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Esophageal squamous cell carcinoma (ESCC) is characterized by molecular heterogeneity with various immune cell infiltration patterns, which have been associated with therapeutic sensitivity and resistance. In particular, dendritic cells (DCs) are recently discovered to be associated with prognosis and survival in cancer. However, how DCs differ among ESCC patients has not been fully comprehended. Recently, the advance of single-cell RNA sequencing (scRNA-seq) enables us to profile the cell types, states, and lineages in the heterogeneous ESCC tissues. Here, we dissect the ESCC tumor microenvironment at high resolution by integrating 192,078 single cells from 60 patients, including 4379 DCs. We then used Scissor, a method that identifies cell subpopulations from single-cell data that are associated bulk samples with genomic and clinical information, to stratify DCs into Scissorhi and Scissorlow subtypes. We applied the Scissorhi gene signature to stratify ESCC scRNAseq patient, and we found that PD-L1, TIGIT, PVR and IL6 ligand-receptor-mediated cell interactions existed mainly in Scissorhi patients. Finally, based on the Scissor results, we successfully developed a validated prognostic risk model for ESCC and further validated the reliability of the risk prediction model by recruiting 40 ESCC clinical patients. This information highlights the importance of these genes in assessing patient prognosis and may help in the development of targeted or personalized therapies for ESCC.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Pronóstico , Carcinoma de Células Escamosas de Esófago/genética , Neoplasias Esofágicas/genética , Reproducibilidad de los Resultados , Inmunidad , Células Dendríticas , Microambiente Tumoral/genéticaRESUMEN
In this study, charge-transfer-type compounds comprising synthesized naphthalenediimide derivative (H4NDISA) or its Pb-based coordination polymer (Pb-NDISA) and suitable primary or secondary amine organic molecules were prepared by the solvent-free mechanical grinding method. The coloration phenomenon arising from charge transfer during grinding serves as a discriminative tool for distinguishing various organic guest molecules. The porous structure of Pb-NDISA crystals facilitates the infiltration of guest molecules and contributes to the preservation of the intermolecular charge transfer state. Moreover, the intermolecular charge transfer induced by grinding exhibits remarkable stability in an ambient atmosphere, underscoring the pivotal role of well-ordered molecules in the mechanical grinding procedure. This mechanochromic phenomenon holds promise for the detection and sensing of organic molecules, while the exceptional charge-transfer absorption characteristics offer the potential for efficient near-infrared photothermal conversion.
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BACKGROUND: Long noncoding RNA (LncRNA) play a vital role in the development and pathophysiology of osteosarcoma (OS). However, the LncRNA activated by HES1-10 in OS has not been furthered investigated. This present study aims to show the possible function of Lnc-HES1-10 in OS. METHODS: Cell proliferation in vitro were assessed by the MTT assay, whereas the migration and invasion abilities of OS cell lines were measured by wound-healing migration assay and transwell invasion assay, respectively. Quantitative reverse transcriptase polymerase chain reaction and western blot analysis was used to detected the expression level of HES1-10. RESULTS: The present study demonstrated that the Lnc-HES1-10 is overexpressed in OS and associated with poor prognosis of patients. In addition, the results revealed that Lnc-HES1-10 is overexpressed in MG63 and 143B OS cell lines and promote proliferation on both cell lines in vitro. Furthermore, migration and invasion abilities of MG63 and 143B cells are suppressed after silencing Lnc-HES1-10. CONCLUSION: Our finding demonstrates that HES1-10 plays a crucial role in regulating OS growth and metastasis.
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Neoplasias Óseas , MicroARNs , Osteosarcoma , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Osteosarcoma/patología , Proliferación Celular/genética , Neoplasias Óseas/patología , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Factor de Transcripción HES-1/genética , Factor de Transcripción HES-1/metabolismoRESUMEN
PURPOSE: This meta-analysis aimed to investigate the effectiveness of conservative and surgical treatments of scaphoid fracture. METHODS: The literature databases of Pubmed, Cochrane library, and Embase were searched in March 2022. This work extracted the data based on healing time, grip strength, range of wrist motion, nonunion, time before returning to work, and complications (including persistent pain, malunion of the fracture, wound infection, scar sensitivity, hypertrophic scar, and implant-related complications). Stata 14.0 software was used for statistical analysis. RESULTS: Twelve RCTs studies met our inclusion criteria. The surgical group had a shorter healing-time and time before returning to work than the conservative group. In addition, the surgical group had significantly better grip strength and range of wrist motion than the conservative group (P < 0.01). However, there was no significant difference between nonunion (P = 0.538) and complications (P = 0.661) between the two groups. CONCLUSION: This meta-analysis showed that surgical treatment of scaphoid fracture achieved better grip strength and range of wrist motion, and had a lower healing time and time before returning to work than the conservative treatment. The two treatments had similar results in nonunion and complications. Further RCTs were required for the research.
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Tratamiento Conservador , Fracturas Óseas , Hueso Escafoides , Humanos , Tratamiento Conservador/efectos adversos , Fracturas Óseas/cirugía , Fracturas Óseas/terapia , Complicaciones Posoperatorias/epidemiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Rango del Movimiento Articular , Hueso Escafoides/lesiones , Hueso Escafoides/cirugía , Resultado del TratamientoRESUMEN
OBJECTIVES: To reveal the effect and mechanism of methyltransferase-like 3 (METTL3) on cancer stem cells (CSCs) of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: First, we analyzed 14-HNSCC-patients' scRNA-seq dataset and TCGA dataset of HNSCC. Then, Mettl3 knockout or overexpression mice models were studied via tracing and staining technologies. In addition, we took flow cytometry sorting and sphere formation assays to observe tumorigenicity and used cell transfection and western blotting to verify target protein expression levels. Furthermore, methylated RNA immunoprecipitation sequencing (MeRIP-seq) and MeRIP-quantitative real-time PCR (MeRIP-qPCR) were taken to identify the mechanism of Mettl3 regulating Bmi1+ CSCs in HNSCC. RESULTS: Due to SOX4 transcriptional regulation, METTL3 regulated the malignant behavior of BMI1+ HNSCC stem cells through cell division pathway. The progression and malignancy of HNSCC were decreased after Mettl3 knocked-out, while increased after Mettl3 knocked-in in Bmi1+ CSCs in vivo. Knockdown of Mettl3 inhibited stemness properties of CSCs in vitro. Mechanically, Mettl3 mediated the m6 A modification of ALDH1A3 and ALDH7A1 mRNA in Bmi1+ HNSCC CSCs. CONCLUSION: Regulated by SOX4, METTL3-mediated ALDH m6 A methylation regulates the malignant behavior of BMI1+ HNSCC CSCs through cell division pathway.
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OBJECTIVE: Head and neck squamous cell carcinoma (HNSCC) is the most common type of malignancy in the head and neck region worldwide. The therapeutic strategies for HNSCC remain unsatisfying and limited. Here, we found a population of resistant Bmi1-expressing cells in the presence of cetuximab treatment and reported a novel role of SRY-box transcription factor 18 (SOX18), a member of the SOX family, in promoting HNSCC resistance to cetuximab. This study aimed to investigate the regulatory mechanism of Sox18 in Bmi1-positive cells and to search for better therapeutic targets. METHODS: We successfully obtained Bmi1CreER , RosatdTomato , and RosaDTA mice and identified Bmi1-expressing cells through lineage tracing. SOX18 expression in HNSCC and normal tissues was analyzed by immunohistochemistry, colocalization of Sox18, and Bmi1-expressing cells was analyzed by immunofluorescence, and SOX18 expression in SCC9 cell lines was quantified by western blotting and quantitative real-time PCR. The investigation of the mechanism of SOX18-mediated cetuximab resistance in Bmi1-positive cells was based on the analysis of single-cell RNA-seq data obtained from the Gene Expression Omnibus (GEO) database. Western blotting was performed to verify the results obtained from the single-cell RNA-seq analysis. RESULTS: In our study, we demonstrated that Bmi1-expressing cells were resistant to cetuximab treatment and that depletion of Bmi1-expressing cells improved cetuximab efficacy in HNSCC. We then discovered that Sox18 mediated the stem cell-like properties of Bmi1-expressing cells and promoted cellular cetuximab resistance through an oxidative phosphorylation pathway. There was a significant downregulation of key genes in the oxidative phosphorylation pathway in Sox18 knockout cell lines. CONCLUSIONS: Taken together, the findings of our study suggest that Sox18 mediates the resistance of Bmi1-expressing cells to cetuximab in HNSCC via the oxidative phosphorylation pathway.
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Chemoresistance has been a major challenge in advanced gastric cancer (GC) therapy. Exosomal transfer of oncogenic miRNAs implicates important effects in mediating recipient cell chemoresistance by transmitting active molecules. In this study, we found that microRNA-500a-3p was highly expressed in cisplatin (DDP) resistant GC cells (MGC803/DDP and MKN45/DDP) and their secreted exosomes than that in the corresponding parental cells. MGC803/DDP-derived exosomes enhance DDP resistance and stemness properties of MGC803 recipient cells via exosomal delivery of miR-500a-3p in vitro and in vivo through targeting FBXW7. However, reintroduction of FBXW7 in MGC803 cells reverses miR-500a-3p-mediated DDP resistance as well as stemness properties. Furthermore, elevated miR-500a-3p in the plasma exosomes of GC patients is correlated with DDP resistance and thereby results in poor progression-free prognosis. Our finding highlights the potential of exosomal miR-500a-3p as an potential modality for the prediction and treatment of GC with chemoresistance.
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Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , Exosomas/genética , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , MicroARNs/genética , Células Madre Neoplásicas/patología , Neoplasias Gástricas/genética , Animales , Línea Celular Tumoral , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Pronóstico , Neoplasias Gástricas/patologíaRESUMEN
Diabetes mellitus (DM) is one of the prominent risk factors for pathological development and progression of tendinopathy. One feature of DM-related changes in tendinopathy is accumulation of advanced glycation end products (AGEs) in affected tendons. Pioglitazone (Pio), a peroxisome proliferator-activated receptor γ agonist, performs a protective effect against AGEs. The present study aimed to investigate the pathogenetic role of AGEs on tendon-derived stem cells (TDSCs) and to determine the effect of Pio on AGEs-induced TDSC dysfunctions. Results indicated that AGEs induced TDSC apoptosis as well as compensatory activation of autophagy. Pharmacologic activation/inhibition of autophagy leaded to alleviate/exacerbate apoptosis induced by AGEs. We further confirmed the effect of Pio on autophagy, which ameliorated apoptosis and abnormal calcification caused by AGEs both in vitro and in vivo. Thus, we suggest that Pio ameliorates the dysfunctions of TDSCs against AGEs by promoting autophagy, and we also reveal that Pio is a potential pharmacological choice for tendinopathy.
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Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Calcificación Fisiológica/efectos de los fármacos , Productos Finales de Glicación Avanzada/metabolismo , Pioglitazona/farmacología , Células Madre/efectos de los fármacos , Tendones/efectos de los fármacos , Animales , Masculino , PPAR gamma/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Células Madre/metabolismo , Tendones/metabolismoRESUMEN
Here, we report the large-scale emission color tunability in Ba3La(PO4)3:Tb3+, Sm3+ (BLPO:TS) system based on the detailed discussion on the concentration-driven selectivity of energy transfer (ET) channels from Tb3+ to Sm3+. It is induced by the concentration-dependent 5D3 and 5D4 emissions of Tb3+ and the different interaction mechanisms of ET from Tb3+ to Sm3+ via 5D3 and 5D4 channels. In the diluted Tb3+ scenario, the red emission of Sm3+ is efficiently sensitized via the 5D3 channel, while in the concentrated Tb3+ case, the contribution of 5D4 channel is dominant. Therefore, by simply adjusting the doping concentrations of Tb3+ and Sm3+, the emission color of the phosphors can be tuned from green to red. In view of the phosphors with red emissions are critical to the warm white light-emitting diodes (WLEDs), an orange-red Tb3+, Sm3+ coactivated phosphor Ba3La0.90Tb0.05Sm0.05(PO4)3 (BLPO:5T5S) with good thermal and chromaticity stability and internal quantum efficiency â¼67% is developed in the system. Then, a near-UV WLED (CCT ≈ 4500 K, Ra ≈ 81) is fabricated using this phosphor. These findings not only indicate that the orange-red phosphor BLPO:5T5S is available for near-UV warm white LEDs but also deliver new insights into the ET processes in Tb3+ and Sm3+ activated phosphors.
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Almost all the deformable mirror (DM) based adaptive optics systems (AOSs) used on large aperture telescopes work at the infrared waveband due to the limitation of the number of actuators. To extend the imaging waveband to the visible, we propose a DM and Liquid crystal wavefront corrector (DM/LCWFC) combination AOS. The LCWFC is used to correct the high frequency aberration corresponding to the visible waveband and the aberrations of the infrared are corrected by the DM. The calculated results show that, to a 10 m telescope, DM/LCWFC AOS which contains a 1538 actuators DM and a 404 × 404 pixels LCWFC is equivalent to a DM based AOS with 4057 actuators. It indicates that the DM/LCWFC AOS is possible to work from visible to infrared for larger aperture telescopes. The simulations and laboratory experiment are performed for a 2 m telescope. The experimental results show that, after correction, near diffraction limited resolution USAF target images are obtained at the wavebands of 0.7-0.9 µm, 0.9-1.5 µm and 1.5-1.7 µm respectively. Therefore, the DM/LCWFC AOS may be used to extend imaging waveband of larger aperture telescope to the visible. It is very appropriate for the observation of spatial objects and the scientific research in astronomy.
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For more than a decade, the backfilling approach for the immobilization of DNA probes has been routinely adopted for the construction of functional interfaces; however, reliably reproducing electrochemical signal amplification by this method is a challenge. In this research, we demonstrate that the insertion approach significantly bolsters the reproducibility of electrochemical signal amplification via DNA superstructures. The combination of the backfilling approach and the DNA superstructure formation poses a big challenge to reliably reproducing electrochemical signal amplification. In order to use the detection of Hg(2+) as a prototype of this new strategy, a thymine-rich DNA probe that is specific to mercury ion was applied in this study. The presence of Hg(2+) induces the folding of the DNA probes and inhibits the formation of DNA superstructures. By using electroactive probes ([Ru(NH3)6](3+)) that are electrostatically adsorbed onto the double strands, differential pulse voltammetry (DPV) could quantitatively confirm the presence of Hg(2+). A limit of detection (LOD) and a limit of quantification (LOQ) (LOQ) as low as 0.3 and 9.5 pM, respectively, were achieved. Furthermore, excellent selectivity and real sample analysis demonstrated the promising potential of this approach in future applications.
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ADN/química , Técnicas de Amplificación de Ácido Nucleico/métodos , Electroquímica , Agua Dulce/análisis , Indicadores y Reactivos , Mercurio/análisis , Oligonucleótidos/química , Reproducibilidad de los Resultados , Contaminantes Químicos del Agua/análisisRESUMEN
Enoblituzumab, an immunotherapeutic agent targeting CD276, shows both safety and efficacy in activating T cells and oligodendrocyte-like cells against various cancers. Preclinical studies and mouse models suggest that therapies targeting CD276 may outperform PD1/PD-L1 blockade. However, data from mouse models indicate a significant non-responsive population to anti-CD276 treatment, with the mechanisms of resistance still unclear. In this study, we evaluate the activity of anti-CD276 antibodies in a chemically-induced murine model of head and neck squamous cell carcinoma. Using models of induced and orthotopic carcinogenesis, we identify ITGB6 as a key gene mediating differential responses to anti-CD276 treatment. Through single-cell RNA sequencing and gene-knockout mouse models, we find that ITGB6 regulates the expression of the tumor-associated chemokine CX3CL1, which recruits and activates PF4+ macrophages that express high levels of CX3CR1. Inhibition of the CX3CL1-CX3CR1 axis suppresses the infiltration and secretion of CXCL16 by PF4+ macrophages, thereby reinvigorating cytotoxic CXCR6+ CD8+ T cells and enhancing sensitivity to anti-CD276 treatment. Further investigations demonstrate that inhibiting ITGB6 restores sensitivity to PD1 antibodies in mice resistant to anti-PD1 treatment. In summary, our research reveals a resistance mechanism associated with immune checkpoint inhibitor therapy and identifies potential targets to overcome resistance in cancer treatment.
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Antígenos B7 , Neoplasias de Cabeza y Cuello , Ratones Noqueados , Animales , Ratones , Antígenos B7/metabolismo , Antígenos B7/genética , Antígenos B7/antagonistas & inhibidores , Humanos , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Receptor 1 de Quimiocinas CX3C/metabolismo , Receptor 1 de Quimiocinas CX3C/genética , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Línea Celular Tumoral , Ratones Endogámicos C57BL , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Modelos Animales de Enfermedad , Femenino , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
Pyroptosis, a lytic and pro-inflammatory cell death, is important in various pathophysiological processes. Host- and bacteria-derived extracellular vesicles (EVs), as natural nanocarriers messengers, are versatile mediators of intercellular communication between different types of cells. Recently, emerging research has suggested that EVs exhibit multifaceted roles in disease progression by manipulating pyroptosis. This review focuses on new findings concerning how EVs shape disease progression in infectious and non-infectious diseases by regulating pyroptosis. Understanding the characteristics and activity of EVs-mediated pyroptotic death may conducive to the discovery of novel mechanisms and more efficient therapeutic targets in infectious and non-infectious diseases.
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Vesículas Extracelulares , Piroptosis , Humanos , Vesículas Extracelulares/metabolismo , Animales , Enfermedades Transmisibles/metabolismo , Enfermedades Transmisibles/inmunologíaRESUMEN
Glioblastoma (GBM) presents significant challenges due to its invasive nature and genetic heterogeneity. In this study, we investigated the impact of Small VCP/P97-Interacting Protein (SVIP) on GBM progression. Our results revealed elevated expression of Insulin-like Growth Factor Binding Protein 2 (IGFBP-2) and STIP1 homology and U-box containing protein 1 (STUB1), coupled with reduced SVIP levels in GBM samples. Notably, high IGFBP-2 expression correlated with poor prognosis. Mechanistically, SVIP competitively inhibited STUB1, selectively binding to VCP/p97, thereby reducing PTEN degradation. This SVIP-mediated regulation exerted influence on the PTEN/PI3K/AKT/mTOR pathway, leading to the suppression of GBM progression. Co-localization experiments demonstrated that SVIP hindered PTEN ubiquitination and degradation by outcompeting STUB1 for VCP/p97 binding. Moreover, SVIP overexpression resulted in reduced activation of AKT/mTOR signaling and facilitated autophagy. In vivo experiments using a GBM xenograft model substantiated the tumor-suppressive effects of SVIP, evident by suppressed tumor growth, decreased IGFBP-2 expression, and improved survival rates. Collectively, our findings underscore the functional significance of SVIP in GBM progression. By inhibiting STUB1 and stabilizing PTEN, SVIP modulates the expression of IGFBP-2 and attenuates the activation of the PI3K/AKT/mTOR pathway, thereby emerging as a promising therapeutic target for GBM treatment.
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BACKGROUND: CD276 (B7-H3), a pivotal immune checkpoint, facilitates tumorigenicity, invasiveness, and metastasis by escaping immune surveillance in a variety of tumors; however, the underlying mechanisms facilitating immune escape in esophageal squamous cell carcinoma (ESCC) remain enigmatic. METHODS: We investigated the expression of CD276 in ESCC tissues from patients by using immunohistochemistry (IHC) assays. In vivo, we established a 4-nitroquinoline 1-oxide (4NQO)-induced CD276 knockout (CD276wKO) and K14cre; CD276 conditional knockout (CD276cKO) mouse model of ESCC to study the functional role of CD276 in ESCC. Furthermore, we used the 4NQO-induced mouse model to evaluate the effects of anti-CXCL1 antibodies, anti-Ly6G antibodies, anti-NK1.1 antibodies, and GSK484 inhibitors on tumor growth. Moreover, IHC, flow cytometry, and immunofluorescence techniques were employed to measure immune cell proportions in ESCC. In addition, we conducted single-cell RNA sequencing analysis to examine the alterations in tumor microenvironment following CD276 depletion. RESULTS: In this study, we elucidate that CD276 is markedly upregulated in ESCC, correlating with poor prognosis. In vivo, our results indicate that depletion of CD276 inhibits tumorigenesis and progression of ESCC. Furthermore, conditional knockout of CD276 in epithelial cells engenders a significant downregulation of CXCL1, consequently reducing the formation of neutrophil extracellular trap networks (NETs) via the CXCL1-CXCR2 signaling axis, while simultaneously augmenting natural killer (NK) cells. In addition, overexpression of CD276 promotes tumorigenesis via increasing NETs' formation and reducing NK cells in vivo. CONCLUSIONS: This study successfully elucidates the functional role of CD276 in ESCC. Our comprehensive analysis uncovers the significant role of CD276 in modulating immune surveillance mechanisms in ESCC, thereby suggesting that targeting CD276 might serve as a potential therapeutic approach for ESCC treatment.
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Antígenos B7 , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Trampas Extracelulares , Animales , Femenino , Humanos , Masculino , Ratones , Antígenos B7/metabolismo , Quimiocina CXCL1/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/inmunología , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Trampas Extracelulares/metabolismo , Ratones Noqueados , Receptores de Interleucina-8B/metabolismo , Escape del Tumor , Microambiente TumoralRESUMEN
Head and neck squamous cell carcinoma (HNSCC) is characterized by high recurrence or distant metastases rate and the prognosis is challenging. There is mounting evidence that tumor-infiltrating B cells (TIL-Bs) have a crucial, synergistic role in tumor control. However, little is known about the role TIL-Bs play in immune microenvironment and the way TIL-Bs affect the outcome of immune checkpoint blockade. Using single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database, the study identified distinct gene expression patterns in TIL-Bs. HNSCC samples were categorized into TIL-Bs inhibition and TIL-Bs activation groups using unsupervised clustering. This classification was further validated with TCGA HNSCC data, correlating with patient prognosis, immune cell infiltration, and response to immunotherapy. We found that the B cells activation group exhibited a better prognosis, higher immune cell infiltration, and distinct immune checkpoint levels, including elevated PD-L1. A prognostic model was also developed and validated, highlighting four genes as potential biomarkers for predicting survival outcomes in HNSCC patients. Overall, this study provides a foundational approach for B cells-based tumor classification in HNSCC, offering insights into targeted treatment and immunotherapy strategies.
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Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Pronóstico , Biomarcadores , Neoplasias de Cabeza y Cuello/terapia , Análisis de la Célula Individual , Microambiente TumoralRESUMEN
Articular cartilage tissue has limited self-repair capabilities, with damage frequently progressing to irreversible degeneration. Engineered tissues constructed through bioprinting and embedded with stem cell aggregates offer promising therapeutic alternatives. Aggregates of bone marrow mesenchymal stromal cells (BMSCs) demonstrate enhanced and more rapid chondrogenic differentiation than isolated cells, thus facilitating cartilage repair. However, it remains a key challenge to precisely control biochemical microenvironments to regulate cellular adhesion and cohesion within bioprinted matrices simultaneously. Herein, this work reports a bioprintable hydrogel matrix with high cellular adhesion and aggregation properties for cartilage repair. The hydrogel comprises an enhanced cell-adhesive gelatin methacrylate and a cell-cohesive chitosan methacrylate (CHMA), both of which are subjected to photo-initiated crosslinking. By precisely adjusting the CHMA content, the mechanical stability and biochemical cues of the hydrogels are finely tuned to promote cellular aggregation, chondrogenic differentiation and cartilage repair implantation. Multi-layer constructs encapsulated with BMSCs, with high cell viability reaching 91.1%, are bioprinted and photo-crosslinked to support chondrogenic differentiation for 21 days. BMSCs rapidly form aggregates and display efficient chondrogenic differentiation both on the hydrogels and within bioprinted constructs, as evidenced by the upregulated expression of Sox9, Aggrecan and Collagen 2a1 genes, along with high protein levels. Transplantation of these BMSC-laden bioprinted hydrogels into cartilaginous defects demonstrates effective hyaline cartilage repair. Overall, this cell-responsive hydrogel scaffold holds immense promise for applications in cartilage tissue engineering.
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Bioimpresión , Condrogénesis , Hidrogeles , Células Madre Mesenquimatosas , Regeneración , Condrogénesis/efectos de los fármacos , Hidrogeles/química , Hidrogeles/farmacología , Animales , Células Madre Mesenquimatosas/citología , Regeneración/efectos de los fármacos , Cartílago Articular , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Diferenciación Celular/efectos de los fármacos , Ingeniería de Tejidos , Metacrilatos/química , Supervivencia Celular/efectos de los fármacos , Cartílago/metabolismo , Cartílago/citología , Células Cultivadas , HumanosRESUMEN
Ameloblastoma is a benign tumor characterized by locally invasive phenotypes, leading to facial bone destruction and a high recurrence rate. However, the mechanisms governing tumor initiation and recurrence are poorly understood. Here, we uncovered cellular landscapes and mechanisms that underlie tumor recurrence in ameloblastoma at single-cell resolution. Our results revealed that ameloblastoma exhibits five tumor subpopulations varying with respect to immune response (IR), bone remodeling (BR), tooth development (TD), epithelial development (ED), and cell cycle (CC) signatures. Of note, we found that CC ameloblastoma cells were endowed with stemness and contributed to tumor recurrence, which was dominated by the EZH2-mediated program. Targeting EZH2 effectively eliminated CC ameloblastoma cells and inhibited tumor growth in ameloblastoma patient-derived organoids. These data described the tumor subpopulation and clarified the identity, function, and regulatory mechanism of CC ameloblastoma cells, providing a potential therapeutic target for ameloblastoma.
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Ameloblastoma , Humanos , Ameloblastoma/genética , Ameloblastoma/patología , Recurrencia Local de Neoplasia , Fenotipo , Transformación Celular Neoplásica , Perfilación de la Expresión GénicaRESUMEN
Interplay between innate and adaptive immune cells is important for the antitumor immune response. However, the tumor microenvironment may turn immune suppressive, and tumor associated macrophages are playing a role in this transition. Here, we show that CD276, expressed on tumor-associated macrophages (TAM), play a role in diminishing the immune response against tumors. Using a model of tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine in BLCA male mice we show that genetic ablation of CD276 in TAMs blocks efferocytosis and enhances the expression of the major histocompatibility complex class II (MHCII) of TAMs. This in turn increases CD4 + and cytotoxic CD8 + T cell infiltration of the tumor. Combined single cell RNA sequencing and functional experiments reveal that CD276 activates the lysosomal signaling pathway and the transcription factor JUN to regulate the expression of AXL and MerTK, resulting in enhanced efferocytosis in TAMs. Proving the principle, we show that simultaneous blockade of CD276 and PD-1 restrain tumor growth better than any of the components as a single intervention. Taken together, our study supports a role for CD276 in efferocytosis by TAMs, which is potentially targetable for combination immune therapy.
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Macrófagos Asociados a Tumores , Neoplasias de la Vejiga Urinaria , Animales , Masculino , Ratones , Eferocitosis , Evasión Inmune , Macrófagos/metabolismo , Factores de Transcripción/metabolismo , Microambiente Tumoral , Neoplasias de la Vejiga Urinaria/metabolismoRESUMEN
Objective: The purpose of this study was to evaluate the cumulative live birth rate (CLBR) of mild stimulation and conventional stimulation for the low-prognosis population undergoing PPOS protocols. Methods: This was a retrospective cohort study. We included women with a low prognosis. All women underwent PPOS protocols, and the starting gonadotropin (Gn) dose was 150 IU or 300 IU. The primary outcome measure was CLBR. The secondary outcome measures were the number of oocytes retrieved, number of 2PN oocytes and number of available embryos. Results: In total, 171 women with mild stimulation and 1810 women with conventional stimulation met the criteria. In the PSM model, 171 mild stimulation cycles were matched with 513 conventional stimulation cycles. The gonadotropin dosage in the mild stimulation group was significantly lower than that in the conventional stimulation group (1878.6 ± 1065.7 vs. 2854.7 ± 821.0, P<0.001). The numbers of oocytes retrieved, 2PN oocytes, available embryos and high-quality embryos were also higher in the conventional stimulation group than in the mild stimulation group (P<0.05). There was no significant between-group difference in the cumulative clinical pregnancy rate (26.3% vs. 27.5%, P=0.77). The CLBR after mild stimulation was similar to that after conventional stimulation (21.1% vs. 22.0%, P=0.79). Conclusion: In our study, we found that the CLBRs of mild stimulation and conventional stimulation were similar, despite conventional stimulation resulting in significantly more oocytes and embryos. Thus, mild stimulation can be considered an option for women with a low prognosis in PPOS protocols.