 1 receptor (NK1R)), as determined by flow-cytometry was significantly elevated in response to cisplatin in all three cells. We determined that treatment with aprepitant, an SP-receptor antagonist decreased cisplatin-induced, loss of viability (studied by MTT assay), production of reactive oxygen species (by DCFDA assay) and apoptosis (by flow-cytometry) in PC12 cells while it was increased in the two TNBC cells. Furthermore, we demonstrated that important genes associated with metastases, inflammation, chemoresistance and cell cycle progression are attenuated by SP-receptor antagonism in the TNBC cell line, Sum 185. These studies implicate that SP-receptor antagonism in combination with cisplatin may possibly serve as a novel, more efficacious and safer therapeutic option than existing therapies for TNBC.

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