RESUMO
Tumor-infiltrating lymphocyte (TIL) deficiency is the most conspicuous obstacle to limit the cancer immunotherapy. Immune checkpoint inhibitors (ICIs), such as anti-PD-1 antibody, have achieved great success in clinical practice. However, due to the limitation of response rates of ICIs, some patients fail to benefit from monotherapy. Thus, novel combination therapy that could improve the response rates emerges as new strategies for cancer treatment. Here, we reported that the natural product rocaglamide (RocA) increased tumor-infiltrating T cells and promoted Th17 differentiation of CD4+ TILs. Despite RocA monotherapy upregulated PD-1 expression of TILs, which was considered as the consequence of T cell activation, combining RocA with anti-PD-1 antibody significantly downregulated the expression of PD-1 and promoted proliferation of TILs. Taken together, these findings demonstrated that RocA could fuel the T cell anti-tumor immunity and revealed the remarkable potential of RocA as a therapeutic candidate when combining with the ICIs.
Assuntos
Benzofuranos , Diferenciação Celular , Inibidores de Checkpoint Imunológico , Linfócitos do Interstício Tumoral , Receptor de Morte Celular Programada 1 , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Animais , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Humanos , Diferenciação Celular/efeitos dos fármacos , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Feminino , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linhagem Celular TumoralRESUMO
BACKGROUND: Digital histopathology provides valuable information for clinical decision-making. We hypothesized that a deep risk network (DeepRisk) based on digital pathology signature (DPS) derived from whole-slide images could improve the prognostic value of the tumor, node, and metastasis (TNM) staging system and offer chemotherapeutic benefits for gastric cancer (GC). METHODS: DeepRisk is a multi-scale, attention-based learning model developed on 1120 GCs in the Zhongshan dataset and validated with two external datasets. Then, we assessed its association with prognosis and treatment response. The multi-omics analysis and multiplex Immunohistochemistry were conducted to evaluate the potential pathogenesis and spatial immune contexture underlying DPS. RESULTS: Multivariate analysis indicated that the DPS was an independent prognosticator with a better C-index (0.84 for overall survival and 0.71 for disease-free survival). Patients with low-DPS after neoadjuvant chemotherapy responded favorably to treatment. Spatial analysis indicated that exhausted immune clusters and increased infiltration of CD11b+CD11c+ immune cells were present at the invasive margin of high-DPS group. Multi-omics data from the Cancer Genome Atlas-Stomach adenocarcinoma (TCGA-STAD) hint at the relevance of DPS to myeloid derived suppressor cells infiltration and immune suppression. CONCLUSION: DeepRisk network is a reliable tool that enhances prognostic value of TNM staging and aid in precise treatment, providing insights into the underlying pathogenic mechanisms.
Assuntos
Adenocarcinoma , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Terapia Neoadjuvante , Tomada de Decisão Clínica , Inteligência Artificial , PrognósticoRESUMO
BACKGROUND AND AIMS: Monocarboxylate transporter (MCT) 4 is a high-affinity lactate transporter that is primarily involved in the maintenance of intracellular pH homeostasis and highly expressed in different tumors. However, the role of MCT4 in modulating immune responses against HCC remains unknown. APPROACH AND RESULTS: In this study, we demonstrated that MCT4 was overexpressed in HCC, which was associated with poor prognosis in patients. Genetic or pharmacological inhibition of MCT4 using VB124 (a highly potent MCT4 inhibitor) suppressed HCC tumor growth in immunocompetent mice model by enhancing CD8 + T cell infiltration and cytotoxicity. Such improved immunotherapy response by MCT4 targeting was due to combined consequences characterized by the alleviated acidification of tumor microenvironment and elevated the chemokine (C-X-C motif) ligand (CXCL) 9/CXCL10 secretion induced by reactive oxygen species/NF-κB signaling pathway. Combining MCT4 inhibition improved the therapeutic benefit of anti-programmed cell death 1 immunotherapy in HCC and prolonged mice survival. Moreover, higher MCT4 expression was observed in tumor tissues from nonresponder patients with HCC receiving neoadjuvant therapy with toripalimab. CONCLUSIONS: Our results revealed that lactate exportation by MCT4 has a tumor-intrinsic function in generating an immunosuppressive HCC environment and demonstrated the proof of the concept of targeting MCT4 in tailoring HCC immunotherapeutic approaches.
Assuntos
Carcinoma Hepatocelular , Imunoterapia , Neoplasias Hepáticas , Transportadores de Ácidos Monocarboxílicos , Animais , Camundongos , Carcinoma Hepatocelular/terapia , Ácido Láctico/metabolismo , Neoplasias Hepáticas/terapia , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Microambiente Tumoral , HumanosRESUMO
This study aimed to evaluate the correlation between measuring proton-density fat fraction (PDFF) in bone marrow using multi-echo chemical shift-encoded MRI and osteoporosis, assessing its effectiveness as a biomarker for osteoporosis. A systematic review was conducted by two independent researchers using Cochrane, PubMed, EMBASE, and Web of Science databases up to December 2023. Quality assessments were evaluated using the Cochrane risk of bias tool and the Agency for Healthcare Research and Quality (AHRQ) checklist. Fourteen studies involving 1495 patients were analyzed. The meta-analysis revealed a significant difference in PDFF values between the osteoporosis/osteopenia group and the normal control group, with a mean difference of 11.04 (95% CI: 9.17 to 12.92, Z=11.52, P < 0.00001). Measuring PDFF via MRI shows potential as an osteoporosis biomarker and may serve as a risk factor for osteoporosis. This insight opens new avenues for future diagnostic and therapeutic strategies, potentially improving osteoporosis management and patient care. OBJECTIVE: This study aims to assess the correlation between measuring proton-density fat fraction (PDFF) in bone marrow using multi-echo chemical shift-encoded MRI and osteoporosis, evaluating its effectiveness as a biomarker for osteoporosis. MATERIALS AND METHODS: This systematic review was carried out by two independent researchers using Cochrane, PubMed, EMBASE, and Web of Science databases up to December 2023. Quality assessments were evaluated using the Cochrane risk of bias tool and the Agency for Healthcare Research and Quality (AHRQ) checklist. RESULTS: Fourteen studies involving 1495 patients were analyzed. The meta-analysis revealed a significant difference in PDFF values between the osteoporosis/osteopenia group and the normal control group, with a (MD = 11.04, 95% CI: 9.17 to 12.92, Z = 11.52, P < 0.00001). Subgroup analyses indicated that diagnostic methods, gender, and echo length did not significantly impact the PDFF-osteoporosis association. CONCLUSION: PDFF measurement via MRI shows potential as an osteoporosis biomarker and may serve as a risk factor for osteoporosis. This insight opens new avenues for future diagnostic and therapeutic strategies, potentially improving osteoporosis management and patient care.
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BACKGROUND AND AIMS: We aimed to investigate the correlation and to explore which MAFLD subtypes have the greatest influence on progression of arterial stiffness risk. METHODS AND RESULTS: Using data from a health examination-based cohort, a total of 12,129 participants who underwent two repeated health examinations that included brachial-ankle pulse wave velocity (baPWV) from 2012 to 2020 were enrolled. Participants were separated into non-MAFLD, overweight/obese (OW-MAFLD), lean/normal weight (lean-MAFLD) and diabetes (DM-MAFLD) groups. Among the participants with a median follow-up of 2.17 years, 4511 (37.2%) participants had MAFLD at baseline, among which 3954 (87.7%), 123 (2.7%), and 434 (9.6%) were OW-, lean- and DM-MAFLD, respectively. Analyses using linear regression models confirmed that compared with the non-MAFLD group, the elevated baPWV change rates (cm/s/year) were 12.87 (8.81-16.94), 25.33 (7.84-42.83) and 38.49 (27.88-49.10) in OW, lean and DM-MAFLD, respectively, while the increased change proportions (%) were 1.53 (1.10-1.95), 3.56 (1.72-5.40) and 3.94 (2.82-5.05), respectively. Similar patterns were observed when these two baPWV parameters were transformed in the form of the greatest increase using Cox proportional hazards model analyses. Furthermore, the risk of arterial stiffness progression across MAFLD subtypes presented a significant, gradient, inverse relationship in the order of DM-, lean-, OW with metabolic abnormalities (MA)-, and OW without MA-MAFLD. CONCLUSION: MAFLD, especially DM-MAFLD and lean-MAFLD, was significantly associated with arterial stiffness progression, providing evidence that stratification screening and surveillance strategies for CVD risk have important clinical implications.
Assuntos
Índice Tornozelo-Braço , Progressão da Doença , Hepatopatia Gordurosa não Alcoólica , Rigidez Vascular , Humanos , Masculino , Feminino , Estudos Prospectivos , Pessoa de Meia-Idade , Adulto , Medição de Risco , Fatores de Tempo , Fatores de Risco , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Análise de Onda de Pulso , Prognóstico , Magreza/fisiopatologia , Magreza/epidemiologia , Magreza/diagnóstico , Obesidade/fisiopatologia , Obesidade/epidemiologia , Obesidade/diagnóstico , IdosoRESUMO
PURPOSE: To develop an MR-conditional microwave needle that generates a spherical ablation zone and clear MRI visibility for MR-guided microwave ablation. METHODS: An MR-conditional microwave needle consisting of zirconia tip and TA18 titanium alloy tube was investigated. The numerical model was created to optimize the needle's geometry and analyze its performance. A geometrically optimized needle was produced using non-magnetic materials based on the electromagnetics simulation results. The needle's mechanical properties were tested per the Chinese pharmaceutical industry standard YY0899-2013. The MRI visibility performance and ablation characteristics of the needle was tested both in vitro (phantom) and in vivo (rabbit) at 1.5T. The RF-induced heating was evaluated in ex vivo porcine liver. RESULTS: The needle's mechanical properties met the specified requirements. The needle susceptibility artifact was clearly visible both in vitro and in vivo. The needle artifact diameter (A) was small in in vivo (Ashaft: 4.96 ± 0.18 mm for T1W-FLASH, 3.13 ± 0.05 mm for T2-weighted fast spin-echo (T2W-FSE); Atip: 2.31 ± 0.09 mm for T1W-FLASH, 2.29 ± 0.08 mm for T2W-FSE; tip location error [TLE]: -0.94 ± 0.07 mm for T1W-FLASH, -1.10 ± 0.09 mm for T2W-FSE). Ablation zones generated by the needle were nearly spherical with an elliptical aspect ratio ranging from 0.79 to 0.90 at 30 W, 50 W for 3, 5, 10 min duration ex vivo ablations and 0.86 at 30 W for 10 min duration in vivo ablations. CONCLUSION: The designed MR-conditional microwave needle offers excellent mechanical properties, reliable MRI visibility, insignificant RF-induced heating, and a sufficiently spherical ablation zone. Further clinical development of MR-guided microwave ablation appears warranted.
Assuntos
Técnicas de Ablação , Ablação por Cateter , Técnicas de Ablação/métodos , Animais , Artefatos , Ablação por Cateter/métodos , Fígado/diagnóstico por imagem , Fígado/cirurgia , Imageamento por Ressonância Magnética , Micro-Ondas/uso terapêutico , Imagens de Fantasmas , Coelhos , SuínosRESUMO
Intrahepatic cholangiocarcinoma (ICC) remains a highly heterogeneous disease with poor prognosis. Tumor-infiltrating lymphocytes were predictive in various cancers, but their prognostic value in ICC is less clear. A total of 168 ICC patients who had received liver resection were enrolled and assigned to the derivation cohort. Sixteen immune markers in tumor and peritumor regions were examined by immunohistochemistry. A least absolute shrinkage and selection operator model was used to identify prognostic markers and to establish an immune signature for ICC (ISICC ). An ISICC -applied prediction model was built and validated in another independent dataset. Five immune features, including CD3peritumor (P) , CD57P , CD45RAP , CD66bintratumoral (T) and PD-L1P , were identified and integrated into an individualized ISICC for each patient. Seven prognostic predictors, including total bilirubin, tumor numbers, CEA, CA19-9, GGT, HBsAg and ISICC , were integrated into the final model. The C-index of the ISICC -applied prediction model was 0.719 (95% CI, 0.660-0.777) in the derivation cohort and 0.667 (95% CI, 0.581-0.732) in the validation cohort. Compared with the conventional staging systems, the new model presented better homogeneity and a lower Akaike information criteria value in ICC. The ISICC -applied prediction model may provide a better prediction performance for the overall survival of patients with resectable ICC in clinical practice.
Assuntos
Colangiocarcinoma/cirurgia , Neoplasias Hepáticas/cirurgia , Linfócitos do Interstício Tumoral/patologia , Prognóstico , Idoso , Colangiocarcinoma/epidemiologia , Colangiocarcinoma/patologia , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Hepatectomia , Humanos , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genéticaRESUMO
BACKGROUND: Immunoscore have shown a promising prognostic value in many cancers. We aimed to establish and validate an immune classifier to predict survival after curative resection of hepatocellular carcinoma (HCC) patients who have undergone curative resection. METHODS: The immunohistochemistry (IHC) classifier assay was performed on 664 patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A HCC. A nine-feature-based HCC-IHC classifier was then constructed by the least absolute shrinkage and selection operator method. The associations between the HCC-IHC classifier and patient outcomes were assessed. Herein, a nomogram was generated from the Cox regression coefficients and evaluated by decision curve analysis. RESULTS: We constructed an HCC-IHC classifier based on nine features; significant differences were found between the low-HCC-IHC classifier patients and high-HCC-IHC classifier patients in the training cohort in the 5-year relapse-free survival rates (46.7% vs. 26.7%, respectively; P < 0.001). The HCC-IHC classifier-based nomogram presented better accuracy than traditional staging systems. CONCLUSIONS: In conclusion, the HCC-IHC classifier could effectively predict recurrence in early-stage HCC patients and supplemented the prognostic value of the BCLC staging system. The HCC-IHC classifier may facilitate patient decision-making and individualise the management of postoperative patients with early-stage HCC.
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Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/diagnóstico , Proteínas de Neoplasias/genética , Recidiva Local de Neoplasia/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imuno-Histoquímica/métodos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Transcriptoma/genéticaRESUMO
BACKGROUND: The prognosis of patients with combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma (CHC) is usually poor, and effective adjuvant therapy is missing making it important to investigate whether these patients may benefit from adjuvant transarterial chemoembolization (TACE). We aimed to evaluate the efficiency of adjuvant TACE for long-term recurrence and survival after curative resection before and after propensity score matching (PSM) analysis. METHODS: In this retrospective study, of 230 patients who underwent resection for CHC between January 1994 and December 2014, 46 (18.0%) patients received adjuvant TACE. Univariate and multivariate regression analyses were used to identify the independent predictive factors of survival. Cox regression analyses and log-rank tests were used to compare overall survival (OS) and disease-free survival (DFS) between patients who did or did not receive adjuvant TACE. RESULTS: A total of 230 patients (mean age 52.2 ± 11.9 years; 172 men) were enrolled, and 46 (mean age 52.7 ± 11.1 years; 38 men) patients received TACE. Before PSM, in multivariate regression analysis, γ-glutamyl transpeptidase (γ-GT), tumour nodularity, macrovascular invasion (MVI), lymphoid metastasis, and extrahepatic metastasis were associated with OS. Alanine aminotransferase (ALT), MVI, lymphoid metastasis, and preventive TACE (HR: 2.763, 95% CI: 1.769-4.314, p < 0.001) were independent prognostic factors for DFS. PSM created 46 pairs of patients. Before PSM, adjuvant preventive TACE was not associated with an increased risk of OS (HR: 0.911, 95% CI: 0.545-1.520, p = 0.720) or DFS (HR: 3.345, 95% CI: 1.686-6.638, p = 0.001). After PSM, the 5-year OS and DFS rates were comparable in the TACE group and the non-TACE group (OS: 22.7% vs 14.9%, respectively, p = 0.75; DFS: 11.2% vs 14.4%, respectively, p = 0.06). CONCLUSIONS: The present study identified that adjuvant preventive TACE did not influence DFS or OS after curative resection of CHC.
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Neoplasias dos Ductos Biliares/mortalidade , Carcinoma Hepatocelular/mortalidade , Quimioembolização Terapêutica/mortalidade , Colangiocarcinoma/mortalidade , Hepatectomia/mortalidade , Neoplasias Hepáticas/mortalidade , Recidiva Local de Neoplasia/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/terapia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Quimioterapia Adjuvante , Colangiocarcinoma/patologia , Colangiocarcinoma/terapia , Terapia Combinada , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Hydrogen sulfide (H2 S) has a significant effect on the regulation of interleukin-6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) activities, while IL-6 directly regulates hepcidin expression via STAT3. We therefore hypothesized that H 2 S has a role in body iron homeostasis by regulating the expression of iron transport proteins via the IL-6/STAT3/Hepcidin pathway. Here, we investigated the effects of two H 2 S donors sodium hydrosulfide and GYY4137 on the expression of ferroportin-1 (Fpn1), transferrin receptor-1 (TfR1), hepcidin, IL-6 and pSTAT3 in the spleen of mice in vivo and peritoneal macrophage in vitro. We also examined the effects of H 2 S on serum iron, transferrin saturation, and ferritin light chain contents in the spleen, and on nitrite content, nuclear factor erythroid 2-related factor-2 (Nrf2) and iron regulatory protein 1 (IRP1) in the macrophages. We demonstrated that H 2 S regulates the expression of TfR1 and Fpn1 in the spleen in vivo and in peritoneal macrophages in vitro predominantly via the IL-6/pSTAT3/hepcidin pathway, under the conditions of inflammation induced by lipopolysaccharides. We also provide evidence that under uninflamed conditions, the regulation of Fpn1 and TfR1 expression by H 2 S, both in vivo and in vitro, are mediated by the nitric oxide (NO)/Nrf2 and iron regulatory protein/iron responsive element pathways, respectively, which are independent of IL-6/pSTAT3/hepcidin signals. These findings show that H 2 S is a key player in iron homeostasis under not only the inflamed conditions but also uninflamed conditions.
Assuntos
Proteínas de Transporte de Cátions/metabolismo , Sulfeto de Hidrogênio/farmacologia , Ferro/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Receptores da Transferrina/metabolismo , Baço/efeitos dos fármacos , Sulfetos/farmacologia , Animais , Células Cultivadas , Hepcidinas/genética , Hepcidinas/metabolismo , Inflamação/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Proteínas Reguladoras de Ferro/metabolismo , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Morfolinas/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Compostos Organotiofosforados/metabolismo , Fosforilação , Fator de Transcrição STAT3/metabolismo , Baço/metabolismo , Sulfetos/metabolismoRESUMO
Intrahepatic cholangiocarcinoma (ICC) is a rare malignancy with poor prognosis. The evaluation of recurrence risk after liver resection is of great importance for ICCs. We aimed to assess the prognostic value of intra- and peritumoral immune infiltrations and to establish a novel histopathology-related immunoscore (HRI) associated with ICC recurrence. A total of 280 ICC patients who received curative resection between February 2005 and July 2011 were enrolled in our study. Patients were randomly assigned to the derivation cohort (n = 176) or the validation cohort (n = 104). Sixteen immune biomarkers in both intra- and peritumoral tissues were examined by immunohistochemistry. The least absolute shrinkage and selection operator (LASSO) Cox model was used to establish the HRI score. Cox regression analysis was used for multivariate analysis. Nine recurrence-related immune features were identified and integrated into the HRI score. The HRI score was used to categorize patients into low-risk and high-risk groups using the X-tile software. Kaplan-Meier analysis presented that the HRI score showed good stratification between low-risk and high-risk groups in both the derivation cohort (P < 0.001) and the validation cohort (P = 0.014), respectively. Multivariate analysis demonstrated that serum γ-glutamyl transpeptidase, carbohydrate antigen 19-9, lymphoid metastasis, tumor numbers, and the HRI score were independent risk factors associated with recurrence-free survival (RFS). The combination of Shen's model and HRI score provided better performance in recurrence prediction compared with traditional staging systems. The HRI score might serve as a promising RFS predictor for ICC with prognostic values.
Assuntos
Antígenos Glicosídicos Associados a Tumores/metabolismo , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/diagnóstico , Neoplasias Hepáticas/diagnóstico , Fígado/metabolismo , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Estudos de Coortes , Feminino , Hepatectomia , Humanos , Fígado/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Prognóstico , Projetos de Pesquisa , Análise de Sobrevida , Carga Tumoral , gama-Glutamiltransferase/metabolismoRESUMO
BACKGROUND: Intratumoral immune infiltrates have manifested a robust prognostic signature in patients with hepatocellular carcinoma (HCC). We hypothesized that a novel tissue-related immune signature (TRIS) could improve the prediction of postoperative survival for patients diagnosed with early/intermediate HCC. METHODS: Twenty-eight immune features were immunohistochemically examined on 352 HCC specimens. The LASSO Cox regression model was used to construct a five-feature-based TRIS. The univariate and multivariate Cox analyses were performed. Based on independent predictors, the immune-clinical prognostic index (ICPI) was established. Performance assessment was measured with C-index and compared with seven traditional staging systems. The independent validation cohort (n = 393) was included to validate the model. RESULTS: By using the LASSO method, the TRIS were constructed on the basis of five immune features, CD3intratumoral (T), CD27T, CD68peritumoral (P), CD103T, and PD1T. Multivariate Cox analysis showed that the TRIS was an independent prognostic predictor. In the training cohort, γ-glutamyl transferase, tumor diameter, tumor differentiation, and TRIS were incorporated into the ICPI. The ICPI presented satisfactory discrimination ability, with C-index values of 0.691 and 0.686 in the training and validation cohorts, respectively. Compared with seven conventional staging systems (C-index, training cohort, 0.548-0.597; validation cohort, 0.519-0.610), the ICPI exhibited better performance for early/intermediate-stage HCCs. Further, the patients were categorized into three subgroups with X-tile software, and the stratified ICPI presented a superior corrected Akaike information criterion and homogeneity in both cohorts. CONCLUSIONS: Our ICPI was a useful and reliable prognostic tool which may offer good individualized prediction capability for HCC patients with early/intermediate stage.
Assuntos
Carcinoma Hepatocelular/diagnóstico , Imunofenotipagem , Neoplasias Hepáticas/diagnóstico , Linfócitos do Interstício Tumoral/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica , Imunofenotipagem/métodos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Linfócitos/patologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Análise Serial de Tecidos , TranscriptomaRESUMO
Cystathionine ß-synthase (CBS) catalyzes the transsulfuration pathway and contributes, among other functions, to the generation of hydrogen sulfide. In view of the exceptionally high expression of CBS in the liver and the common interleukin-6 pathway used in the regulatory systems of hydrogen sulfide and hepcidin, we speculate that CBS is involved in body iron homeostasis. We found that CBS knockout (CBS-/- ) mice exhibited anemia and a significant increase in iron content in the serum, liver, spleen, and heart, along with severe damage to the liver, displaying a hemochromatosis-like phenotype. A high level of hepatic and serum hepcidin was also found. A major cause of the systemic iron overload is the reduced iron usage due to suppressed erythropoiesis, which is consistent with an increase in interleukin-6 and reduced expression of erythropoietin. Importantly, in the liver, absence of CBS caused both a reduction in the transcriptional factor nuclear factor erythroid 2-related factor-2 and an up-regulation of hepcidin that led to a decrease in the iron export protein ferroportin 1. The resulting suppression of iron export exacerbates iron retention, causing damage to hepatocytes. Finally, administration of CBS-overexpressing adenovirus into CBS mutant mice could partially reverse the iron-related phenotype. CONCLUSION: Our findings point to a critical role of CBS in iron homeostasis of the body, and the liver in particular; it is likely that a hemochromatosis-like phenotype in patients can be induced by aberration not only in the expression of key molecules in the hepcidin pathway but also of those related to CBS. (Hepatology 2018;67:21-35).
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Anemia Ferropriva/enzimologia , Anemia Ferropriva/patologia , Cistationina beta-Sintase/metabolismo , Hepatócitos/enzimologia , Ferro/metabolismo , Fígado/enzimologia , Anemia Ferropriva/metabolismo , Animais , Biópsia por Agulha , Western Blotting , Células Cultivadas , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Hepatócitos/metabolismo , Hepcidinas/metabolismo , Homeostase , Humanos , Imuno-Histoquímica , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise Multivariada , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real/métodos , Valores de ReferênciaRESUMO
Invading cancer cells extend cell protrusions, which guide cancer-cell migration and invasion, eventually leading to metastasis. The formation and activity of cell protrusions involve the localization of molecules and organelles at the cell front; however, it is challenging to precisely isolate these subcellular structures at the single-cell level for molecular analysis. Here, we describe a newly developed microfluidic platform capable of high-throughput isolation of cell protrusions at single-cell precision for profiling subcellular gene expression. Using this microfluidic platform, we demonstrate the efficient generation of uniform cell-protrusion arrays (more than 5000 cells with protrusions) for a series of cell types. We show precise isolation of cell protrusions with high purity at single-cell precision for subsequent RNA-Seq analysis, which was further validated by RT-qPCR and RNA FISH. Our highly controlled protrusion isolation method opens a new avenue for the study of subcellular functional mechanisms and signaling pathways in metastasis.
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Perfilação da Expressão Gênica/métodos , Ensaios de Triagem em Larga Escala/métodos , Microfluídica/métodos , Análise de Célula Única/métodos , Movimento Celular , HumanosRESUMO
The significant positive correlation between ghrelin and iron and hepcidin levels in the plasma of children with iron deficiency anemia prompted us to hypothesize that ghrelin may affect iron metabolism. Here, we investigated the effects of fasting or ghrelin on the expression of hepcidin, ferroportin 1 (Fpn1), transferrin receptor 1 (TfR1), ferritin light chain (Ft-L) proteins, and ghrelin, and also hormone secretagogue receptor 1 alpha (GHSR1α) and ghrelin O-acyltransferase (GOAT) mRNAs in the spleen and/or macrophage. We demonstrated that fasting induces a significant increase in the expression of ghrelin, GHSR1α, GOAT, and hepcidin mRNAs, as well as Ft-L and Fpn1 but not TfR1 proteins in the spleens of mice in vivo. Similar to the effects of fasting on the spleen, ghrelin induced a significant increase in the expression of Ft-L and Fpn1 but not TfR1 proteins in macrophages in vitro. In addition, ghrelin was found to induce a significant enhancement in phosphorylation of ERK as well as translocation of pERK from the cytosol to nuclei. Furthermore, the increased pERK and Fpn1 induced by ghrelin was demonstrated to be preventable by pre-treatment with either GHSR1α antagonist or pERK inhibitor. Our findings support the hypothesis that fasting upregulates Fpn1 expression, probably via a ghrelin/GHSR/MAPK signaling pathway.
Assuntos
Proteínas de Transporte de Cátions/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Jejum/metabolismo , Grelina/metabolismo , Macrófagos Peritoneais/enzimologia , Receptores de Grelina/metabolismo , Transdução de Sinais , Baço/enzimologia , Aciltransferases/genética , Aciltransferases/metabolismo , Animais , Apoferritinas/genética , Apoferritinas/metabolismo , Proteínas de Transporte de Cátions/genética , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Grelina/genética , Antagonistas de Hormônios/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Masculino , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Grelina/antagonistas & inibidores , Receptores de Grelina/genética , Baço/efeitos dos fármacos , Regulação para CimaRESUMO
OBJECTIVE: To explore the effects of shRNA-mediated downregulating lncRNA HOTAIR on the invasion,nude mouse tumorigenicity and snail expression of epithelial ovarian cancer SKOV3 cells. METHODS: The expression of lncRNA HOTAIR was detected by RT-PCR in SKOV3 cells. The shRNA targeting the lncRNA HOTAIR gene was cloned into RNA interference plasmid. The construction shHOTAIR vector was transfected into ovarian cancer SKOV3 cells by lipofectamine 2000,and the stably transfected cells were isolated by G418 and single clone selection. The downregulating expression of lncRNA HOTAIR was detected by quantitative real time PCR(qRT-PCR). The characteristics of shHOTAIR transfected SKOV3 cells were analyzed from the assays of invasion and nude mouse tumorigenicity,as well as the expression of snail and E-cadherin mRNA detected by qRT-PCR,and snail detected by immunohistochemistry and Western blot methods in xenograft tumor,respectively. RESULTS: The lncRNA HOTAIR expression was proved by RT-PCR in SKOV3 cells. The lncRNA HOTAIR expression in shHOTAIR transfected SKOV3 cells was significantly lower than the scramble control (P<0.01). The shHOTAIR transfected SKOV3 cells show that the invasion ability was significantly decreased compared with the scramble control (P<0.01). The nude mouse tumorigenicity,including tumorigenicity mouse number and tumor volume,was significantly decreased compared with the control group (P<0.01). The snail protein expression detected by IHC and Western blot in shHOTAIR-SKOV3 xenograft tumor was significantly decreased compared with the control scramble- SKOV3 group (P<0.05). The lncRNA HOTAIR low expression resulted in increasing E-cadherin and decreasing snail expression detected by qRT-PCR in the shHOTAIR transfected SKOV3 cells of xenograft tumor,compared with the scramble control (P<0.05). CONCLUSION: Targeting lncRNA HOTAIR expression in SKOV3 cells with RNA interference can decrease snail,increase E-cadherin and significantly reduce the invasion and tumorigenicity of epithelial ovarian cancer SKOV3 cells. These results suggest that the lncRNA HOTAIR could be an effective therapeutic target for human epithelial ovarian caner treatment.
Assuntos
Carcinoma Epitelial do Ovário/patologia , Invasividade Neoplásica , RNA Longo não Codificante/genética , RNA Interferente Pequeno , Animais , Caderinas/metabolismo , Carcinoma Epitelial do Ovário/genética , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Nus , Neoplasias Ovarianas , Fatores de Transcrição da Família Snail/metabolismo , TransfecçãoRESUMO
Aspirin down regulates transferrin receptor 1 (TfR1) and up regulates ferroportin 1 (Fpn1) and ferritin expression in BV-2 microglial cells treated without lipopolysaccharides (LPS), as well as down regulates hepcidin and interleukin 6 (IL-6) in cells treated with LPS. However, the relevant mechanisms are unknown. Here, we investigate the effects of aspirin on expression of hepcidin and iron regulatory protein 1 (IRP1), phosphorylation of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3) and P65 (nuclear factor-κB), and the production of nitric oxide (NO) in BV-2 microglial cells treated with and without LPS. We demonstrated that aspirin inhibited hepcidin mRNA as well as NO production in cells treated with LPS, but not in cells without LPS, suppresses IL-6, JAK2, STAT3, and P65 (nuclear factor-κB) phosphorylation and has no effect on IRP1 in cells treated with or without LPS. These findings provide evidence that aspirin down regulates hepcidin by inhibiting IL6/JAK2/STAT3 and P65 (nuclear factor-κB) pathways in the cells under inflammatory conditions, and imply that an aspirin-induced reduction in TfR1 and an increase in ferritin are not associated with IRP1 and NO.
Assuntos
Aspirina/farmacologia , Hepcidinas/biossíntese , Interleucina-6/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Lipopolissacarídeos/toxicidade , Microglia/efeitos dos fármacos , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição RelA/antagonistas & inibidores , Animais , Linhagem Celular , Hepcidinas/genética , Inflamação/patologia , Proteína 1 Reguladora do Ferro/biossíntese , Janus Quinase 2/metabolismo , Camundongos , Óxido Nítrico/biossíntese , Fosforilação/efeitos dos fármacos , RNA Mensageiro/biossíntese , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismoRESUMO
Hepatocellular carcinoma (HCC) is well characterized as a heterogeneous disease. Its late-stage diagnosis and chemotherapy resistance make it one of the refractory tumors in China. Natural killer (NK) cells play a significant role in immune surveillance. However, NK cells become dysfunctional in the progression of HCC, leading to tumor immune escape. This article reviews the recent progress on different strategies of NK cell-based immunotherapy in treating HCC, including direct adoptive NK cell transfer, gene engineering in NK cell, NK cell receptor targeting, immunosuppressive microenvironment modification, and tumor toxicity enhancement by cytokines or traditional Chinese medicine. These NK cell-based strategies have shown promising therapeutic potential.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Imunoterapia , Células Matadoras Naturais , Receptores de Células Matadoras Naturais , Microambiente TumoralRESUMO
Background: Previous studies have highlighted the crucial role of immune cells in lung cancer development; however, the direct link between immunophenotypes and lung cancer remains underexplored. Methods: We applied two-sample Mendelian randomization (MR) analysis, using genetic variants as instruments to determine the causal influence of exposures on outcomes. This method, unlike traditional randomized controlled trials (RCTs), leverages genetic variants inherited randomly at conception, thus reducing confounding and preventing reverse causation. Our analysis involved three genome-wide association studies to assess the causal impact of 731 immune cell signatures on lung cancer using genetic instrumental variables (IVs). We initially used the standard inverse variance weighted (IVW) method and further validated our findings with three supplementary MR techniques (MR-Egger, weighted median, and MR-PRESSO) to ensure robustness. We also conducted MR-Egger intercept and Cochran's Q tests to assess heterogeneity and pleiotropy. Additionally, reverse MR analysis was performed to explore potential causality between lung cancer subtypes and identified immunophenotypes, using R software for all statistical calculations. Results: Our MR analysis identified 106 immune signatures significantly associated with lung cancer. Notably, we found five suggestive associations across all sensitivity tests (P<0.05): CD25 on IgD- CD24- cells in small cell lung carcinoma (ORIVW =0.885; 95% CI: 0.798-0.983; P IVW =0.022); CD27 on IgD+ CD24+ cells in lung squamous cell carcinoma (ORIVW =1.054; 95% CI: 1.010-1.100; P IVW =0.015); CCR2 on monocyte cells in lung squamous cell carcinoma (ORIVW =0.941; 95% CI: 0.898-0.987; P IVW =0.012); CD123 on CD62L+ plasmacytoid dendritic cells (ORIVW =0.958; 95% CI: 0.924-0.992; P IVW =0.017) as well as on plasmacytoid dendritic cells (ORIVW =0.958; 95% CI: 0.924-0.992; P IVW =0.017) in lung squamous cell carcinoma. Conclusion: This study establishes a significant genomic link between immune cells and lung cancer, providing a robust basis for future clinical research aimed at lung cancer management.
Assuntos
Estudo de Associação Genômica Ampla , Neoplasias Pulmonares , Análise da Randomização Mendeliana , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Fatores de Risco , ImunofenotipagemRESUMO
BACKGROUND: Magnetoencephalography (MEG) and magnetic resonance imaging (MRI) are non-invasive imaging techniques that offer effective means for disease diagnosis. A more straightforward and optimized method is presented for designing gradient coils which are pivotal parts of the above imaging systems. PURPOSE: A novel design method based on stream function combining an optimization algorithm is proposed to obtain highly linear gradient coil. METHODS: Two-dimensional Fourier expansion of the current field on the surface where the coil is located and the equipotential line of the expansion term superposition according to the number of turns of the coil are used to represent the coil shape. Particle swarm optimization is utilized to optimize the coil shape while linearity and field uniformity are used as parameters to evaluate the coil performance. Through this method, the main parameters such as input current distribution region, coil turns, desired magnetic field strength, expansion order and iteration times can be combined in a given solution space to optimize coil design. RESULTS: Simulation results show that the maximum linearity spatial deviation of the designed bi-planar x-gradient coil compared with that of target field method is reduced from 14% to 0.54%, and that of the bi-planar z-gradient coil is reduced from 8.98% to 0.52%. Similarly, that of the cylindrical x-gradient coil is reduced from 2% to 0.1%, and that of the cylindrical z-gradient coil is reduced from 0.87% to 0.45%. The similar results are found in the index of inhomogeneity error. Moreover, it has also been verified experimentally that the result of measured magnetic field is consist with simulated result. CONCLUSIONS: The proposed method provides a straightforward way that simplifies the design process and improves the linearity of designed gradient coil, which could be beneficial to realize better magnetic field in engineering applications.