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1.
Stem Cells Int ; 2023: 8282961, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37197688

RESUMO

Chronic refractory wounds (CRW) are one of the most serious clinical challenges for surgeons to address. Stromal vascular fraction gels (SVFG), including human adipose stem cells (hASCs), have excellent vascular regenerative and tissue repair properties. Here, we combined single-cell RNA sequencing (scRNA-seq) of leg subcutaneous adipose tissue samples with scRNA-seq data from abdominal subcutaneous adipose tissue, leg subcutaneous adipose tissue, and visceral adipose tissue samples from public databases. The results showed specific differences in cellular levels in adipose tissue from different anatomical site sources. We identified cells including CD4+ T cells, hASCs, adipocyte (APC), epithelial (Ep) cells, and preadipocyte. In particular, the dynamics between groups of hASCs, epithelial cells, APCs, and precursor cells in adipose tissue of different anatomical site origins were more significant. Furthermore, our analysis reveals alterations at the cellular level and molecular level, as well as the biological signaling pathways involved in these subpopulations of cells with specific alterations. In particular, certain subpopulations of hASCs have higher cell stemness, which may be related to lipogenic differentiation capacity and may be beneficial in promoting CRW treatment and healing. In general, our study captures a human single-cell transcriptome profile across adipose depots, the cell type identification and analysis of which may help dissect the function and role of cells with specific alterations present in adipose tissue and may provide new ideas and approaches for the treatment of CRW in the clinical setting.

2.
Front Immunol ; 13: 934078, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36172351

RESUMO

Denosumab (DMAB), a human monoclonal antibody against the receptor activator of the nuclear factor-kappa B ligand, is used for the treatment for unresectable giant cell tumor of bone (GCTB). However, little is known about the molecular and functional characteristics of GCTB-infiltrating lymphocytes after DMAB treatment. Here, we performed single-cell RNA sequencing and immunostaining assays to delineate the immune landscape of GCTB in the presence and absence of DMAB. We found that exhausted CD8+ T cells were preferentially enriched in DMAB-treated GCTB. A distinct M2-skewed type of tumor-associated macrophages (TAMs) comprises the majority of GCTB TAMs. We identified cytokines, including interleukin-10, and inhibitory receptors of M2 TAMs as important mediators of CD8+ T cell exhaustion. We further revealed that DMAB treatment notably increased the expression levels of periostin (POSTN) in GCTB cells. Furthermore, POSTN expression was transcriptionally regulated by c-FOS signaling and correlated with GCTB recurrence in patients after DMAB treatment. Collectively, our findings reveal that CD8+ T-cells undergo unappreciated exhaustion during DMAB therapy and that GCTB cell-derived POSTN educates TAMs and establishes a microenvironmental niche that facilitates GCTB recurrence.


Assuntos
Neoplasias Ósseas , Tumor de Células Gigantes do Osso , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linfócitos T CD8-Positivos/patologia , Denosumab/farmacologia , Denosumab/uso terapêutico , Perfilação da Expressão Gênica , Tumor de Células Gigantes do Osso/tratamento farmacológico , Tumor de Células Gigantes do Osso/genética , Tumor de Células Gigantes do Osso/patologia , Humanos , Interleucina-10 , Ligantes
3.
Opt Express ; 29(7): 10285-10306, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33820168

RESUMO

This paper presents a passive autofocus algorithm applicable to interferometric microscopes. The proposed algorithm uses the number of slope variations in an image mask to locate the focal plane (based on focus-inflection points) and identify the two neighboring planes at which fringes respectively appear and disappear. In experiments involving a Mirau objective lens, the proposed algorithm matched the autofocusing performance of conventional algorithms, and significantly outperformed detection schemes based on zero-order interference fringe in dealing with all kinds of surface blemish, regardless of severity. In experiments, the proposed algorithm also proved highly effective in cases without fringes.

4.
Biomater Sci ; 8(21): 5888-5899, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33001086

RESUMO

Anti-angiogenic tyrosine kinase inhibitors (TKIs) have been proved to be effective in prolonging progression-free survival in advanced osteosarcoma. However, osteosarcoma stem-like cells persist for a long time and ultimately cause disease recurrence and therapy resistance. Here, we reveal that inefficient accumulation of Apatinib, an anti-angiogenic TKI, induces the expression of ribosome-associated genes in osteosarcoma, and confers apoptosis resistance. An engineered nanoscale delivery system based on hydrophobic poly(ester amide) has been established to effectively deliver Apatinib to improve the treatment. Notably, the considerable uptake by osteosarcoma cells enables this nanodrug to distribute increasingly inside the tumor. Furthermore, the delivered nano-Apatinib can suppress osteosarcoma stemness and enhance osteosarcoma stem-like cell apoptosis, and overcomes the crucial bottleneck of the unfavorable stem-like cell residue for TKI therapy. Importantly, nano-Apatinib significantly inhibits the osteosarcoma stem-like cell-derived tumor growth in contrast with free Apatinib, with minimal side effects. These results suggest that this Apatinib-loaded nano delivery system may serve as a promising strategy to solve the issue of TKI therapeutic resistance existing in advanced osteosarcoma.


Assuntos
Antineoplásicos , Neoplasias Ósseas , Nanopartículas , Osteossarcoma , Amidas/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ésteres , Humanos , Osteossarcoma/tratamento farmacológico , Piridinas
5.
Signal Transduct Target Ther ; 5(1): 196, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32973147

RESUMO

The adaptation of osteosarcoma cells to therapeutic pressure impedes the efficacy of chemotherapy for osteosarcoma. However, the characteristics and cellular organization of therapy-resistant cells in osteosarcoma tumors remain elusive. Here, we utilized single-cell transcriptomics to systematically map the cell-type-specific gene expression in a chemotherapy-resistant osteosarcoma tumor. Our data demonstrated the VEGFR2-JMJD3-abundant subsets as quiescent stem-like cells, thereby establishing the hierarchy of therapy-resistant actively cycling progenitor pools (JMJD3-abundant) in osteosarcoma. VEGFR2 inhibitor and JMJD3 inhibitor synergistically impeded osteosarcoma cell propagation and tumor growth. Although osteosarcoma cells are predisposed to apoptosis induced by the synergistic therapy through activation of the CHOP pro-apoptotic factor via the endoplasmic reticulum (ER) stress, the stem-like/progenitor cells exhibit an adaptive response, leading to their survival. Reduction in cellular glutathione levels in stem-like/progenitor cells caused by the treatment with a glutathione synthesis inhibitor increases ER stress-induced apoptosis. Importantly, the marked therapeutic improvement of synergistic therapy against stem-like/progenitor cells was achieved by using glutathione-scavenging nanoparticles, which can load and release the drug pair effectively. Overall, our study provides a framework for understanding glutathione signaling as one of the therapeutic vulnerabilities of stem-like/progenitor cells. Broadly, these findings revealed a promising arsenal by encapsulating glutathione-scavenging nanoparticles with co-targeting VEGFR2 and JMJD3 to eradicate chemotherapy-resistant osteosarcoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Perfilação da Expressão Gênica , Nanopartículas/toxicidade , Células-Tronco Neoplásicas , Osteossarcoma , Análise de Célula Única , Animais , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Biomed Pharmacother ; 123: 109728, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31846842

RESUMO

BACKGROUND: H3K27me3 modification inactivates gene transcription by resulting in condensed chromatin. However, the landscape and biological functions of H3K27me3 in breast cancer remain unclear. METHODS: Fluorescence enzyme assay was used to analyze the cell proliferation. Transwell assay was used to test the ability of migration and invasion in MDA-MB-231 cells with designed treatment. Transfection of exogenous plasmid was used to intervene specific gene expression. Nude mouse tumor xenograft model was employed to detect the effect of GSKJ-4 in vivo. ChIP-Seq analyzed the modification state of H3K27me3 around the TSS of the gene CEMIP. RNA-Seq was used to analyze the mRNA levels after treating with GSKJ-4 in MDA-MB-231 cells. RESULTS: Loss of H3K27me3 is specific for aggressive subtypes of breast cancer and may be a useful diagnostic marker. Epigenetic chemical screening identified histone H3K27me3 demethylation inhibition as a therapeutic strategy for triple-negative breast cancer (TNBC). Functional studies and RNA-seq/ChIP-seq data revealed that inactivation of the protein CEMIP (which is translated by oncogene KIAA1199) by increasing H3K27me3 leads to decreased tumor cell growth and migration. Moreover, survival analysis showed that CEMIP was associated with poor outcome in TNBC. CONCLUSIONS: Our data suggest H3K27me3 loss as an important event in CEMIP mediated breast cancer carcinogenesis and progression. Loss of H3K27me3 is specific for aggressive subtypes of breast cancer and may be a useful diagnostic marker.


Assuntos
Benzazepinas/farmacologia , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Histonas/metabolismo , Hialuronoglucosaminidase/metabolismo , Pirimidinas/farmacologia , Animais , Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Carcinogênese , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Histonas/genética , Humanos , Hialuronoglucosaminidase/genética , Camundongos , Camundongos Nus , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
7.
Mol Cancer Res ; 18(1): 57-67, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31615908

RESUMO

Osteosarcoma is an aggressive malignancy with poor prognosis. Super-enhancers (SE) have been highlighted as critical oncogenic elements required for maintaining the cancer cell characteristics. However, the regulatory role of SEs in osteosarcoma properties has not yet been elucidated. In the current study, we found that osteosarcoma cells and clinical specimens shared a significant fraction of SEs. Moreover, leukemia-inhibitory factor (LIF) was identified as an essential factor under the control of osteosarcoma-specific SE. The expression of LIF was positively correlated with the stem cell core factor genes in osteosarcoma. Furthermore, LIF recombinant protein-treated osteosarcoma cells displayed enhanced stem cell-like characteristics, such as increased sphere-forming potential, stimulated self-renewal, upregulated metastasis ability, and increased stemness-related gene expression. Notably, the histone 3 lysine 27 tri-methylation (H3K27me3) demethylase UTX was found as a key activator of LIF transcription in osteosarcoma. The UTX inhibitor, GSK-J4, induced H3K27me3 accumulation and impaired histone 3 lysine 27 acetylation (H3K27ac) at LIF gene locus, leading to LIF signaling pathway inhibition. GSK-J4 treatment resulted in profound defects in stem cell-like characteristics and stemness-related gene activation in osteosarcoma by modulating the H3K27ac of NOTCH1 signaling pathway gene loci. The NOTCH1 inhibitor Crenigacestat (TargetMol, T3633) repressed LIF-mediated activation of the stemness-related genes in osteosarcoma patient-derived primary tissues. IMPLICATIONS: This study reveals osteosarcoma SE profiles and uncovers a distinct tumor-stemness epigenetic regulatory mechanism in which an osteosarcoma-specific SE-mediated factor, LIF, promotes osteosarcoma stemness gene activation via NOTCH1 signaling pathway.


Assuntos
Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Fator Inibidor de Leucemia/genética , Células-Tronco Neoplásicas/patologia , Osteossarcoma/genética , Osteossarcoma/patologia , Animais , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Modelos Animais de Doenças , Epigênese Genética , Feminino , Xenoenxertos , Humanos , Fator Inibidor de Leucemia/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Osteossarcoma/metabolismo
8.
Cancer Biother Radiopharm ; 33(1): 3-7, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29466035

RESUMO

BACKGROUND: Gastric carcinoma is the most popular cancer worldwide. Anoctamin-1 is a calcium-activated channel and highly expressed in various tumors. A previous study indicated that suppressed Anoctamin-1 expression decreased cancer cell proliferation or migration. As a signal transduction and transcription activator, STAT6 is a novel agonist for Anoctamin-1 promoter. However, its role in tumor cell proliferation or migration remains unclear. Therefore, this study aimed to suppress STAT6 and Anoctamin-1 protein expression in gastric cancer cells to test the inhibitory effects on gastric cancer cell migration or invasion. MATERIALS AND METHODS: MTT colorimetry was used to test cell proliferation. Western blot was used to measure STAT6 and Anoctamin-1 expression before and after small interfering RNA (siRNA) treatment. A scratch assay was performed to measure cell migration, followed by Transwell chamber assay analysis of cell invasion. RESULTS: After STAT6 siRNA interference, the expression of STAT6 and Anoctamin-1 was significantly decreased in the gastric carcinoma cell line. Anoctamin-1 siRNA interference only decreased its protein expression, but not STAT6 protein expression. Interference of STAT6 or Anoctamin-1 reduced their protein expression and inhibited proliferation, migration, or invasion of gastric cancer cells. CONCLUSIONS: Inhibition of STAT6/Anoctamin-1 activation decreased proliferation, migration, or invasion of gastric cancer cells, suggesting that the STAT6/Anoctamin-1 pathway might be a novel target for treating gastric cancer.


Assuntos
Anoctamina-1/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Fator de Transcrição STAT6/antagonistas & inibidores , Neoplasias Gástricas/metabolismo , Anoctamina-1/biossíntese , Anoctamina-1/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Técnicas de Silenciamento de Genes , Humanos , Invasividade Neoplásica , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Fator de Transcrição STAT6/biossíntese , Fator de Transcrição STAT6/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Transfecção
9.
Med Sci Monit ; 21: 2893-9, 2015 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-26410168

RESUMO

BACKGROUND: Nuclear factor E2-related factor 2 (Nrf2) plays an anti-oxidative and phase II detoxification function via its up-regulation on various antioxidant response elements (ARE) genes. Nrf2 can protect both normal and cancer cells from damages of cell stress, thereby exerting a critical role in the development of cancer. The expression and significance of Nrf2 in gastric cancer, however, has not been reported. This study thus aimed to investigate the expression of Nrf2 in gastric cancer tissues via immunohistochemical (IHC) staining. MATERIAL AND METHODS: Gastric carcinoma tissues from a total of 175 patients during surgical resection were examined for Nfr2 expression profiles using IHC staining on paraffin-embedded slides. Between-group-comparisons were performed by chi-square, Fisher's exact, or Mann-Whitney U test. The correlation between Nfr2 expression and clinical indexes was further analyzed by Kaplan-Meier test, univariate/multivariate analysis, and log-rank test. RESULTS: Nrf2 is mainly expressed in nuclei of gastric carcinoma tissues, with significant correlation with clinical indexes, including tumor size, invasive depth, lymph node metastasis, and invasion. Patients with Nrf2-positive expression had significantly lower survival rates compared to those in the negative group (p<0.01), with chemo-resistance against 5-fluorouracil (5-FU) (p<0.05). CONCLUSIONS: Nrf2 expression is positively correlated with invasive gastric cancer, suggesting its utility as a predictive index for unfavorable prognosis.


Assuntos
Regulação Neoplásica da Expressão Gênica , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Antioxidantes/química , Carcinoma/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Fluoruracila/uso terapêutico , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Prognóstico , Elementos de Resposta , Regulação para Cima
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