RESUMO
BACKGROUND: Tyrosine kinase inhibitors (TKIs) are crucial in the targeted treatment of advanced colorectal cancer (CRC). Anlotinib, a multi-target TKI, has previously been demonstrated to offer therapeutic benefits in previous studies. Circular RNAs (circRNAs) have been implicated in CRC progression and their unique structural stability serves as promising biomarkers. The detailed molecular mechanisms and specific biomarkers related to circRNAs in the era of targeted therapies, however, remain obscure. METHODS: The whole transcriptome RNA sequencing and function experiments were conducted to identify candidate anlotinib-regulated circRNAs, whose mechanism was confirmed by molecular biology experiments. CircHAS2 was profiled in a library of patient-derived CRC organoids (n = 22) and patient-derived CRC tumors in mice. Furthermore, a prospective phase II clinical study of 14 advanced CRC patients with anlotinib-based therapy was commenced to verify drug sensitivity (ClinicalTrials.gov identifier: NCT05262335). RESULTS: Anlotinib inhibits tumor growth in vitro and in vivo by downregulating circHAS2. CircHAS2 modulates CCNE2 activation by acting as a sponge for miR-1244, and binding to USP10 to facilitate p53 nuclear export as well as degradation. In parallel, circHAS2 serves as a potent biomarker predictive of anlotinib sensitivity, both in patient-derived organoids and xenograft models. Moreover, the efficacy of anlotinib inclusion into the treatment regimen yields meaningful clinical responses in patients with high levels of circHAS2. Our findings offer a promising targeted strategy for approximately 52.9% of advanced CRC patients who have high circHAS2 levels. CONCLUSIONS: CircHAS2 promotes cell proliferation via the miR-1244/CCNE2 and USP10/p53/CCNE2 bidirectional axes. Patient-derived organoids and xenograft models are employed to validate the sensitivity to anlotinib. Furthermore, our preliminary Phase II clinical study, involving advanced CRC patients treated with anlotinib, confirmed circHAS2 as a potential sensitivity marker.
Assuntos
Neoplasias Colorretais , Indóis , MicroRNAs , Quinolinas , Humanos , Animais , Camundongos , RNA Circular/genética , Proteína Supressora de Tumor p53 , Estudos Prospectivos , MicroRNAs/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Proliferação de Células/genética , Biomarcadores , Ubiquitina Tiolesterase/metabolismo , Ciclinas/metabolismoRESUMO
BACKGROUND: Fractures of hands and feet are common in children, but relevant epidemiological studies are currently lacking. We aim to study the epidemiological characteristics of hand and foot fractures and growth plate injuries in children and provide a theoretical basis for their prevention, diagnosis, and treatment. METHODS: We retrospectively analyzed the data of children with hand and foot fractures who were hospitalized at Shenzhen Children's Hospital between July 2015 and December 2020. Data on demographic characteristics, fracture site, treatment method, etiology of injury, and accompanying injuries were collected. The children were divided into four age groups: infants, preschool children, school children, and adolescents. The fracture sites were classified as first-level (the first-fifth finger/toe, metacarpal, metatarsal, carpal, and tarsal) and second-level (the first-fifth: proximal phalanx, middle phalanx, distal phalanx, metacarpal, and metatarsal) sites. The changing trends in fracture locations and injury causes among children in each age group were analyzed. RESULTS: Overall, 1301 children (1561 fractures; 835 boys and 466 girls) were included. The largest number of fractures occurred in preschool children (n = 549, 42.20%), with the distal phalanx of the third finger being the most common site (n = 73, 15.57%). The number of fractures in adolescents was the lowest (n = 158, 12.14%), and the most common fracture site was the proximal phalanx of the fifth finger (n = 45, 29.61%). Of the 1561 fractures, 1143 occurred in the hands and 418 in the feet. The most and least common first-level fracture sites among hand fractures were the fifth (n = 300, 26.25%) and first (n = 138, 12.07%) fingers, respectively. The most and least common first-level foot fracture locations were the first (n = 83, 19.86%) and fourth (n = 26, 6.22%) toes, respectively. The most common first-level and second level etiologies were life related injuries (n = 1128, 86.70%) and clipping injuries (n = 428, 32.90%), respectively. The incidence of sports injuries gradually increased with age, accounting for the highest proportion in adolescents (26.58%). Hand and foot fractures had many accompanying injuries, with the top three being nail bed injuries (570 cases, 36.52%), growth plate injuries (296 cases, 18.96%), and distal severed fracture (167 cases, 10.70%). Among the 296 growth plate injuries, 246 occurred on the hands and 50 on the feet. CONCLUSIONS: In contrast to previous epidemiological studies on pediatric hand and foot fractures, we mapped the locations of these fractures, including proximal, shaft, distal, and epiphyseal plate injuries. We analyzed the changing trends in fracture sites and injury etiologies with age. Hand and foot fractures have many accompanying injuries that require attention during diagnosis and treatment. Doctors should formulate accident protection measures for children of different ages, strengthen safety education, and reduce the occurrence of accidental injuries.
Assuntos
Traumatismos do Pé , Fraturas Ósseas , Traumatismos da Mão , Ossos Metacarpais , Fraturas Salter-Harris , Masculino , Pré-Escolar , Lactente , Feminino , Adolescente , Criança , Humanos , Estudos Retrospectivos , Fraturas Salter-Harris/complicações , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Fraturas Ósseas/diagnóstico , Traumatismos da Mão/epidemiologia , Traumatismos da Mão/etiologia , Traumatismos da Mão/terapia , Ossos Metacarpais/lesões , Traumatismos do Pé/epidemiologia , Traumatismos do Pé/etiologia , Traumatismos do Pé/terapiaRESUMO
PURPOSE: To compare the postoperative outcomes of 4 different femoral drilling techniques in anterior cruciate ligament reconstruction. METHODS: Three databases were searched for randomized controlled trials comparing any 2 or more of the following femoral drilling techniques in anterior cruciate ligament reconstruction: standard transtibial (sTT), anteromedial portal (AMP), outside-in (OI), or modified transtibial (mTT) technique. A Bayesian network meta-analysis was performed to assess postoperative stability and functional recovery in terms of the side-to-side difference (measured by arthrometry), Lachman test, pivot-shift test, International Knee Documentation Committee subjective and objective scores, Lysholm score, and Tegner score. The Fisher exact probability test and χ2 test were used to compare the incidences of infection and graft rupture, respectively. RESULTS: We included 20 randomized controlled trials involving 1,515 patients. The AMP technique showed a lower side-to-side difference (standardized mean difference, -0.33; 95% credible interval [CrI], -0.53 to -0.12), higher negative rate on the pivot-shift test (odds ratio, 2.19; 95% CrI, 1.38 to 3.44), and higher International Knee Documentation Committee objective score (odds ratio, 3.13; 95% CrI, 1.42 to 7.82) than the sTT technique. However, knee stability and functional outcomes did not differ significantly between the OI and sTT techniques. Safety outcomes of the mTT technique were unavailable. The incidence of graft rupture was 5.20% for the OI technique, 2.27% for the AMP technique, and 1.51% for the sTT technique. The OI technique had a significantly higher incidence of graft rupture than the sTT technique (χ2 = 4.421, P = .035). No significant difference in the incidence of infection was found between the sTT, AMP, and OI techniques (P = .281). CONCLUSIONS: The AMP technique, but not the OI technique, was superior to the sTT technique in knee stability and functional recovery. The OI technique had a higher incidence of graft rupture than the sTT technique. There was no significant difference between the AMP and OI techniques or between the mTT technique and any other femoral drilling technique. LEVEL OF EVIDENCE: Level II, meta-analysis of Level I and II studies.
Assuntos
Lesões do Ligamento Cruzado Anterior , Reconstrução do Ligamento Cruzado Anterior , Humanos , Ligamento Cruzado Anterior/cirurgia , Teorema de Bayes , Metanálise em Rede , Lesões do Ligamento Cruzado Anterior/cirurgia , Articulação do Joelho/cirurgia , Fêmur/cirurgia , Reconstrução do Ligamento Cruzado Anterior/métodos , Resultado do TratamentoRESUMO
For locally advanced colorectal cancer (CRC), neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision or complete mesocolic excision is the standard therapeutic strategy, which is key to patient survival. Involvement of the tumor immune microenvironment is a factor that regulates tumor progression and sensitivity to nCRT in CRC. In this study, we aimed to identify the effect of heat-shock protein 70 (HSP70)/toll-like receptor-2 (TLR-2) on mFOLFOX sensitization for CRC. A total of 22 patients with advanced CRC who had received neoadjuvant mFOLFOX were enrolled and classified into the mFOLFOX-insensitive or -sensitive group, according to the tumor regression grade. The abundance of immune infiltrates was significantly higher in the post-operative pathological specimens of the mFOLFOX-insensitive group, as compared to those of the mFOLFOX-sensitive group. After transcriptome sequencing, differentially expressed genes between the two groups were annotated to inflammatory and immune responses using Gene Ontology (GO) analysis, and the TLR signaling pathway was analyzed using Kyoto Encyclopedia of Genes and Genomes pathway analysis. Significantly higher expression levels of HSP60, HSP70, HSP90, and TLR-2 in the mFOLFOX-insensitive group were detected using immunofluorescence assays. TIMER2.0 platform was introduced to further narrow the scope of HSP70 (HSPA6 or HSPA7) and TLR-2, which exhibited positive correlations with dendritic cells, Tregs, or CD4+ T cells and negative correlations with CD3+ or CD8+ T cells, implying that HSP70/TLR-2 activation mediates immunosuppressive cells to counteract CD8+ T cells, which may be a novel target of CRC treatment. A promising synergistic effect of mFOLFOX combined with a TLR-2 inhibitor was observed in vivo in mouse allograft models, which could be partly rescued by recombinant HSP70 protein. Immunohistochemical staining of allografts and immunofluorescence assays of clinical specimens corroborated the regulatory effects of the immune microenvironment. In summary, HSP70/TLR-2 activation can regulate the tumor immune microenvironment of CRC and further remodel its sensitivity to mFOLFOX. However, the specific mechanisms remain unclear and require further investigation. This study is expected to provide a new direction for the clinical treatment of CRC.
Assuntos
Neoplasias Colorretais , Proteínas de Choque Térmico HSP70 , Receptor 2 Toll-Like , Microambiente Tumoral , Animais , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Chaperonina 60 , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Receptor 2 Toll-Like/genética , HumanosRESUMO
BACKGROUND: The mechanisms of Gastric cancer (GC) initiation and progression are complicated, at least partly owing to the dynamic changes of gene regulation during carcinogenesis. Thus, investigations on the changes in regulatory networks can improve the understanding of cancer development and provide novel insights into the molecular mechanisms of cancer. METHODS: Differential co-expression analysis (DCEA), differential gene regulation network (GRN) modeling and differential regulation analysis (DRA) were integrated to detect differential transcriptional regulation events between gastric normal mucosa and cancer samples based on GSE54129 dataset. Cytological experiments and IHC staining assays were used to validate the dynamic changes of CREB1 regulated targets in different stages. RESULTS: A total of 1955 differentially regulated genes (DRGs) were identified and prioritized in a quantitative way. Among the top 1% DRGs, 14 out of 19 genes have been reported to be GC relevant. The four transcription factors (TFs) among the top 1% DRGs, including CREB1, BPTF, GATA6 and CEBPA, were regarded as crucial TFs relevant to GC progression. The differentially regulated links (DRLs) around the four crucial TFs were then prioritized to generate testable hypotheses on the differential regulation mechanisms of gastric carcinogenesis. To validate the dynamic alterations of gene regulation patterns of crucial TFs during GC progression, we took CREB1 as an example to screen its differentially regulated targets by using cytological and IHC staining assays. Eventually, TCEAL2 and MBNL1 were proved to be differentially regulated by CREB1 during tumorigenesis of gastric cancer. CONCLUSIONS: By combining differential networking information and molecular cell experiments verification, testable hypotheses on the regulation mechanisms of GC around the core TFs and their top ranked DRLs were generated. Since TCEAL2 and MBNL1 have been reported to be potential therapeutic targets in SCLC and breast cancer respectively, their translation values in GC are worthy of further investigation.
Assuntos
Neoplasias Gástricas , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Neoplasias Gástricas/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The covalent cross-linking is an essential prerequisite for achieving the unique entropic elasticity of rubber products; however, the formation of a 3D cross-linked network and permanent cross-links makes thermosetting rubbers difficult to be recycled, causing serious environmental pollution at the end of their life. Herein, a facile, green, and promising strategy to introduce the exchangeable and cleavable acetal bonds into the chemically cross-linked networks of diene-typed rubbers is reported. For the first time, the hydroxyl-functionalized styrene-butadiene rubber (ESBR-HEMA) is prepared by introducing 2-hydroxyethyl methacrylate (HEMA) during the emulsion polymerization of styrene-butadiene rubber (ESBR). Then, based on hydroxyl-vinyl ether addition reactions, divinyl ether (DVE) could serve as a cross-linking agent to facilely and effectively cross-link hydroxyl-functionalized rubbers without additional additives, producing exchangeable and hydrolyzable acetal linkages. What's more, the acetal-containing cross-linked network in ESBR-HEMA vulcanizates could rearrange their topologies at elevated temperatures, endowing them with malleable and thermal reprocessing abilities. Moreover, the hydrolyzable acetal bonds could be selectively cleaved into hydroxyl and aldehyde groups in acidic conditions, resulting in a closed-loop chemical recycling of the ESBR-HEMA rubber. Hence, this work provides a facile and green cross-linking strategy for hydroxyl-functionalized rubbers to address the inherent problems brought from the covalent cross-linking of rubbers.
Assuntos
Acetais , Borracha , Butadienos/química , Elastômeros , Borracha/química , EstirenosRESUMO
The evaporation concentrate of gas field wastewater (EC-GFW) is a new type of refractory actual wastewater produced by the three-effect evaporation of gas field wastewater, exhibiting extremely high salinity and complex organic components. This study proposed a set of processes consisting of AOPs, precipitation, distillation, and crystallization for the systematic treatment of EC-GFW. In this paper, the optimal conditions for the processes after pre-treatment were investigated. The optimal operating parameters of UV/Fenton process were determined to be 180 min of reaction time, 4 of initial pH, 0.6 mol/L of H2O2 dosage, 10:1 of n(H2O2): n(Fe2+) value, and 30 W of UV power. Fenton's reagent was added in two steps (0 min and 90 min) for effective utilization. The results showed that the TOC (Total organic carbon) removal efficiency during the two-stage oxidation reached 93% with TOC in the effluent of 132 mg/L. Then, 82.3% of sulfate ions were removed by the desulfurization process using 50 g/L of CaCl2 within 10 min at a pH of 5 before distillation. It was found that the TOC in the influent of distillation played a decisive role in the quality of the effluent and purity of the crystalline salt, which was expected to be controlled lower than 132 mg/L. The final condensate could utilize to reuse, 99% of main pollutants of which have been removed, reducing the pressure of water supply on site. Simultaneously, the industrial-grade NaCl with extensive application prospect can be recovered. The harmless disposal and resource utilization of EC-GFW was achieved on a laboratory scale, providing the data support and theoretical guidance for treating EC-GFW at gas field project site.
Assuntos
Águas Residuárias , Poluentes Químicos da Água , Cristalização , Destilação , Estudos de Viabilidade , Peróxido de Hidrogênio/química , Campos de Petróleo e Gás , Oxirredução , Salinidade , Eliminação de Resíduos Líquidos/métodos , Águas Residuárias/química , Poluentes Químicos da Água/análiseRESUMO
BACKGROUND: Hypoxia-induced angiogenesis functions importantly in anaplastic thyroid cancer (ATC) progression. However, the therapeutic potential of broad-spectrum anti-angiogenic agent remains undefined. Anlotinib conventionally targets VEGFR, FGFR and PDGFR. Here, a novel role of anlotinib on ATC angiogenesis was illustrated. METHODS: Molecular expressions were established via tissue microarray. Multiple assays (tubule formation, 3D sprouting and chicken chorioallantoic membrane model) were used for angiogenic evaluation. Panels of molecular screening were achieved by antibody and PCR arrays. The loop binding motif of EGFR for homology modelling was prepared using Maestro. RESULTS: Anlotinib could dose- and time-dependently inhibit cell viability under normoxia and hypoxia and could repress hypoxia-activated angiogenesis more efficiently in vitro and in vivo. CXCL11 and phospho-EGFR were hypoxia-upregulated with a positive correlation. The cancer-endothelium crosstalk could be mediated by the positive CXCL11-EGF-EGFR feedback loop, which could be blocked by anlotinib directly targeting EGFR via a dual mechanism by simultaneous inhibitory effects on cancer and endothelial cells. The AKT-mTOR pathway was involved in this regulatory network. CONCLUSIONS: The newly identified CXCL11-EGF-EGFR signalling provided mechanistic insight into the interaction between cancer and endothelial cells under hypoxia, and EGFR was a novel target. Anlotinib may be the encouraging therapeutic candidate in ATC.
Assuntos
Quimiocina CXCL11/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Indóis/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Quinolinas/administração & dosagem , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Receptores ErbB/metabolismo , Retroalimentação Fisiológica/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/farmacologia , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Gene expression and alternative splicing (AS) interact in complex ways to regulate biological process which is associated with cancer development. Here, by integrated analysis of gene expression and AS events, we aimed to identify the hub AS events and splicing factors relevant in gastric cancer development (GC). RNA-seq data, clinical data and AS events of 348 GC samples were obtained from the TCGA and TCGASpliceSeq databases. Cox univariable and multivariable analyses, KEGG and GO pathway analyses were performed to identify hub AS events and splicing factor/spliceosome genes, which were further validated in 53 GCs. By bioinformatics methods, we found that gene AS event- and gene expression-mediated GC progression shared the same mechanisms, such as PI3K/AKT pathway, but the involved genes were different. Though expression of 17 hub AS events were confirmed in 53 GC tissues, only 10 AS events in seven genes were identified as critical candidates related to GC progression, notably the AS events (Exon Skip) in CLSTN1 and SEC16A. Expression of these AS events in GC correlated with activation of the PI3K/AKT pathway. Genes with AS events associated with clinical parameters and prognosis were different from the genes whose mRNA levels were related to clinical parameters and prognosis. Besides, we further revealed that QKI and NOVA1 were the crucial splicing factors regulating expression of AS events in GC, but not spliceosome genes. Our integrated analysis revealed hub AS events in GC development, which might be the potential therapeutic targets for GC.
Assuntos
Processamento Alternativo/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Fatores de Processamento de RNA/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Feminino , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Spliceossomos/metabolismo , Células Estromais/patologiaRESUMO
Homozygous deletion of chromodomain helicase DNA binding protein 1 (CHD1) is among the most frequent genetic alterations in prostate cancer. CHD1 is converted from a non-essential to an essential gene for prostate cancer cell survival when phosphatase and tensin homolog (PTEN), another frequently deleted gene in prostate cancer, is disrupted. It remains unknown whether this PTEN-CHD1 genetic and functional relationship also operates in other solid tumors. Here, we address this question by using genetically engineered mouse models. Inducible deletion of Pten and p53 in all somatic cells of adult mice led to widespread PI3K/Akt pathway activation and hyperplastic phenotypes, causing multi-organ failure and lethality. Remarkably, when Chd1 was co-deleted in the Pten/p53 model, the lethality remained unperturbed. At the protein level, Chd1 was stabilized upon Pten deletion in prostate, but not in other organs examined (lung, liver, kidney, colon, mammary). These results shed mechanistic insight on the cancer type-specific copy number alteration pattern of PTEN and CHD1.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Especificidade de Órgãos , PTEN Fosfo-Hidrolase/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Variações do Número de Cópias de DNA/genética , Proteínas de Ligação a DNA/deficiência , Modelos Animais de Doenças , Dosagem de Genes , Masculino , Camundongos Knockout , Camundongos Transgênicos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tamoxifeno/farmacologia , Proteína Supressora de Tumor p53/deficiênciaRESUMO
ETS transcription factors play important roles in tumor cell invasion, differentiation and angiogenesis. In this study, we initially demonstrated that ETS translocation variant 5 (ETV5) is abnormally upregulated in colorectal cancer (CRC), is positively correlated with CRC tumor size, lymphatic metastasis and tumor node metastasis (TNM) stage and indicates shorter survival and disease-free survival in CRC patients. In vitro and in vivo experiments revealed that the downregulation of ETV5 could significantly suppress CRC cell proliferation. Moreover, overexpression of ETV5 could stimulate CRC angiogenesis in vitro and in vivo, which is consistent with RNA-seq results. Then, we identified platelet-derived growth factor BB (PDGF-BB) as a direct target of ETV5 that plays an important role in ETV5-mediated CRC angiogenesis through an angiogenesis antibody microarray. Additionally, PDGF-BB could activate VEGFA expression via the PDGFR-ß/Src/STAT3 pathway in CRC cells and appeared to be positively correlated with ETV5 in CRC tissues. Finally, we revealed that ETV5 could bind directly to the promoter region of PDGF-BB and regulate its expression through ChIP and luciferase assays. Overall, our study suggested that the transcription factor ETV5 could stimulate CRC malignancy and promote CRC angiogenesis by directly targeting PDGF-BB. These findings suggest that EVT5 may be a potential new diagnostic and prognostic marker in CRC and that targeting ETV5 might be a potential therapeutic option for inhibiting CRC angiogenesis.
Assuntos
Becaplermina/metabolismo , Neoplasias Colorretais/irrigação sanguínea , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/metabolismo , Animais , Becaplermina/genética , Células CACO-2 , Linhagem Celular Tumoral , Embrião de Galinha , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Feminino , Células HCT116 , Células HT29 , Xenoenxertos , Células Endoteliais da Veia Umbilical Humana , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Transcrição Gênica , Regulação para CimaRESUMO
BACKGROUND/AIMS: Anaplastic thyroid carcinoma (ATC) is one of the most lethal human malignancies, and there is no efficient method to slow its process. Apatinib, a novel tyrosine kinase inhibitor (TKI), has been confirmed for its efficacy and safety in the treatment of advanced gastric carcinoma patients. However, the effects of Apatinib in ATC are still unknown. METHODS: In this study, we explored the effects and mechanisms of Apatinib on tumor growth and angiogenesis in vitro and in vitro in ATC cells. Angiogenesis antibodies array was utilized to detect the expression of angiogenesis-related genes after Apatinib treatment in ATC cells. In addition, we used Akt activator, Akt inhibitor and GSK3ß inhibitor to further study the mechanism for how Apatinib suppressed angiogenesis. RESULTS: Apatinib treatment could suppress the growth of ATC cells in a dose- and time-dependent manner via inducing apoptosis and blocking cell cycle progression at G0/G1 phase. Moreover, Apatinib treatment decreased the expression of angiogenin (ANG) and inhibited angiogenesis of ATC cells in vitro and in vitro. We further confirmed that recombinant human ANG (rhANG) significantly abrogated Apatinib-mediated anti-angiogenic ability in ATC cells. Additionally, Apatinib treatment decreased the level of p-Akt and p-GSK3ß. Moreover, the Apatinib-mediated decrease of ANG and anti-angiogenic ability were partly reversed when an Akt activator, SC79, was administered. Furthermore, the anti-angiogenic ability of Apatinib can be enhanced in the presence of Akt inhibitor, and the inhibition of GSK3ß attenuated the anti-angiogenic ability of Apatinib. CONCLUSION: Our results demonstrated that Apatinib treatment inhibited tumor growth, and Apatinib-induced suppression of Akt/GSK3ß/ANG signaling pathway may play an important role in the inhibition of angiogenesis in ATC, supporting a potential therapeutic approach for using Apatinib in the treatment of ATC.
Assuntos
Antineoplásicos/toxicidade , Neovascularização Fisiológica/efeitos dos fármacos , Piridinas/toxicidade , Transdução de Sinais/efeitos dos fármacos , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Ribonuclease Pancreático/genética , Ribonuclease Pancreático/metabolismo , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Transplante HeterólogoRESUMO
As a basic parameter of rock, the rock bridge angle plays an important role in maintaining the stability of rock masses. To study the size effect of rock bridge angle on the uniaxial compressive strength of rocks, this paper adopts the principle of regression analysis and combines numerical simulation to carry out relevant research. The research results indicate that: (1) the uniaxial compressive strength decreases with the increase of the rock bridge angle, showing a power function relationship; (2) The uniaxial compressive strength decreases with the increase of rock size and tends to stabilize when the rock size is greater than 350 mm, showing a significant size effect. (3) The fluctuation coefficient of compressive strength increases with the increase of rock bridge angle and decreases with the increase of rock size; When the rock size is 350 mm, the fluctuation coefficient is less than 5%; (4) The characteristic compressive strength and characteristic size both increase with the increase of the rock bridge angle.
Assuntos
Força Compressiva , Análise de Regressão , Modelos TeóricosRESUMO
The synthesis of highly efficient NiFe-layered double hydroxides (NiFe-LDHs) to catalyze the oxygen evolution reaction (OER) is urgent and challenging. Herein, NiFe-FeCl3-x and NiFe-FeCl2-x samples (where FeCl3 and FeCl2 represent the Fe sources and x represents the imposed reaction time: 6, 12, and 24 h) were prepared via one-pot hydrothermal synthesis using Fe sources characterized by Fe(III) or Fe(II) valence states. In the presence of triethanolamine, when FeCl3 was used as the Fe source, pure NiFe-LDH was obtained, whose crystallinity increased with increasing hydrothermal treatment time. In contrast, when FeCl2 was used as the Fe source, a mixture of NiFe-LDH, Fe2O3, and trace amounts of Fe3O4 was obtained. The content of NiFe-LDH in the mixture increased under longer hydrothermal treatment and NiFe-FeCl3-x catalysts exhibited better OER performance than NiFe-FeCl2-x catalysts. Specifically, NiFe-FeCl3-6 afforded the highest OER performance with an overpotential of 246.8 mV at 10 mA cm-2 and a Tafel slope of 46.1 mV dec-1. Herein, we investigated the effects of the valence state of Fe precursors on the structures and OER activities of the prepared catalysts; the mechanism of NiFe-LDH formation via hydrothermal synthesis in the presence of triethanolamine was also proposed.
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Adenomatous polyps, a common premalignant lesion, are often classified into villous adenoma (VA) and tubular adenoma (TA). VA has a higher risk of malignancy, whereas TA typically grows slowly and has a lower likelihood of cancerous transformation. Accurate classification is essential for tailored treatment. In this study, we develop a deep learning-based approach for the localization and classification of adenomatous polyps using endoscopic images. Specifically, a pre-trained EGE-UNet is first adopted to extract regions of interest from original images. Multi-level feature maps are then extracted by the feature extraction pipeline (FEP). The deep-level features are fed into the Pyramid Pooling Module (PPM) to capture global contextual information, and the squeeze body edge (SBE) module is then used to decouple the body and edge parts of features, enabling separate analysis of their distinct characteristics. The Group Aggregation Bridge (GAB) and Boundary Enhancement Module (BEM) are then applied to enhance the body features and edge features, respectively, emphasizing their structural and morphological characteristics. By combining the features of the body and edge parts, the final output can be obtained. Experiments show the proposed method achieved promising results on two private datasets. For adenoma vs. non-adenoma classification, It achieved a mIoU of 91.41%, mPA of 96.33%, mHD of 11.63, and mASD of 2.33. For adenoma subclassification (non-adenomas vs. villous adenomas vs. tubular adenomas), it achieved a mIoU of 91.21%, mPA of 94.83%, mHD of 13.75, and mASD of 2.56. These results demonstrate the potential of our approach for precise adenomatous polyp classification.
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Postmenopausal osteoporosis (PMO) is characterized by bone loss and microstructural damage, and it is most common in older adult women. Currently, there is no cure for PMO. The flavonoid chemical 7,8-dihydroxyflavone (7,8-DHF) specifically activates tropomyosin receptor kinase B (TRKB). Furthermore, 7,8-DHF has various biological characteristics, including anti-inflammatory and antioxidant effects. However, the specific implications and fundamental mechanisms of 7,8-DHF in PMO remain unclear. We used protein imprinting, flow cytometry, tissue staining, and other methods to estimate the preventive mechanisms of 7,8-DHF against hydrogen peroxide (H2O2)-induced apoptosis in primary mouse bone marrow mesenchymal stem cells (BMSCs), osteogenic differentiation ability, and bone mass in ovariectomized (OVX) mice. We found that 7,8-DHF effectively prevented H2O2-induced reductions in the viability and osteogenic differentiation capacity of primary BMSCs. Mechanistically, 7,8-DHF induced the TRKB to activate the PI3K/AKT/NRF2 pathway. In vivo experiments with the OVX mouse model confirmed that 7,8-DHF can inhibit oxidative stress and promote bone formation, indicating that 7,8-DHF improves the viability and osteogenic differentiation ability of BMSCs stimulated via H2O2 by activating the TRKB/PI3K/AKT and NRF2 pathways, thereby improving PMO.
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Introduction: Patients undergoing maintenance hemodialysis are vulnerable to coronavirus disease 2019 (COVID-19), exhibiting a high risk of hospitalization and mortality. Thus, early identification and intervention are important to prevent disease progression in these patients. Methods: This was a two-center retrospective observational study of patients on hemodialysis diagnosed with COVID-19 at the Lingang and Xuhui campuses of Shanghai Sixth People's Hospital. Patients were randomized into the training (130) and validation cohorts (54), while 59 additional patients served as an independent external validation cohort. Artificial intelligence-based parameters of chest computed tomography (CT) were quantified, and a nomogram for patient outcomes at 14 and 28 days was created by screening quantitative CT measures, clinical data, and laboratory examination items, using univariate and multivariate Cox regression models. Results: The median dialysis duration was 48 (interquartile range, 24-96) months. Age, diabetes mellitus, serum phosphorus level, lymphocyte count, and chest CT score were identified as independent prognostic indicators and included in the nomogram. The concordance index values were 0.865, 0.914, and 0.885 in the training, internal validation, and external validation cohorts, respectively. Calibration plots showed good agreement between the expected and actual outcomes. Conclusion: This is the first study in which a reliable nomogram was developed to predict short-term outcomes and survival probabilities in patients with COVID-19 on hemodialysis. This model may be helpful to clinicians in treating COVID-19, managing serum phosphorus, and adjusting the dialysis strategies for these vulnerable patients to prevent disease progression in the context of COVID-19 and continuous emergence of novel viruses.
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For the diagnosis and outcome prediction of gastric cancer (GC), machine learning methods based on whole slide pathological images (WSIs) have shown promising performance and reduced the cost of manual analysis. Nevertheless, accurate prediction of GC outcome may rely on multiple modalities with complementary information, particularly gene expression data. Thus, there is a need to develop multimodal learning methods to enhance prediction performance. In this paper, we collect a dataset from Ruijin Hospital and propose a multimodal learning method for GC diagnosis and outcome prediction, called GaCaMML, which is featured by a cross-modal attention mechanism and Per-Slide training scheme. Additionally, we perform feature attribution analysis via integrated gradient (IG) to identify important input features. The proposed method improves prediction accuracy over the single-modal learning method on three tasks, i.e., survival prediction (by 4.9% on C-index), pathological stage classification (by 11.6% on accuracy), and lymph node classification (by 12.0% on accuracy). Especially, the Per-Slide strategy addresses the issue of a high WSI-to-patient ratio and leads to much better results compared with the Per-Person training scheme. For the interpretable analysis, we find that although WSIs dominate the prediction for most samples, there is still a substantial portion of samples whose prediction highly relies on gene expression information. This study demonstrates the great potential of multimodal learning in GC-related prediction tasks and investigates the contribution of WSIs and gene expression, respectively, which not only shows how the model makes a decision but also provides insights into the association between macroscopic pathological phenotypes and microscopic molecular features.
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Aprendizado de Máquina , Neoplasias Gástricas , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Prognóstico , Perfilação da Expressão Gênica/métodosRESUMO
Cetuximab (Cet) and oxaliplatin (OXA) are used as first-line drugs for patients with colorectal carcinoma (CRC). In fact, the heterogeneity of CRC, mainly caused by K-ras mutations and drug resistance, undermines the effectiveness of drugs. Recently, a hydrophobic prodrug, (1E,4E)-6-((S)-1-(isopentyloxy)-4-methylpent-3-en-1-yl)-5,8-dimethoxynaphthalene-1,4dione dioxime (DMAKO-20), has been shown to undergo tumor-specific CYP1B1-catalyzed bioactivation. This process results in the production of nitric oxide and active naphthoquinone mono-oximes, which exhibit specific antitumor activity against drug-resistant CRC. In this study, a Cet-conjugated bioresponsive DMAKO-20/PCL-PEOz-targeted nanocodelivery system (DMAKO@PCL-PEOz-Cet) was constructed to address the issue of DMAKO-20 dissolution and achieve multitargeted delivery of the cargoes to different subtypes of CRC cells to overcome K-ras mutations and drug resistance in CRC. The experimental results demonstrated that DMAKO@PCL-PEOz-Cet efficiently delivered DMAKO-20 to both K-ras mutant and wild-type CRC cells by targeting the epidermal growth factor receptor (EGFR). It exhibited a higher anticancer effect than OXA in K-ras mutant cells and drug-resistant cells. Additionally, it was observed that DMAKO@PCL-PEOz-Cet reduced the expression of glutathione peroxidase 4 (GPX4) in CRC cells and significantly inhibited the growth of heterogeneous HCT-116 subcutaneous tumors and patient-derived tumor xenografts (PDX) model tumors. This work provides a new strategy for the development of safe and effective approaches for treating CRC. STATEMENT OF SIGNIFICANCE: (1) Significance: This work reports a new approach for the treatment of colorectal carcinoma (CRC) using the bioresponsible Cet-conjugated PCL-PEOz/DMAKO-20 nanodelivery system (DMAKO@PCL-PEOz-Cet) prepared with Cet and PCL-PEOz for the targeted transfer of DMAKO-20, which is an anticancer multitarget drug that can even prevent drug resistance, to wild-type and K-ras mutant CRC cells. DMAKO@PCL-PEOz-Cet, in the form of nanocrystal micelles, maintained stability in peripheral blood and efficiently transported DMAKO-20 to various subtypes of colorectal carcinoma cells, overcoming the challenges posed by K-ras mutations and drug resistance. The system's secure and effective delivery capabilities have also been confirmed in organoid and PDX models. (2) This is the first report demonstrating that this approach simultaneously overcomes the K-ras mutation and drug resistance of CRC.
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Antineoplásicos , Neoplasias Colorretais , Humanos , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Sistemas de Liberação de Fármacos por Nanopartículas , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Mutação , Concentração de Íons de HidrogênioRESUMO
Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet persistent challenges such as low response rate and significant heterogeneity necessitate attention. The pivotal role of the major histocompatibility complex (MHC) in ICI efficacy, its intricate impacts and potentials as a prognostic marker, warrants comprehensive exploration. This study integrates single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, and spatial transcriptomic analyses to unveil pan-cancer immune characteristics governed by the MHC transcriptional feature (MHC.sig). Developed through scRNA-seq analysis of 663,760 cells across diverse cohorts and validated in 30 solid cancer types, the MHC.sig demonstrates a robust correlation between immune-related genes and infiltrating immune cells, highlighting its potential as a universal pan-cancer marker for anti-tumor immunity. Screening the MHC.sig for therapeutic targets using CRISPR data identifies potential genes for immune therapy synergy and validates its predictive efficacy for ICIs responsiveness across diverse datasets and cancer types. Finally, analysis of cellular communication patterns reveals interactions between C1QC+macrophages and malignant cells, providing insights into potential therapeutic agents and their sensitivity characteristics. This comprehensive analysis positions the MHC.sig as a promising marker for predicting immune therapy outcomes and guiding combinatorial therapeutic strategies.