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2.
Mol Med ; 28(1): 37, 2022 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-35317721

RESUMO

BACKGROUND: Chronic liver injury induces pathological repair, resulting in fibrosis, during which hepatic stellate cells (HSCs) are activated and transform into myofibroblasts. CD248 is mainly expressed on myofibroblasts and was considered as a promising target to treat fibrosis. The primary aim of this study was to generate a CD248 specific antibody-drug conjugate (ADC) and evaluate its therapeutic efficacy for liver fibrosis and its safety in vivo. METHODS: CD248 expression was examined in patients with liver cirrhosis and in mice with CCl4-induced liver fibrosis. The ADC IgG78-DM1, which targets CD248, was prepared and its bioactivity on activated primary HSCs was studied. The anti-fibrotic effects of IgG78-DM1 on liver fibrosis were evaluated in CCl4-induced mice. The reproductive safety and biosafety of IgG78-DM1 were also evaluated in vivo. RESULTS: CD248 expression was upregulated in patients with liver cirrhosis and in CCl4-induced mice, and was mainly expressed on alpha smooth muscle actin (α-SMA)+ myofibroblasts. IgG78-DM1 was successfully generated, which could effectively bind with and kill CD248+ activated HSCs in vitro and inhibit liver fibrosis in vivo. In addition, IgG78-DM1 was demonstrated to have qualified biosafety and reproductive safety in vivo. CONCLUSIONS: Our study demonstrated that CD248 could be an ideal target for myofibroblasts in liver fibrosis, and CD248-targeting IgG78-DM1 had excellent anti-fibrotic effects in mice with liver fibrosis. Our study provided a novel strategy to treat liver fibrosis and expanded the application of ADCs beyond tumors.


Assuntos
Imunoconjugados , Miofibroblastos , Animais , Antígenos CD/metabolismo , Antígenos de Neoplasias/efeitos adversos , Antígenos de Neoplasias/metabolismo , Fibrose , Células Estreladas do Fígado/metabolismo , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/metabolismo , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Camundongos , Miofibroblastos/metabolismo
3.
Sci Rep ; 12(1): 2219, 2022 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-35140317

RESUMO

Bladder cancer (BLCA) is the most common malignancy whose early diagnosis can ensure a better prognosis. However, the predictive accuracy of commonly used predictors, including patients' general condition, histological grade, and pathological stage, is insufficient to identify the patients who need invasive treatment. Autophagy is regarded as a vital factor in maintaining mitochondrial function and energy homeostasis in cancer cells. Whether autophagy-related genes (ARGs) can predict the prognosis of BLCA patients deserves to be investigated. Based on BLCA data retrieved from the Cancer Genome Atlas and ARGs list obtained from the Human Autophagy Database website, we identified prognosis-related differentially expressed ARGs (PDEARGs) through Wilcox text and constructed a PDEARGs-based prognostic model through multivariate Cox regression analysis. The predictive accuracy, independent forecasting capability, and the correlation between present model and clinical variables or tumor microenvironment were evaluated through R software. Enrichment analysis of PDEARGs was performed to explore the underlying mechanism, and a systematic prognostic signature with nomogram was constructed by integrating clinical variables and the aforementioned PDEARGs-based model. We found that the risk score generated by PDEARGs-based model could effectively reflect deteriorated clinical variables and tumor-promoting microenvironment. Additionally, several immune-related gene ontology terms were significantly enriched by PDEARGs, which might provide insights for present model and propose potential therapeutic targets for BLCA patients. Finally, a systematic prognostic signature with promoted clinical utility and predictive accuracy was constructed to assist clinician decision. PDEARGs are valuable prognostic predictors and potential therapeutic targets for BLCA patients.


Assuntos
Autofagia/genética , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Biomarcadores Tumorais/genética , Correlação de Dados , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Análise Multivariada , Nomogramas , Prognóstico , Fatores de Risco , Microambiente Tumoral/genética
4.
Cancers (Basel) ; 14(4)2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35205714

RESUMO

The incidence rate of prostate cancer is higher in male cancers. With a hidden initiation of disease and long duration, prostate cancer seriously affects men's physical and mental health. Prostate cancer is initially androgen-dependent, and endocrine therapy can achieve good results. However, after 18-24 months of endocrine therapy, most patients eventually develop castration-resistant prostate cancer (CRPC), which becomes metastatic castration resistant prostate cancer (mCRPC) that is difficult to treat. Chimeric Antigen Receptor T cell (CAR-T) therapy is an emerging immune cell therapy that brings hope to cancer patients. CAR-T has shown considerable advantages in the treatment of hematologic tumors. However, there are still obstacles to CAR-T treatment of solid tumors because the physical barrier and the tumor microenvironment inhibit the function of CAR-T cells. In this article, we review the progress of CAR-T therapy in the treatment of prostate cancer and discuss the prospects and challenges of armed CAR-T and combined treatment strategies. At present, there are still many obstacles in the treatment of prostate cancer with CAR-T, but when these obstacles are solved, CAR-T cells can become a favorable weapon for the treatment of prostate cancer.

5.
Acta Parasitol ; 2022 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-35175460

RESUMO

PURPOSE: Strongyloidiasis is mainly prevalent in developing countries with poor economic and sanitary conditions. The clinical manifestations of Strongyloides stercoralis infection are complex and diverse, lacking specificity, which can easily lead to misdiagnosis and delayed treatment. METHODS: An elderly male patient, repeated cough and expectoration for 4 years, with exacerbation and dyspnea for 10 days, was admitted to hospital. Sputum culture and smear were taken for examination. Nematode larvae were found under the microscope. Nematodes were also found in feces. RESULTS: Upon confirmation, the patient was diagnosed with a pulmonary infection caused by Strongyloides stercoralis. After treatment with albendazole, the symptoms improved, and the patient was discharged. CONCLUSION: In this case report, combination of microscopic examination of sputum and alveolar lavage fluid and CT scan were used to quickly identify the cause of the patient, it provides a diagnostic basis and method for clinical treatment.

6.
Aging (Albany NY) ; 14(4): 1879-1890, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35202002

RESUMO

OBJECTIVES: The aim of this study was to explore the expression of Galectin-9 in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), evaluate its clinicopathological significance, and investigate whether Galecin-9 expression has prognostic value in HBV-associated HCC. METHODS: Immunohistochemistry staining was performed to examine the expression of Galectin-9 in paraffin-embedded tissues from 140 cases of HBV-associated HCC specimens. The association between Gal-9 expression, clinicopathological features and prognosis was analyzed by Kaplan-Meier method, log-rank test and Cox regression analysis. Dual immunofluorescence (IF) staining was performed to identify the cell types that have positive Gal-9 expression. RESULTS: Among the 140 cases of HBV-associated HCC, 39 (27.9%) cases showed high Gal-9 expression (score≥6), 21 (15%) cases showed moderate Gal-9 expression (6>score≥3), 33 (23.6%) cases showed weak Gal-9 expression (3>score>0), and 47 (33.6%) cases had no detectable Gal-9 expression (score=0). Positive Gal-9 expression (score>0) was associated with lymph node metastasis (P=0.029), Ki-67 proliferation index (P=0.009) and poor prognosis. Univariate and multivariate analyses showed that Gal-9 expression could be used as an independent prognostic marker for HBV-associated HCC. Dual IF staining indicated that Gal-9 was mainly expressed in CD68+CD163+ Kupffer cells (KCs) in HBV-associated HCC. CONCLUSIONS: Gal-9 was specifically expressed in certain HBV-associated HCC. Positive Gal-9 expression was significantly associated with poor prognosis, and Gal-9 could be used as a prognostic marker in HBV-associated HCC. Specific expression of Gal-9 on KCs indicated it may have immunosuppressive function in HBV-associated HCC.


Assuntos
Carcinoma Hepatocelular , Galectinas/metabolismo , Hepatite B , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Hepatite B/complicações , Vírus da Hepatite B , Humanos , Neoplasias Hepáticas/patologia , Prognóstico
7.
Int J Environ Health Res ; : 1-16, 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34983264

RESUMO

Evidence of more recent studies should be updated to evaluate the effect of long-term exposure to particulate matter (PM) on blood pressure and hypertension.        Studies of long-term effects of PM1, PM2.5 and PM10 on blood pressure (SBP, DBP, MAP), hypertension were searched in Pubmed, Web of Science and Embase before May, 2021. Meta-analysis of 41 studies showed that exposure to PM1, PM2.5 was associated with SBP (1.76 mmHg (95%CI:0.71, 2.80) and 0.63 mmHg (95%CI:0.40, 0.85), per 10 µg/m3 increase in PM), all three air pollutants (PM1, PM2.5, PM10) was associated with DBP (1.16 mmHg (95%CI:0.34, 1.99), 0.31 mmHg (95%CI:0.16, 0.47), 1.17 mmHg (95%CI:0.24, 2.09), respectively. As for hypertension, PM1, PM2.5 and PM10 were all significantly associated with higher risk of hypertension (OR=1.27 (95%CI:1.06, 1.52), 1.15 (95%CI:1.10, 1.20) and 1.11 (95%CI:1.07, 1.16). In conclusion, our study indicated a positive association between long-term exposure to particulate matter and increased blood pressure, hypertension.

8.
BMC Genomics ; 23(1): 20, 2022 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-34996351

RESUMO

BACKGROUND: Carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP) causes serious infections with significant morbidity and mortality. However, the epidemiology and transmission mechanisms of CR-hvKP and the corresponding carbapenem-resistant plasmids require further investigation. Herein, we have characterized an ST11 K. pneumoniae strain EBSI041 from the blood sample encoding both hypervirulence and carbapenem resistance phenotypes from a patient in Egypt. RESULTS: K. pneumoniae strain EBSI041 showed multidrug-resistance phenotypes, where it was highly resistant to almost all tested antibiotics including carbapenems. And hypervirulence phenotypes of EBSI041 was confirmed by the model of Galleria mellonella infection. Whole-genome sequencing analysis showed that the hybrid plasmid pEBSI041-1 carried a set of virulence factors rmpA, rmpA2, iucABCD and iutA, and six resistance genes aph(3')-VI, armA, msr(E), mph(E), qnrS, and sul2. Besides, blaOXA-48 and blaSHV-12 were harboured in a novel conjugative IncL-type plasmid pEBSI041-2. The blaKPC-2-carrying plasmid pEBSI041-3, a non-conjugative plasmid lacking the conjugative transfer genes, could be transferred with the help of pEBSI041-2, and the two plasmids could fuse into a new plasmid during co-transfer. Moreover, the emergence of the p16HN-263_KPC-like plasmids is likely due to the integration of pEBSI041-3 and pEBSI041-4 via IS26-mediated rearrangement. CONCLUSION: To the best of our knowledge, this is the first report on the complete genome sequence of KPC-2- and OXA-48-coproducing hypervirulent K. pneumoniae from Egypt. These results give new insights into the adaptation and evolution of K. pneumoniae during nosocomial infections.


Assuntos
Infecções por Klebsiella , Klebsiella pneumoniae , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Carbapenêmicos/farmacologia , Egito , Humanos , Infecções por Klebsiella/epidemiologia , Klebsiella pneumoniae/genética , Plasmídeos/genética , beta-Lactamases/genética
9.
FASEB J ; 36(2): e22102, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34972243

RESUMO

Myofibroblasts, or activated fibroblasts, play a critical role in the process of renal fibrosis. Targeting myofibroblasts to inhibit their activation or induce specific cell death has been considered to be an effective strategy to attenuate renal fibrosis. However, specific biomarkers for myofibroblasts are needed to ensure the efficacy of these strategies. Here, we verified that CD248 was mainly expressed in myofibroblasts in patients with chronic kidney disease, which was inversely correlated with renal function. The same result was also confirmed in renal fibrotic mice induced by unilateral ureteral obstruction and aristolochic acid nephropathy. By using an antibody-drug conjugate (ADC) named IgG78-DM1, in which maytansinoid (DM1) was linked to a fully human antibody IgG78 through an uncleavable SMCC linker, we demonstrated that it could effectively bind with and kill CD248+ fibroblasts in vitro and alleviate renal fibrosis in mice models. Besides, we confirmed that IgG78-DM1 had qualified biosafety in vivo. Our results confirmed that CD248 can be used as a specific marker for myofibroblasts, and specific killing of CD248+ myofibroblasts by IgG78-DM1 has excellent anti-fibrotic effect in renal fibrotic mice. Our study expanded the application of ADC and provided a novel strategy for the treatment of renal fibrosis.


Assuntos
Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Sistemas de Liberação de Medicamentos , Imunoconjugados/farmacologia , Maitansina/farmacologia , Miofibroblastos/metabolismo , Insuficiência Renal Crônica , Animais , Fibrose , Masculino , Camundongos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo
10.
Front Oncol ; 11: 771036, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34869004

RESUMO

BACKGROUND: Urothelial carcinoma of the bladder (UCB) is a common cancer of the urinary system. Despite substantial improvements in available treatment options, the survival outcome of patients with advanced UCB is unsatisfactory. Therefore, it is necessary to identify new prognostic biomarkers for monitoring and therapy guidance of UCB. In recent years, prostate-specific membrane antigen (PSMA) and CD248 have been identified promising candidate bio7markers. METHODS: In this study, we first examined PSMA and CD248 expression in tissues from 124 patients with UCB using immunohistochemical and immunofluorescent staining. We then analyzed the association between the expression of the two biomarkers and other clinicopathological features and prognosis. Finally, we performed bioinformatic analysis of CD248 and FOLH 1 (PSMA) using the TCGA-BLCA dataset to explore the underlying mechanism of PSMA and CD248 in the progression of UCB. RESULTS: Among the 124 cases, PSMA and CD248 were confirmed to be expressed in tumor-associated vessels. Vascular PSMA and CD248 expression levels were associated significantly with several deteriorated clinicopathological features. Furthermore, using univariate and multivariate Cox analyses, high vascular PSMA and CD248 expression levels were observed to be associated significantly with poor prognosis in patients with UCB. As risk factors, both PSMA and CD248 expression showed good performance to predict prognosis. Furthermore, combining these vascular molecules with other clinical risk factors generated a risk score that could promote predictive performance. Bioinformatic analysis showed that both PSMA and CD248 might contribute to angiogenesis and promote further progression of UCB. CONCLUSION: Both PSMA and CD248 are specifically expressed in the tumor-associated vasculature of UCB. These two molecules might be used as novel prognostic biomarkers and vascular therapeutic targets for UCB.

11.
Front Oncol ; 11: 773063, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34970489

RESUMO

BACKGROUND: The tumor microenvironment (TME) plays an important role in the progression of renal cell carcinoma (RCC). Cancer-associated fibroblasts (CAFs) are considered to constitute a major component of the TME and participate in various tumor-promoting molecular events. We have previously confirmed that CD248 represents a promising biomarker of CAFs, which may provide insight into CAF-based tumor-promoting effects. However, CAF-mediated tumor progression and the potential mechanism of CD248 remain largely unknown in RCC patients. METHODS: Expression profiling and clinical data of RCC patients were obtained from The Cancer Genome Atlas (TCGA) database. An MCP-counter algorithm and Kaplan-Meier survival analysis were performed to explore the prognostic value of CAFs and CD248, respectively. A Pearson correlation coefficient test and Student's t-test were employed to evaluate the relationship between immunosuppressive TME and CD248 or CAFs. Immunohistochemistry and immunofluorescence staining were performed to confirm CD248 expression within CAFs. CD248-specific siRNA was used to investigate the potential function of CD248 in CAF tumor promotion. Differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), and enrichment analysis were conducted to clarify the function of CD248+ CAFs in RCC progression and the associated regulatory mechanism. RESULTS: CD248 overexpression and CAF infiltration could predict poor RCC prognosis, which may involve the immunosuppressive TME. CD248 may serve as a promising CAFs biomarker and be involved with the tumor-promoting effect of CAFs. Moreover, CD248+ CAF infiltration may contribute to RCC progression and an immunosuppressive TME through cell-extracellular matrix (ECM) interactions and metabolism regulation. CONCLUSION: CD248+ CAFs participate in the regulation of RCC progression and immunosuppressive TME, which may represent a novel prognostic and therapeutic target for RCC.

12.
Theranostics ; 11(17): 8396-8411, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34373749

RESUMO

Background and Aims: The aims of this study were to establish a maximum standardized uptake value (SUVmax) cutoff to discriminate clinically significant prostate cancer (csPCa) from benign prostate disease (BPD) by 68Ga-labeled prostate-specific membrane antigen (68Ga-PSMA-11) positron emission tomography/computed tomography (PET/CT) in patients with suspected prostate cancer (PCa), and to perform a prospective real-world validation of this cutoff value. Methods: The study included a training cohort to identify an SUVmax cutoff value and a prospective real-world cohort to validate it. A retrospective analysis assessed 135 patients with suspected PCa in a large tertiary care hospital in China who underwent 68Ga-PSMA-11 PET/CT. All patients were suspected of having PCa based on symptoms, digital rectal examination (DRE), total prostate-specific antigen (tPSA) level, and multiparameter magnetic resonance imaging (mpMRI). The 68Ga-PSMA PET/CT results were evaluated using histopathological results from transrectal ultrasound-guided 12-core biopsy with necessary targeted biopsy as references. Patients with Gleason scores (GS) ≥7 from the biopsy results were diagnosed with csPCa, and patients with negative biopsy and follow-up results were diagnosed with BPD. Receiver operating characteristic (ROC) curve analysis was used to identify the optimal SUVmax cutoff value. The cutoff value was prospectively validated in 58 patients with suspected PCa. The diagnostic benefits of the cutoff value for clinical decision making were also evaluated. Results: According to ROC curve analysis, the most appropriate SUVmax cutoff value for discriminating csPCa from BPD was 5.30 (sensitivity, 85.85%; specificity, 86.21%; area under the curve [AUC], 0.893). The cutoff achieved a sensitivity of 83.33%, a specificity of 81.25%, a positive predictive value (PPV) of 92.11%, a negative predictive value (NPV) of 65.00%, and an accuracy of 82.76% in the prospective validation cohort. Metastases were used as an indicator to reduce false negative results in patients with SUVmax ≤ 5.30. In patients without metastases, an SUVmax value of 5.30 was also the best cutoff to diagnose localized csPCa (sensitivity, 80.43%; specificity, 86.21%; AUC, 0.852). The cutoff discriminated localized csPCa from BPD with a sensitivity of 76.19%, a specificity of 81.25%, a PPV of 84.21%, an NPV of 72.22%, and an accuracy of 78.38% in the prospective validation cohort. The cutoff, combined with metastases, achieved an accuracy of 89.12% in all patients, increasing accuracy by 8.29% and reducing equivocal results compared with manual reading. There was a strong correlation between SUVmax and PSMA expression (rs = 0.831, P < 0.001) and a moderate correlation between SUVmax and GS (rs = 0.509, P < 0.001). The PSMA expression and SUVmax values of patients with csPCa were significantly higher than those of patients with BPD (P < 0.001). Conclusion: We established and prospectively validated the best SUVmax cutoff value (5.30) for discriminating csPCa from BPD with high accuracy in patients with suspected PCa. 5.30 is an effective cutoff to discriminate csPCa patients with or without metastases. The cutoff may provide a potential tool for the precise identification of csPCa by 68Ga-PSMA PET/CT, ensuring high accuracy and reducing equivocal results.


Assuntos
Antígenos de Superfície/análise , Glutamato Carboxipeptidase II/análise , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/normas , Neoplasias da Próstata/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Biópsia , China , Radioisótopos de Gálio , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Próstata/química , Próstata/patologia , Antígeno Prostático Específico/análise , Neoplasias da Próstata/metabolismo , Curva ROC , Estudos Retrospectivos
13.
Signal Transduct Target Ther ; 6(1): 236, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34158475

RESUMO

Despite the successful use of the humanized monoclonal antibody trastuzumab (Herceptin) in the clinical treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer, the frequently occurring drug resistance remains to be overcome. The regulatory mechanisms of trastuzumab-elicited immune response in the tumor microenvironment remain largely uncharacterized. Here, we found that the nonclassical histocompatibility antigen HLA-G desensitizes breast cancer cells to trastuzumab by binding to the natural killer (NK) cell receptor KIR2DL4. Unless engaged by HLA-G, KIR2DL4 promotes antibody-dependent cell-mediated cytotoxicity and forms a regulatory circuit with the interferon-γ (IFN-γ) production pathway, in which IFN-γ upregulates KIR2DL4 via JAK2/STAT1 signaling, and then KIR2DL4 synergizes with the Fcγ receptor to increase IFN-γ secretion by NK cells. Trastuzumab treatment of neoplastic and NK cells leads to aberrant cytokine production characterized by excessive tumor growth factor-ß (TGF-ß) and IFN-γ, which subsequently reinforce HLA-G/KIR2DL4 signaling. In addition, TGF-ß and IFN-γ impair the cytotoxicity of NK cells by upregulating PD-L1 on tumor cells and PD-1 on NK cells. Blockade of HLA-G/KIR2DL4 signaling improved the vulnerability of HER2-positive breast cancer to trastuzumab treatment in vivo. These findings provide novel insights into the mechanisms underlying trastuzumab resistance and demonstrate the applicability of combined HLA-G and PD-L1/PD-1 targeting in the treatment of trastuzumab-resistant breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Antígenos HLA-G/genética , Receptor ErbB-2/genética , Receptores KIR2DL4/genética , Trastuzumab/farmacologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/genética , Anticorpos Monoclonais Humanizados/imunologia , Citotoxicidade Celular Dependente de Anticorpos/genética , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Humanos , Interferon gama/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Pessoa de Meia-Idade , Receptores de Células Matadoras Naturais/genética , Receptores de Células Matadoras Naturais/imunologia , Trastuzumab/efeitos adversos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
14.
Front Oncol ; 11: 658669, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33937073

RESUMO

PURPOSE: PLND (pelvic lymph node dissection)-validated nomograms are widely accepted clinical tools to determine the necessity of PLND by predicting the metastasis of lymph nodes (LNMs) in pelvic region. However, these nomograms are in lacking of a threshold to predict the metastasis of extrareolar lymph nodes beyond pelvic region, which is not suitable for PLND. The aim of this study is to evaluate a threshold can be set for current clinical PLND-validated nomograms to predict extrareolar LN metastases beyond pelvic region in high-risk prostate cancer patients, by using 68Ga-PSMA PET/CT as a reference to determine LN metastases (LNMs). EXPERIMENTAL DESIGN: We performed a retrospective analysis of 57 high-risk treatment-naïve PC patients in a large tertiary care hospital in China who underwent 68Ga-PSMA-617 PET/CT imaging. LNMs was detected by 68Ga-PSMA-617 PET/CT and further determined by imaging follow-up after anti-androgen therapy. The pattern of LN metastatic spread of PC patients were evaluated and analyzed. The impact of 68Ga-PSMA PET/CT on clinical decisions based on three clinical PLND-validated nomograms (Briganti, Memorial Sloan Kettering Cancer Center, Winter) were evaluated by a multidisciplinary prostate cancer therapy team. The diagnostic performance and the threshold of these nomograms in predicting extrareolar LNMs metastasis were evaluated via receiver operating characteristic (ROC) curve analysis. RESULTS: LNMs were observed in 49.1% of the patients by 68Ga-PSMA PET/CT, among which 65.5% of LNMs were pelvic-regional and 34.5% of LNMs were observed in extrareolar sites (52.1% of these were located above the diaphragm). The Briganti, MSKCC and Winter nomograms showed that 70.2%-71.9% of the patients in this study need to receive ePLND according to the EAU and NCCN guidelines. The LN staging information obtained from 68Ga-PSMA PET/CT would have led to changes of planned management in 70.2% of these patients, including therapy modality changes in 21.1% of the patients, which were mainly due to newly detected non-regional LNMs. The thresholds of nomograms to predict non-regional LNMs were between 64% and 75%. The PC patients with a score >64% in Briganti nomogram, a score >75% in MSKCC nomogram and a score >67% in Winter nomogram were more likely to have non-regional LNMs. The AUCs (Area under curves) of the clinical nomograms (Briganti, MSKCC and Winter) in predicting non-regional LNMs were 0.816, 0.830 and 0.793, respectively. CONCLUSIONS: By using 68Ga-PSMA PET/CT as reference of LNM, the PLND-validated clinical nomograms can not only predict regional LNMs, but also predict non-regional LNMs. The additional information from 68Ga-PSMA PET/CT may provide added benefit to nomograms-based clinical decision-making in more than two-thirds of patients for reducing unnecessary PLND. We focused on that a threshold can be set for current clinical PLND-validated nomograms to predict extrareolar LN metastases with an AUC accuracy of about 80% after optimizing the simple nomograms which may help to improve the efficiency for PC therapy significantly in clinical practice.

15.
Front Oncol ; 11: 644612, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33791227

RESUMO

Background: Renal cell carcinoma (RCC) is the most common malignancy in the urinary system. Despite substantial improvements in available treatment options, the survival outcome of advanced RCC is unsatisfactory. Identifying novel biomarkers to assist in early diagnosis and to screen patients who are sensitive to immunotherapy would be beneficial. CD248 is a promising candidate that deserves to be investigated. Methods: The Cancer Genome Atlas (TCGA) data set and clinical specimens were adopted to analyze the expression of CD248 between normal and tumor tissues. Univariate and multivariate Cox regression analyses were employed to identify independent prognostic factors and construct a CD248-based prognostic signature. The correlation among the present signature, tumor-infiltrating immune cells (TIICs), the tumor mutation burden (TMB), and immunomodulatory molecules was evaluated. The weighted gene co-expression network analysis (WGCNA), the enrichment analysis, and the miRNA correlation analysis were performed to explore the underlying mechanism of CD248 in the progression of RCC. Results: The overexpression of CD248 in RCC was related to a poor prognosis, and a CD248-based prognostic signature could precisely stratify patients with RCC with different survival outcomes regardless of the training or testing cohort. The present signature could reflect the immunosuppressive landscape of RCC (i.e., increased infiltration of regulatory T cells and upregulated immune checkpoints), accompanied by deteriorated clinicopathologic indexes. The TMB and immunostimulatory molecules expression also increased with the risk score generated from the present signature. CD248 co-expressed gene sets were identified through the WGCNA algorithm, and several immunosuppressive Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were significantly enriched. The result of CD248-correlated miRNA further emphasized the importance of CD248 in RCC. Conclusion: CD248 is a valuable biomarker to improve the diagnostic and therapeutic efficiency of RCC. The immunosuppressive effect of CD248 co-expressed genes may provide insight for the present study, and miRNA would help to reveal the mechanism of the expressive regulation of CD248.

16.
Biochem Biophys Res Commun ; 534: 134-140, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33341068

RESUMO

TIGIT is an emerging novel checkpoint target that is expressed on both tumor-infiltrating T cells and NK cells. Some current investigational antibodies targeting TIGIT have also achieved dramatic antitumor efficacy in late clinical research. Most recently, the relevance of NK cell-associated TIGIT signaling pathway to tumors' evasion of the immune system has been clearly revealed, which endows NK cells with a pivotal role in the therapeutic effects of TIGIT blockade. In this article, we describe a novel anti-TIGIT monoclonal antibody, AET2010, which was acquired from a phage-displayed human single-chain antibody library through a cell panning strategy. With emphasis on its regulation of NK cells, we confirmed the excellent ex vivo and in vivo antitumor immunity of AET2010 mediated by the NK-92MI cells. Intriguingly, our work also revealed that AET2010 displays a lower affinity but parallel avidity and activity relative to MK7684, an investigational monoclonal antibody from MSD, implying a reasonable balance of potency and potential side effects for AET2010. Together, these results are promising and warrant further development of AET2010.


Assuntos
Anticorpos Monoclonais/imunologia , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Receptores Imunológicos/imunologia , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/uso terapêutico , Células CHO , Linhagem Celular , Linhagem Celular Tumoral , Cricetulus , Citotoxicidade Imunológica , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/terapia , Biblioteca de Peptídeos , Receptores Imunológicos/química , Receptores Virais/metabolismo
17.
Ann Transl Med ; 9(23): 1741, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35071435

RESUMO

BACKGROUND: Renal cell carcinoma (RCC) is characterized by significant vascularization and immunogenicity, which contributes to drug resistance and immune escape. CD248, a pericytes marker in tumor vasculature, might help explain tumor microenvironment (TME) remodeling and serve as a novel therapeutic target. METHODS: Transcriptome data and clinical information of RCC patients were obtained from The Cancer Genome Atlas (TCGA) database. ESTIMATE and microenvironment cell population (MCP)-counter algorithms were adopted to calculate immune and stromal contents. The prognostic value of TME was evaluated via Kaplan-Meier and Wilcoxon signed rank test. Pearson's correlation coefficient was employed to explore the correlation between angiogenesis and TME, and the relationship between CD248 and TME or RCC progression. CD248 overexpression and vascular colocalization in RCC were confirmed via histology staining. The weighted gene coexpression network analysis (WGCNA) and enrichment analysis were performed to explore CD248-mediated regulatory mechanism in angiogenesis and TME remodeling. CD248-based drug response was predicted through CellMiner database. RESULTS: Tumor angiogenesis contributed to deteriorated RCC progression, which might be involved with immunosuppression. More specifically, upregulated immune checkpoints exhausted infiltrated T cells. CD248 overexpressed in RCC vessels correlated with TME and predicted a bad survival outcome. CD248 and coexpressed genes participated in angiogenesis and TME remodeling. Several clinical approved drugs that might inhibit CD248-mediated tumor promoting effects were selected. CONCLUSIONS: CD248 appears to contribute to angiogenesis and immunosuppressive TME, and may thus be a promising prognostic and therapeutic target for RCC. CD248-based medication guidance might benefit RCC patients.

18.
Aging (Albany NY) ; 12(24): 26199-26220, 2020 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-33346749

RESUMO

Ring finger protein 2 (RNF2) is an important component of polycomb repressive complex 1. RNF2 is upregulated in many kinds of tumors, and elevated RNF2 expression is associated with a poor prognosis in certain cancers. To assess the function of RNF2 in colorectal cancer, we examined RNF2 protein levels in 313 paired colorectal cancer tissues and adjacent normal tissues. We then analyzed the association of RNF2 expression with the patients' clinicopathologic features and prognoses. RNF2 expression was upregulated in colorectal cancer tissues and was associated with the tumor differentiation status, tumor stage and prognosis. In colorectal cancer cell lines, downregulation of RNF2 inhibited cell proliferation and induced apoptosis. Gene microarray analysis revealed that early growth response 1 (EGR1) was upregulated in RNF2-knockdown cells. Knocking down EGR1 partially reversed the inhibition of cell proliferation and the induction of apoptosis in RNF2-knockdown cells. RNF2 was enriched at the EGR1 promoter, where it mono-ubiquitinated histone H2A, thereby inhibiting EGR1 expression. These results indicate that RNF2 is oncogenic in colorectal cancer and may promote disease progression by inhibiting EGR1 expression. RNF2 is thus a potential prognostic marker and therapeutic target in colorectal cancer.


Assuntos
Apoptose/genética , Proliferação de Células/genética , Neoplasias Colorretais/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Complexo Repressor Polycomb 1/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Progressão da Doença , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Células HCT116 , Código das Histonas/genética , Humanos , Masculino , Pessoa de Meia-Idade , Complexo Repressor Polycomb 1/metabolismo , Prognóstico , Regiões Promotoras Genéticas , Ubiquitinação , Regulação para Cima
19.
Exp Ther Med ; 20(3): 1943-1952, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32782503

RESUMO

The present study aimed to investigate the association between drug resistance and class I, II and III integrons in Acinetobacter baumannii (ABA). Multilocus sequence typing (MLST) is a tool used to analyze the homology among house-keeping gene clusters in ABA and ABA prevalence and further provides a theoretical basis for hospitals to control ABA infections. A total of 96 clinical isolates of non-repeating ABA were harvested, including 74 carbapenem-resistant ABA (CRABA) and 22 non-CRABA strains, and used for bacterial identification and drug susceptibility analysis. Variable regions were sequenced and analyzed. Then, 7 pairs of housekeeping genes were amplified and sequenced via MLST and sequence alignment was performed against the Pub MLST database to determine sequence types (STs) strains and construct different genotypic evolutionary diagrams. The detection rate of CRABA class I integrons was 13.51% (10/74); no class II and III integrons were detected. However, class I, II and III integrons were not detected in non-CRABA strains. The variable regions of 9 of 10 class I integrons were amplified and 10 gene cassettes including aacC1, aac1, aadDA1, aadA1a, aacA4, dfrA17, aadA5, aadA1, aadA22 and aadA23 were associated with drug resistance. The 96 ABA strains were divided into 21 STs: 74 CRABA strains containing 9 STs, primarily ST208 and ST1145 and 22 non-CRABA strains containing 18 STs, primarily ST1145. Class I integrons are a critical factor underlying drug resistance in ABA. CRABA and non-CRABA strains differ significantly; the former primarily contained ST208 and ST1145, and the latter contained ST1145. Most STs were concentrated in intensive care units (ICUs) and the department of Neurology, with the patients from the ICUs being the most susceptible to bacterial infection. In the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, ABA is potentially horizontally transmitted and MLST can be used for clinical ABA genotyping.

20.
Sci Rep ; 10(1): 10963, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620790

RESUMO

The study was aimed at assessing the diagnostic performance of 68Ga-PSMA-617 PET/CT in the detection of prostate cancer (PCa) in patients with a prostate-specific antigen (PSA) level of 4-20 ng/ml and to compare its efficacy with that of multiparametric MRI (mpMRI). We analyzed the data of 67 consecutive patients with PSA levels of 4-20 ng/ml who almost simultaneously underwent 68Ga-PSMA-617 PET/CT and mpMRI. 68Ga-PSMA-617 PET/CT and mpMRI diagnostic performances were compared via receiver operating characteristic (ROC) curve analysis. Of the 67 suspected PCa cases, 33 had pathologically confirmed PCa. 68Ga-PSMA-617 PET/CT showed a patient-based sensitivity, specificity, and positive and negative predictive values (PPVs and NPVs) of 87.88%, 88.24%, 87.88%, and 88.24%, respectively. The corresponding values for mpMRI were 84.85%, 52.94%, 63.64%, and 78.26%. The area under the curve values for 68Ga-PSMA-617 PET/CT and mpMRI were 0.881 and 0.689, respectively. 68Ga-PSMA-617 PET/CT showed a better diagnostic performance than mpMRI in the detection of PCa in patients with PSA levels of 4-20 ng/ml.


Assuntos
Calicreínas/sangue , Imageamento por Ressonância Magnética Multiparamétrica , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Dipeptídeos , Ácido Edético/análogos & derivados , Isótopos de Gálio , Radioisótopos de Gálio , Compostos Heterocíclicos com 1 Anel , Humanos , Masculino , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética Multiparamétrica/estatística & dados numéricos , Oligopeptídeos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/estatística & dados numéricos , Valor Preditivo dos Testes , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Curva ROC , Compostos Radiofarmacêuticos , Sensibilidade e Especificidade
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