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While aqueous zinc-ion batteries exhibit great potential, their performance is impeded by zinc dendrites. Existing literature has proposed the use of hydrogel electrolytes to ameliorate this issue. Nevertheless, the mechanical attributes of hydrogel electrolytes, particularly their modulus, are suboptimal, primarily ascribed to the substantial water content. This drawback would severely restrict the dendrite-inhibiting efficacy, especially under large mass loadings of active materials. Inspired by the structural characteristics of wood, this study endeavors to fabricate the anisotropic carboxymethyl cellulose hydrogel electrolyte through directional freezing, salting-out effect, and compression reinforcement, aiming to maximize the modulus along the direction perpendicular to the electrode surface. The heightened modulus concurrently serves to suppress the vertical deposition of the intermediate product at the cathode. Meanwhile, the oriented channels with low tortuosity enabled by the anisotropic structure are beneficial to the ionic transport between the anode and cathode. Comparative analysis with an isotropic hydrogel sample reveals a marked enhancement in both modulus and ionic conductivity in the anisotropic hydrogel. This enhancement contributes to significantly improved zinc stripping/plating reversibility and mitigated electrochemical polarization. Additionally, a durable quasi-solid-state Zn//MnO2 battery with noteworthy volumetric energy density is realized. This study offers unique perspectives for designing hydrogel electrolytes and augmenting battery performance.
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BACKGROUND: Excessive pericyte coverage promotes tumor growth, and a downregulation may solve this dilemma. Due to the double-edged sword role of vascular pericytes in tumor microenvironment (TME), indiscriminately decreasing pericyte coverage by imatinib causes poor treatment outcomes. Here, we optimized the use of imatinib in a colorectal cancer (CRC) model in high pericyte-coverage status, and revealed the value of multiparametric magnetic resonance imaging (mpMRI) at 9.4T in monitoring treatment-related changes in pericyte coverage and the TME. METHODS: CRC xenograft models were evaluated by histological vascular characterizations and mpMRI. Mice with the highest pericyte coverage were treated with imatinib or saline; then, vascular characterizations, tumor apoptosis and HIF-1α level were analyzed histologically, and alterations in the expression of Bcl-2/bax pathway were assessed through qPCR. The effects of imatinib were monitored by dynamic contrast-enhanced (DCE)-, diffusion-weighted imaging (DWI)- and amide proton transfer chemical exchange saturation transfer (APT CEST)-MRI at 9.4T. RESULTS: The DCE- parameters provided a good histologic match the tumor vascular characterizations. In the high pericyte coverage status, imatinib exhibited significant tumor growth inhibition, necrosis increase and pericyte coverage downregulation, and these changes were accompanied by increased vessel permeability, decreased microvessel density (MVD), increased tumor apoptosis and altered gene expression of apoptosis-related Bcl-2/bax pathway. Strategically, a 4-day imatinib effectively decreased pericyte coverage and HIF-1α level, and continuous treatment led to a less marked decrease in pericyte coverage and re-elevated HIF-1α level. Correlation analysis confirmed the feasibility of using mpMRI parameters to monitor imatinib treatment, with DCE-derived Ve and Ktrans being most correlated with pericyte coverage, Ve with vessel permeability, AUC with microvessel density (MVD), DWI-derived ADC with tumor apoptosis, and APT CEST-derived MTRasym at 1 µT with HIF-1α. CONCLUSIONS: These results provided an optimized imatinib regimen to achieve decreasing pericyte coverage and HIF-1α level in the high pericyte-coverage CRC model, and offered an ultrahigh-field multiparametric MRI approach for monitoring pericyte coverage and dynamics response of the TME to treatment.
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Apoptosis , Neoplasias Colorrectales , Subunidad alfa del Factor 1 Inducible por Hipoxia , Mesilato de Imatinib , Imágenes de Resonancia Magnética Multiparamétrica , Pericitos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Animales , Pericitos/metabolismo , Pericitos/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/diagnóstico por imagen , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Humanos , Ratones Desnudos , Microambiente Tumoral/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Ductal Adenocarcinoma (DAC) and Intraductal Carcinoma of the Prostate (IDC-P) respond poorly to all the currently available conventional therapies. Given their accurate and efficient elimination of cancer cells, Antibody-Drug Conjugates (ADCs) have become one of the most promising anticancer treatments. However, no ADCs have so far been approved for Prostate Cancer (PCa) treatment. This study investigated TROP-2, HER2, and CD46 expression in DAC/IDC-P samples, indirectly analyzing their preliminary feasibility as therapeutic targets for future treatment of the two conditions. PATIENTS AND METHODS: We conducted a retrospective study involving 184 participants (87 DAC/IDC-P patients and 97 Prostatic Acinar Adenocarcinoma (PAC) patients with a Gleason score ≥ 8) without prior treatment between August 2017 and August 2022. Immunohistochemical staining was employed to detect the differential protein expressions of TROP-2, HER2, and CD46 in DAC/IDC-P, PAC, and normal prostate tissues. RESULTS: Compared to pure PAC tissues, TROP-2 expression was significantly higher in DAC/IDC-P and DAC/IDC-P-adjacent PAC tissues (H-score 68.8 vs. 43.8, p < 0.001, and 59.8 vs. 43.8, p = 0.022, respectively). No significant differences in HER2 expression were observed across different cancer tissues. Compared to both DAC/IDC-P-adjacent PAC and pure PAC tissues, CD46 expression was significantly higher in DAC/IDC-P tissues (42.3 vs. 28.6, p = 0.041, and 42.3 vs. 24.3, p = 0.0035, respectively). CONCLUSIONS: Herein, TROP-2 and CD46 expression was higher in DAC/IDC-P tissues than in pure PAC and normal prostate tissues. This finding implies that ADCs targeting the two proteins hold significant promise as potential future treatments for DAC/IDC-P.
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Antígenos de Neoplasias , Moléculas de Adhesión Celular , Estudios de Factibilidad , Inmunoconjugados , Proteína Cofactora de Membrana , Neoplasias de la Próstata , Receptor ErbB-2 , Humanos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Moléculas de Adhesión Celular/metabolismo , Estudios Retrospectivos , Receptor ErbB-2/metabolismo , Anciano , Inmunoconjugados/uso terapéutico , Persona de Mediana Edad , Antígenos de Neoplasias/metabolismo , Proteína Cofactora de Membrana/metabolismo , Carcinoma Ductal/metabolismo , Carcinoma Ductal/patología , Carcinoma Ductal/tratamiento farmacológico , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Low-pass genome sequencing (LP GS) is an alternative to chromosomal microarray analysis (CMA). However, validations of LP GS as a prenatal diagnostic test for amniotic fluid are rare. Moreover, sequencing depth of LP GS in prenatal diagnosis has not been evaluated. OBJECTIVE: The diagnostic performance of LP GS was compared with CMA using 375 amniotic fluid samples. Then, sequencing depth was evaluated by downsampling. RESULTS: CMA and LP GS had the same diagnostic yield (8.3%, 31/375). LP GS showed all copy number variations (CNVs) detected by CMA and six additional variant of uncertain significance CNVs (>100 kb) in samples with negative CMA results; CNV size influenced LP GS detection sensitivity. CNV detection was greatly influenced by sequencing depth when the CNV size was small or the CNV was located in the azoospermia factor c (AZFc) region of the Y chromosome. Large CNVs were less affected by sequencing depth and more stably detected. There were 155 CNVs detected by LP GS with at least a 50% reciprocal overlap with CNVs detected by CMA. With 25 M uniquely aligned high-quality reads (UAHRs), the detection sensitivity for the 155 CNVs was 99.14%. LP GS using samples with 25 M UAHRs showed the same performance as LP GS using total UAHRs. Considering the detection sensitivity, cost and interpretation workload, 25 M UAHRs are optimal for detecting most aneuploidies and microdeletions/microduplications. CONCLUSION: LP GS is a promising, robust alternative to CMA in clinical settings. A total of 25 M UAHRs are sufficient for detecting aneuploidies and most microdeletions/microduplications.
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Líquido Amniótico , Variaciones en el Número de Copia de ADN , Embarazo , Femenino , Humanos , Variaciones en el Número de Copia de ADN/genética , Diagnóstico Prenatal/métodos , Aneuploidia , Análisis por MicromatricesRESUMEN
AIMS: Vessel co-option is responsible for tumor resistance to antiangiogenic therapies (AATs) in patients with colorectal cancer liver metastasis (CRCLM). However, the mechanisms underlying vessel co-option remain largely unknown. Herein, we investigated the roles of a novel lncRNA SYTL5-OT4 and Alanine-Serine-Cysteine Transporter 2 (ASCT2) in vessel co-option-mediated AAT resistance. METHODS: SYTL5-OT4 was identified by RNA-sequencing and verified by RT-qPCR and RNA fluorescence in situ hybridization assays. The effects of SYTL5-OT4 and ASCT2 on tumor cells were investigated by gain- and loss-of-function experiments, and those of SYTL5-OT4 on ASCT2 expression were analyzed by RNA immunoprecipitation and co-immunoprecipitation assays. The roles of SYTL5-OT4 and ASCT2 in vessel co-option were detected by histological, immunohistochemical, and immunofluorescence analyses. RESULTS: The expression of SYTL5-OT4 and ASCT2 was higher in patients with AAT-resistant CRCLM. SYTL5-OT4 enhanced the expression of ASCT2 by inhibiting its autophagic degradation. SYTL5-OT4 and ASCT2 promoted vessel co-option by increasing the proliferation and epithelial-mesenchymal transition of tumor cells. Combination therapy of ASCT2 inhibitor and antiangiogenic agents overcame vessel co-option-mediated AAT resistance in CRCLM. CONCLUSION: This study highlights the crucial roles of lncRNA and glutamine metabolism in vessel co-option and provides a potential therapeutic strategy for patients with AAT-resistant CRCLM.
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Neoplasias Hepáticas , ARN Largo no Codificante , Humanos , Alanina , Proteínas Portadoras , Línea Celular Tumoral , Cisteína , Hibridación Fluorescente in Situ , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Proteínas de la Membrana , Proteínas de Transporte de Membrana , ARN Largo no Codificante/genética , SerinaRESUMEN
INTRODUCTION: Urachal carcinoma is characterized by high malignancy, poor prognosis, and late stage of diagnosis. There is a lack of unanimous clinical treatment guidelines. We summarize the characteristics, treatment, and outcomes of urachal carcinoma from our center, hoping to provide a reference for diagnosis and treatment. METHODS: We retrospectively analyzed the clinical data of 21 patients with urachal carcinoma who were treated at our center from January 2010 to August 2022, and all patients were followed up. RESULTS: The average survival time was 67.1 ± 9.1 (ranging from 49.3 to 84.9) months. The average relapse-free survival was 48.8 ± 9.9 (ranging from 29.5 to 68.2) months. Six patients received adjuvant therapy, mainly chemotherapy. Five patients died during follow-up. CONCLUSIONS: Early physical examination may be helpful for early detection of urachal carcinoma. Surgical treatment is still preferred for localized urachal carcinoma. Lymph node dissection may facilitate accurate staging, and positive margin usually results in a worse prognosis. Adjuvant therapy, mainly chemotherapy, may help improve the prognosis. The application of radiotherapy, targeted therapy, and immunotherapy still needs further exploration.
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OBJECTIVE: Haematogenous dissemination is a prevalent route of colorectal cancer (CRC) metastasis. However, as the gatekeeper of vessels, the role of tumour pericytes (TPCs) in haematogenous metastasis remains largely unknown. Here, we aimed to investigate the heterogeneity of TPCs and their effects on CRC metastasis. DESIGN: TPCs were isolated from patients with CRC with or without liver metastases and analysed by single-cell RNA sequencing (scRNA-seq). Clinical CRC specimens were collected to analyse the association between the molecular profiling of TPCs and CRC metastasis. RNA-sequencing, chromatin immunoprecipitation-sequencing and bisulfite-sequencing were performed to investigate the TCF21-regulated genes and mechanisms underlying integrin α5 on TCF21 DNA hypermethylation. Pericyte-conditional Tcf21-knockout mice were constructed to investigate the effects of TCF21 in TPCs on CRC metastasis. Masson staining, atomic force microscopy, second-harmonic generation and two-photon fluorescence microscopy were employed to observe perivascular extracellular matrix (ECM) remodelling. RESULTS: Thirteen TPC subpopulations were identified by scRNA-seq. A novel subset of TCF21high TPCs, termed 'matrix-pericytes', was associated with liver metastasis in patients with CRC. TCF21 in TPCs increased perivascular ECM stiffness, collagen rearrangement and basement membrane degradation, establishing a perivascular metastatic microenvironment to instigate colorectal cancer liver metastasis (CRCLM). Tcf21 depletion in TPCs mitigated perivascular ECM remodelling and CRCLM, whereas the coinjection of TCF21high TPCs and CRC cells markedly promoted CRCLM. Mechanistically, loss of integrin α5 inhibited the FAK/PI3K/AKT/DNMT1 axis to impair TCF21 DNA hypermethylation in TCF21high TPCs. CONCLUSION: This study uncovers a previously unidentified role of TPCs in haematogenous metastasis and provides a potential diagnostic marker and therapeutic target for CRC metastasis.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Animales , Ratones , Línea Celular Tumoral , Neoplasias Colorrectales/patología , ADN , Regulación Neoplásica de la Expresión Génica , Integrina alfa5/genética , Integrina alfa5/metabolismo , Neoplasias Hepáticas/patología , Metástasis de la Neoplasia , Pericitos/metabolismo , Pericitos/patología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Microambiente TumoralRESUMEN
PURPOSE: Prostate-specific membrane antigen (PSMA)-based PET/CT imaging has limitations in the diagnosis of prostate cancer (PCa). We recruited 207 participants with suspicious PCa to perform PET/CT imaging with radiolabeled gastrin-releasing peptide receptor (GRPR) antagonist, [68Ga]Ga-RM26, and compare with [68Ga]Ga-PSMA-617 and histopathology. METHODS: Every participant with suspicious PCa was scanned with both [68Ga]Ga-RM26 and [68Ga]Ga-PSMA-617 PET/CT. PET/CT imaging was compared using pathologic specimens as a reference standard. RESULTS: Of the 207 participants analyzed, 125 had cancer, and 82 were diagnosed with benign prostatic hyperplasia (BPH). The sensitivity and specificity of [68Ga]Ga-RM26 and [68Ga]Ga-PSMA-617 PET/CT imaging differed significantly for detecting clinically significant PCa. The area under the ROC curve (AUC) was 0.54 for [68Ga]Ga-RM26 PET/CT and 0.91 for [68Ga]Ga-PSMA-617 PET/CT in detecting PCa. For clinically significant PCa imaging, the AUCs were 0.51 vs. 0.93, respectively. [68Ga]Ga-RM26 PET/CT imaging had higher sensitivity for PCa with Gleason score (GS) = 6 (p = 0.03) than [68Ga]Ga-PSMA-617 PET/CT but poor specificity (20.73%). In the group with PSA < 10 ng/mL, the sensitivity, specificity, and AUC of [68Ga]Ga-RM26 PET/CT were lower than [68Ga]Ga-PSMA-617 PET/CT (60.00% vs. 80.30%, p = 0.12, 23.26% vs. 88.37%, p = 0.000, and 0.524 vs. 0.822, p = 0.000, respectively). [68Ga]Ga-RM26 PET/CT exhibited significantly higher SUVmax in specimens with GS = 6 (p = 0.04) and in the low-risk group (p = 0.01), and its uptake did not increase with PSA level, GS, or clinical stage. CONCLUSION: This prospective study provided evidence for the superior accuracy of [68Ga]Ga-PSMA-617 PET/CT over [68Ga]Ga-RM26 PET/CT in detecting more clinically significant PCa. [68Ga]Ga-RM26 PET/CT showed an advantage for imaging low-risk PCa.
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Antígeno Prostático Específico , Neoplasias de la Próstata , Masculino , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Estudios Prospectivos , Radioisótopos de Galio , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patologíaRESUMEN
BACKGROUND: Prostate cancer (PC) is the most common neoplasm and is the second leading cause of cancer-related deaths in men worldwide. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal YAP expression in PC remains to be characterized. METHODS: Western blot was used to measure the protein expression of ATXN3 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; transwell invasion assay was used to measure the invasion ability of PC. The xeno-graft tumor model was used for in vivo study. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between YAP and ATXN3. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. RESULTS: In the present study, we identified ATXN3, a DUB enzyme in the ubiquitin-specific proteases family, as a bona fide deubiquitylase of YAP in PC. ATXN3 was shown to interact with, deubiquitylate, and stabilize YAP in a deubiquitylation activity-dependent manner. Depletion of ATXN3 decreased the YAP protein level and the expression of YAP/TEAD target genes in PC, including CTGF, ANKRD1 and CYR61. Further mechanistic study revealed that the Josephin domain of ATXN3 interacted with the WW domain of YAP. ATXN3 stabilized YAP protein via inhibiting K48-specific poly-ubiquitination process on YAP protein. In addition, ATXN3 depletion significantly decreased PC cell proliferation, invasion and stem-like properties. The effects induced by ATXN3 depletion could be rescued by further YAP overexpression. CONCLUSIONS: In general, our findings establish a previously undocumented catalytic role for ATXN3 as a deubiquitinating enzyme of YAP and provides a possible target for the therapy of PC. Video Abstract.
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Neoplasias de la Próstata , Transducción de Señal , Masculino , Animales , Humanos , Factores de Transcripción/metabolismo , Línea Celular Tumoral , Neoplasias de la Próstata/patología , Vía de Señalización Hippo , Proliferación Celular , Mamíferos/metabolismo , Ataxina-3/metabolismo , Proteínas Represoras/metabolismoRESUMEN
Benign prostate hyperplasia (BPH) is the most commonly seen disease among aging males. Transforming growth factor(TGF)-ß-mediated epithelial-mesenchymal transition (EMT) and epithelial overproliferation might be central events in BPH etiology and pathophysiology. In the present study, long noncoding RNA MIR663AHG, miR-765, and FOXK1 formed a competing endogenous RNAs network, modulating TGF-ß-mediated EMT and epithelial overproliferation in BPH-1 cells. miR-765 expression was downregulated in TGF-ß-stimulated BPH-1 cells; miR-765 overexpression ameliorated TGF-ß-mediated EMT and epithelial overproliferation in BPH-1 cells. MIR663AHG directly targeted miR-765 and negatively regulated miR-765; MIR663AHG knockdown also attenuated TGF-ß-induced EMT and epithelial overproliferation in BPH-1 cells, whereas miR-765 inhibition attenuated MIR663AHG knockdown effects on TGF-ß-stimulated BPH-1 cells. miR-765 directly targeted FOXK1 and negatively regulated FOXK1. FOXK1 knockdown attenuated TGF-ß-induced EMT and epithelial overproliferation and promoted autophagy in BPH-1 cells, and partially attenuated miR-765 inhibition effects on TGF-ß-stimulated BPH-1 cells. In conclusion, this study provides a MIR663AHG/miR-765/FOXK1 axis modulating TGF-ß-induced epithelial proliferation and EMT, which might exert an underlying effect on BPH development and act as therapeutic targets for BPH treatment regimens.
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MicroARNs , Hiperplasia Prostática , Masculino , Humanos , Hiperplasia Prostática/genética , Hiperplasia Prostática/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Próstata/metabolismo , Próstata/patología , Transición Epitelial-Mesenquimal/genética , Hiperplasia/metabolismo , Movimiento Celular , Factor de Crecimiento Transformador beta1/metabolismo , MicroARNs/metabolismo , Proliferación Celular , Células Epiteliales/metabolismo , Factores de Transcripción ForkheadRESUMEN
Angiogenesis is a hallmark of cancer and is required for tumor growth and progression. Antiangiogenic therapy has been revolutionarily developing and was approved for the treatment of various types of cancer for nearly two decades, among which bevacizumab and sorafenib continue to be the two most frequently used antiangiogenic drugs. Although antiangiogenic therapy has brought substantial survival benefits to many cancer patients, resistance to antiangiogenic drugs frequently occurs during clinical treatment, leading to poor outcomes and treatment failure. Cumulative evidence has demonstrated that the intricate interplay among tumor cells, bone marrow-derived cells, and local stromal cells critically allows for tumor escape from antiangiogenic therapy. Currently, drug resistance has become the main challenge that hinders the therapeutic efficacies of antiangiogenic therapy. In this review, we describe and summarize the cellular and molecular mechanisms conferring tumor drug resistance to antiangiogenic therapy, which was predominantly associated with redundancy in angiogenic signaling molecules (e.g., VEGFs, GM-CSF, G-CSF, and IL17), alterations in biological processes of tumor cells (e.g., tumor invasiveness and metastasis, stemness, autophagy, metabolic reprogramming, vessel co-option, and vasculogenic mimicry), increased recruitment of bone marrow-derived cells (e.g., myeloid-derived suppressive cells, tumor-associated macrophages, and tumor-associated neutrophils), and changes in the biological functions and features of local stromal cells (e.g., pericytes, cancer-associated fibroblasts, and endothelial cells). We also review potential biomarkers to predict the response to antiangiogenic therapy in cancer patients, which mainly consist of imaging biomarkers, cellular and extracellular proteins, a certain type of bone marrow-derived cells, local stromal cell content (e.g., pericyte coverage) as well as serum or plasma biomarkers (e.g., non-coding RNAs). Finally, we highlight the recent advances in combination strategies with the aim of enhancing the response to antiangiogenic therapy in cancer patients and mouse models. This review introduces a comprehensive understanding of the mechanisms and biomarkers associated with the evasion of antiangiogenic therapy in cancer, providing an outlook for developing more effective approaches to promote the therapeutic efficacy of antiangiogenic therapy.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos , Neoplasias , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Bevacizumab/uso terapéutico , Células Endoteliales/metabolismo , Células Endoteliales/patología , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Sorafenib/uso terapéuticoRESUMEN
Sluggish storage kinetics and insufficient performance are the major challenges that restrict the transition metal dichalcogenides (TMDs) applied for zinc ion storage, especially at the extreme temperature conditions. Herein, a multiscale interface structure-integrated modulation concept was presented, to unlock the omnidirectional storage kinetics-enhanced porous VSe2-x â n H2 O host. Theory research indicated that the co-modulation of H2 O intercalation and selenium vacancy enables enhancing the interfacial zinc ion capture ability and decreasing the zinc ion diffusion barrier. Moreover, an interfacial adsorption-intercalation pseudocapacitive storage mechanism was uncovered. Such cathode displayed remarkable storage performance at the wide temperature range (-40-60 °C) in aqueous and solid electrolytes. In particular, it can retain a high specific capacity of 173â mAh g-1 after 5000â cycles at 10â A g-1 , as well as a high energy density of 290â Wh kg-1 and a power density of 15.8â kW kg-1 at room temperature. Unexpectedly, a remarkably energy density of 465â Wh kg-1 and power density of 21.26â kW kg-1 at 60 °C also can be achieved, as well as 258â Wh kg-1 and 10.8â kW kg-1 at -20 °C. This work realizes a conceptual breakthrough for extending the interfacial storage limit of layered TMDs to construct all-climate high-performance Zn-ion batteries.
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Abnormal N6-methyladenosine (m6A) modification is closely associated with the occurrence, development, progression and prognosis of cancer, and aberrant m6A regulators have been identified as novel anticancer drug targets. Both traditional medicine-related approaches and modern drug discovery platforms have been used in an attempt to develop m6A-targeted drugs. Here, we provide an update of the latest findings on m6A modification and the critical roles of m6A modification in cancer progression, and we summarize rational sources for the discovery of m6A-targeted anticancer agents from traditional medicines and computer-based chemosynthetic compounds. This review highlights the potential agents targeting m6A modification for cancer treatment and proposes the advantage of artificial intelligence (AI) in the discovery of m6A-targeting anticancer drugs. Three stages of m6A-targeting anticancer drug discovery: traditional medicine-based natural products, modern chemical modification or synthesis, and artificial intelligence (AI)-assisted approaches for the future.
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Inteligencia Artificial , Neoplasias , Adenosina/química , Descubrimiento de Drogas , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , PronósticoRESUMEN
BACKGROUND: At present, standardized parameters for quantitatively evaluating 68 Ga-PSMA-PET/CT outcomes when diagnosing lymph node metastasis in prostate cancer patients are lacking. Inflammatory hematological biomarkers offer value as robust predictors of certain cancer-related outcomes. The present study was thus developed to explore approaches to improving the utility of 68 Ga-PSMA-PET/CT for diagnosing lymph node metastasis through the combined evaluation of inflammatory hematological markers in prostate cancer patients. METHODS: Pretreatment patient details including age, initial TPSA levels, hematological findings, biopsy pathology results (Gleason score and ISUP grouping), radical pathology results, and imaging details were collected. Optimal cutoff values for each predictor then being determined based upon Youden's index, with univariate and multivariate analyses were then used to identify independent predictors of lymph node metastasis and used to construct a nomogram. RESULT: Independent predictors of lymph node metastasis in this patient cohort included SUVmax (odds ratio [OR]: 30.549, 95% confidence interval [CI]: 10.855-85.973, p < 0.001), neutrophil-lymphocyte ratio (OR:8.221, 95%CI: 1.335-50.614, p = 0.023), platelet-lymphocyte ratio (OR:8.221, 95% CI: 1.335-50.614, p = 0.023), initial TPSA (OR:2.761, 95% CI: 1.132-6.733, p = 0.026), and clinical T-stage (T3 vs. T2, OR:11.332, 95% CI:3.929-32.681, p < 0.001; T4 vs. T2, OR:9.101, 95% CI:1.962-42.213, p = 0.005), with corresponding optimal cutoff values of 2.3 (area under the curve [AUC]: 0.873, sensitivity: 0.736, specificity: 0.902), 1.72 (AUC: 0.558, sensitivity: 0.529, specificity: 0.643), 83.305 (AUC: 0.651, sensitivity: 0.299, specificity: 0.979), and 21.875 (AUC: 0.672, sensitivity: 0.736, specificity: 0.601). Subsequent nomogram construction was associated with good predictive ability, with a C-index of 0.887(95% CI: 0.793-0.981) and an AUC of 0.924 (95% CI: 0.882-0.965). CONCLUSION: SUVmax, the neutrophil-lymphocyte ratio, the platelet-lymphocyte ratio, initial TPSA, and clinical T-stage represent valuable independent predictors of lymph node metastasis in prostate cancer patients, offering an opportunity to further optimize lymph node staging for these patients.
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Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Isótopos de Galio , Radioisótopos de Galio , Humanos , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Metástasis Linfática/diagnóstico por imagen , Metástasis Linfática/patología , Linfocitos/patología , Masculino , Estadificación de Neoplasias , Neutrófilos/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Estudios RetrospectivosRESUMEN
In bladder cancer patients, metastasis after surgical resection and serious adverse reactions brought by cisplatin-based systemic chemotherapy make it urgent to explore novel therapeutic methods for improving the clinical outcomes of patients with unsuccessful first-line chemotherapy and disease progression. In this study, GBX2 has been recognized as a differentially expressed transcriptional factor between bladder cases with response to treatment and progressive disease based on online expression profile analysis. Higher GBX2 expression was correlated with poorer OS, DSS, and PFS in bladder cancer patients. GBX2 co-expressed genes were enriched in ECM regulation. ITGA5 was positively correlated with GBX2. GBX2 and ITGA5 were notably elevated in bladder cancer cells. GBX2 and ITGA5 similarly affected bladder cancer cell phenotypes via facilitating cell viability, migration, and invasion. By binding to the promoter region of ITGA5, GBX2 activated ITGA5 transcription, upregulating ITGA5 expression. In bladder cancer cells co-transfected with sh-GBX2 and ITGA5 oe, the inhibitory effects of GBX2 knockdown on bladder cancer cell malignant behaviors were partially eliminated by ITGA5 overexpression. In conclusion, GBX2 and ITGA5 serve as oncogenic factors, promoting the viability, migration, and invasion of bladder cancer cells. GBX2 exerts its functions by targeting the ITGA5 promoter region to activate ITGA5 transcription.
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Integrinas/genética , Neoplasias de la Vejiga Urinaria , Carcinogénesis/genética , Línea Celular Tumoral , Cisplatino , Proteínas de Homeodominio/genética , Humanos , Regiones Promotoras Genéticas , Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/genéticaRESUMEN
PURPOSE: Growing evidence proved the efficacy of multi-parametric MRI (mpMRI) and prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-guided targeted biopsy (TB) in prostate cancer (PCa) diagnosis, but there is no direct comparison between mpMRI-TB and PSMA PET/CT-TB. Gastrin-releasing peptide receptor (GRPR) is highly expressed in PCa, which can compensate for the unstable expression of PSMA in PCa. Therefore, we designed a study to compare the efficiency of mpMRI-TB, dual-tracer (GRPR and PSMA) PET/CT-TB, systematic biopsy, and combined biopsy for the diagnosis of prostate cancer. METHODS: One hundred twelve suspicious PCa patients were enrolled from September 2020 to June 2021. Patients with anyone of positive dual-tracer PET/CT or mpMRI underwent TB, and all enrolled patients underwent systematic biopsy (SB) after TB. The primary outcome was the detection rates of PCa in different biopsy strategies. Secondary outcomes were the performance of three imaging methods, omission diagnostic rates, and upgrading and downgrading of biopsy samples relative to those of prostatectomy specimens in different biopsy strategies. McNemar's tests and Bonferroni correction in multiple comparisons were used to compare the primary and secondary outcomes. RESULTS: In 112 men, clinically significant PCa (grade group[GG] ≥ 2) accounted for 34.82% (39/112), and nonclinically significant PCa (GG = 1) accounted for 4.46% (5/112). 68 Ga-PSMA PET/CT-TB achieved higher PCa detection rate (69.77%) and positive ratio of biopsy cores (0.44) compared with SB (39.29% and 0.12) and mpMRI-TB (36.14% and 0.23), respectively (P < 0.005). Dual-tracer PET/CT screen out patients for avoiding 52.67% (59/112) unnecessary biopsy, whereas dual-tracer PET/CT-TB plus SB achieved high detection rate (77.36%) without misdiagnosis of csPCa. CONCLUSION: Dual-tracer PET/CT might screen patients for avoiding unnecessary biopsy. Dual-tracer PET/CT-TB plus SB might be a more effective and promising strategy for the definite diagnosis of clinically significant PCa than mpMRI-TB.
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Imágenes de Resonancia Magnética Multiparamétrica , Neoplasias de la Próstata , Biopsia , Radioisótopos de Galio , Humanos , Biopsia Guiada por Imagen , Masculino , Proyectos Piloto , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/patología , Receptores de BombesinaRESUMEN
Tumor angiogenesis is an important biological process involved in the proliferation and migration of endothelial cells, regulated by Ang/Tie-2 signaling pathways, which is essential for tumor growth and metastasis. Therefore, blocking Ang/Tie-2 signaling pathways is a promising anti-angiogenic strategy for tumor treatment. 2,5-Diketopiperazines (DKPs) are a kind of bioactive compounds derived from marine fungi and they present a wide spectrum of pharmacological properties, particularly in the field of cancer treatment. Herein, a DKP marine natural product, Cryptoechinuline D (Cry D) was applied to structural modification and twelve derivatives were synthesized. Among which, compound 5 showed significant inhibitory activity against HUVECs with an IC50 value of 12.6 µmol/L, which weakened the proliferation, migration and invasion of HUVECs by inhibiting the Ang2/Tie-2 signaling pathway. The results of these evaluations indicated that compound 5 might be a promising anti-angiogeneic agent and worth further optimization and development for cancer therapy.
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Productos Biológicos , Neoplasias , Inhibidores de la Angiogénesis/farmacología , Productos Biológicos/metabolismo , Productos Biológicos/farmacología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Neoplasias/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismoRESUMEN
Eight new 2,6-disubstituted piperidin-3-ol alkaloids (1-8), featuring a C10 unsaturated alkyl side chain, together with three previously reported analogues (9-11) were isolated from the leaves of medicinal plant Microcos paniculata. Their structures and absolute configurations were elucidated unambiguously by means of 1D and 2D NMR spectroscopic data analysis, modified Mosher's method, Snatzke's method, and quantum chemical electronic circular dichroism (ECD) calculations, as well as single-crystal X-ray crystallography. The isolates were evaluated for their antiangiogenic effects on human umbilical vein endothelial cells (HUVECs). Compound 2 displayed an inhibitory effect on tube formation of HUVECs in a concentration-dependent manner.
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Alcaloides , Malvaceae , Alcaloides/química , Dicroismo Circular , Células Endoteliales , Humanos , Estructura Molecular , Piperidinas/química , Piperidinas/farmacología , Hojas de la Planta/químicaRESUMEN
OBJECTIVES: Renal cancer is a common malignancy of the urinary system, and the partial nephrectomy is a common surgical modality for early renal cancer. 3D printing technology can create a visual three-dimensional model by using 3D digital models of the patient's imaging data. With this model, surgeons can perform preoperative assessment to clarify the location, depth, and blood supply of the tumor, which helps to develop preoperative plans and achieve better surgical outcomes. In this study, the R.E.N.A.L scoring system was used to stratify patients with renal tumors and to explore the clinical application value of 3D printing technology in laparoscopic partial nephrectomy. METHODS: A total of 114 renal cancer patients who received laparoscopic partial nephrectomy in Xiangya Hospital from June 2019 to December 2020 were enrolled. The patients were assigned into an experimental group (n=52) and a control group (n=62) according to whether 3D printing technology was performed, and the differences in perioperative parameters between the 2 groups were compared. Thirty-nine patients were assigned into a low-complexity group (4-6 points), 32 into a moderate-complexity group (7-9 points), and 43 into a high-complexity group (10-12 points) according to R.E.N.A.L score, and the differences in perioperative parameters between the experimental group and the control group in each score group were compared. RESULTS: The experimental group had shorter operative time, renal ischemia time, and postoperative hospital stay (all P<0.05), less intraoperative blood loss (P=0.047), and smaller postoperative blood creatinine change (P=0.032) compared with the control group. In the low-complexity group, there were no statistically significant differences between the experimental group and the control group in operation time, renal ischemia time, intraoperative blood loss, postoperative blood creatinine changes, and postoperative hospital stay (all P>0.05). In the moderate- and high- complexity groups, the experimental group had shorter operative time, renal ischemia time, and postoperative hospital stay (P<0.05 or P<0.001), less intraoperative blood loss (P=0.022 and P<0.001, respectively), and smaller postoperative blood creatinine changes (P<0.05 and P<0.001, respectively) compared with the control group. CONCLUSIONS: Compared with renal tumor patients with R.E.N.A.L score<7, renal cancer patients with R.E.N.A.L score≥7 may benefit more from 3D printing assessment before undergoing partial nephrectomy.
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Neoplasias Renales , Laparoscopía , Pérdida de Sangre Quirúrgica , Creatinina , Femenino , Humanos , Isquemia , Neoplasias Renales/cirugía , Laparoscopía/métodos , Masculino , Nefrectomía/métodos , Impresión Tridimensional , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Invasive bladder tumors cause a worse prognosis in patients and remain a clinical challenge. Epithelial-mesenchymal transition (EMT) is associated with bladder cancer metastasis. In the present research, we attempted to demonstrate a novel mechanism by which a long noncoding RNA (lncRNA)-miRNA-mRNA axis regulates EMT and metastasis in bladder cancer. METHODS: Immunofluorescence (IF) staining was used to detect Vimentin expression. The protein expression of ZEB1, Vimentin, E-cadherin, and Snail was investigated by using immunoblotting assays. Transwell assays were performed to detect the invasive capacity of bladder cancer cells. A wound healing assay was used to measure the migratory capacity of bladder cancer cells. RESULTS: Herein, we identified lncRNA VIM-AS1 as a highly- expressed lncRNA in bladder cancer, especially in metastatic bladder cancer tissues and high-metastatic bladder cancer cell lines. By acting as a ceRNA for miR-655, VIM-AS1 competed with ZEB1 for miR-655 binding, therefore eliminating the miR-655-mediated suppression of ZEB1, finally promoting EMT in both high- and low-metastatic bladder cancer cells and enhancing cancer cell metastasis. CONCLUSIONS: In conclusion, the VIM-AS1/miR-655/ZEB1 axis might be a promising target for improving bladder cancer metastasis via an EMT-related mechanism.