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1.
Bioorg Med Chem ; 69: 116891, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35764031

RESUMO

The treatment of acute ischemic stroke (AIS) remains a tough challenge in clinic. Here, we report the anti-AIS activity of R- and S-FMPB generated from hybridization of ring-opened R- and S-3-N-butylphthalide (R- and S-NBP) derivatives (R- and S-APB) with 4-fluro-edaravone (4-F-Eda), respectively. S-FMPB (10 mg/kg, iv) significantly improved the neurological score and alleviated cerebral infarction and edema of rats suffered from transient middle cerebral artery occlusion (tMCAO), superior to RS- and R-FMPB, as well as better than RS-FMPB by oral administration in previous studies. Importantly, S-FMPB is more active not only than the equimolar S-APB and 4-F-Eda alone or in combination but also than the clinical drugs NBP and edaravone (Eda) in combination at the equimolar doses. Furthermore, S-FMPB showed relative stability in plasma or liver microsome of rats but could be converted into two active metabolites (S-NBP and 4-F-Eda) in rats with good pharmacokinetic properties in terms of longer half-life period (t1/2) and mean residence time (MRT) as well as larger area under the concentration-time curve (AUC) of S-NBP than those from S-NBP and 4-F-Eda single or in combination by iv administration, suggesting that S-NBP and 4-F-Eda may synergistically play the anti-AIS activity. Our findings suggest that S-FMPB may be used as a potential anti-AIS agent to further study.


Assuntos
Benzofuranos , AVC Isquêmico , Fármacos Neuroprotetores , Acidente Vascular Cerebral , Animais , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Edaravone/uso terapêutico , AVC Isquêmico/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Acidente Vascular Cerebral/tratamento farmacológico
2.
Front Cell Dev Biol ; 10: 896080, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35733852

RESUMO

Background: Actin-related protein 2/3 complex subunit 2 (ARPC2) plays a fundamental role in actin filament nucleation and is critical for tumor cell migration and invasion. However, its abnormal expression, clinical significance, and biological function in human pan-cancer have been poorly explored. Thus, we focused on ARPC2 as an entry point for identifying novel pan-cancer prognostic biomarkers. Methods: The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases were used to assess the differential expression of ARPC2 in pan-cancer. The Human Protein Atlas was used for the tissue/cell-specific expression analysis of ARPC2. The genetic alteration information of ARPC2 was obtained from the cBioPortal database and the GSCALite platform. The prognostic value of ARPC2 was explored in pan-cancer using Cox regression and Kaplan-Meier analyses. Spearman correlation analysis was performed to investigate the relationship between ARPC2 expression and tumor mutational burden (TMB), DNA methyltransferases, microsatellite instability (MSI), immune-related genes, and mismatch repairs (MMRs). The ESTIMATE and CIBERSORT algorithms were used to evaluate the association between ARPC2 expression and the tumor microenvironment (TME) and immune infiltrating cells. We also conducted differential expression analysis of ARPC2 in hepatocellular carcinoma (HCC) tissues and cell lines using qPCR, western blotting, and immunohistochemistry and explored its role in tumor proliferation, migration, and invasion of HCC cells. Results: ARPC2 expression was significantly upregulated in multiple tumor types and significantly correlated with worse prognosis and higher clinicopathological stage. Genetic alterations and DNA methylation in tumor tissues may contribute to the aberrant expression of ARPC2. ARPC2 expression was significantly correlated with the tumor microenvironment (TME), infiltrating immune cells, TMB, microsatellite instability (MSI), and immune checkpoint-related genes in certain cancer types. In this experimental study, we found that the expression of ARPC2 was dramatically upregulated in HCC tissues and cell lines compared to adjacent liver tissues and normal liver cell lines. Functionally, ARPC2 silencing in HCC cells significantly inhibited cell proliferation, migration, and invasion, while the overexpression of ARPC2 promotes tumor proliferation, migration, and invasion. Conclusion: ARPC2 is a promising prognostic and immunological biomarker for multiple tumor types and is likely to play an important role in HCC progression and metastasis.

3.
Front Med (Lausanne) ; 9: 850343, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35685422

RESUMO

Introduction: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with poor prognosis. Epithelial-mesenchymal transition (EMT) is crucial for cancer progression and metastasis. Thus, we aimed to construct an EMT-related lncRNA signature for predicting the prognosis of HCC patients. Methods: Cox regression analysis and LASSO regression method were used to build an EMT-related lncRNAs risk signature based on TCGA database. Kaplan-Meier survival analysis was conducted to compare the overall survival (OS) in different risk groups. ROC curves and Cox proportional-hazards analysis were performed to evaluate the performance of the risk signature. RT-qPCR was conducted in HCC cell lines and tissue samples to detect the expression of some lncRNAs in this risk model. Furthermore, a nomogram involving the risk score and clinicopathological features was built and validated with calibration curves and ROC curves. In addition, we explored the association between risk signature and tumor immunity, somatic mutations status, and drugs sensitivity. Results: Twelve EMT-related lncRNAs were obtained to construct the prognostic risk signature for patients with HCC. The Kaplan-Meier curve analysis revealed that patients in the high-risk group had worse overall survival (OS) than those in low-risk group. ROC curves and Cox regression analysis suggested the risk signature could predict HCC survival exactly and independently. The prognostic value of the risk model was confirmed in the testing and entire groups. We also found AC099850.3 and AC092171.2 were highly expressed in HCC cells and HCC tissues. The nomogram could accurately predict survival probability of HCC patients. Gene set enrichment analysis (GSEA) and gene ontology (GO) analysis showed that cancer-related pathways and cell division activity were enriched in high-risk group. The SNPs showed that the prevalence of TP53 mutations was significantly different between high- and low-risk groups; the TP53 mutations and the high TMB were both associated with a worse prognosis in patients with HCC. We also observed widely associations between risk signature and drugs sensitivity in HCC. Conclusion: A novel EMT-related lncRNAs risk signature, including 12 lncRNAs, was established and identified in patients with HCC, which can accurately predict the prognosis of HCC patients and may be used to guide individualized treatment in the clinical practice.

6.
Eur Radiol ; 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35381853

RESUMO

OBJECTIVES: Objective response rate (ORR) under mRECIST criteria after transarterial chemoembolization (TACE) is a well-perceived surrogate endpoint of overall survival (OS). However, its optimal time point remains controversial and may be influenced by tumor burden. We aim to investigate the surrogacy of initial/best ORR in relation to tumor burden. METHODS: A total of 1549 eligible treatment-naïve patients with unresectable hepatocellular carcinoma (HCC), Child-Pugh score ≤ 7, and performance status score ≤ 1 undergoing TACE between January 2010 and May 2016 from 17 academic hospitals were retrospectively analyzed. Based on "six-and-twelve" criteria, tumor burden was graded as low, intermediate, and high if the sum of the maximum tumor diameter and tumor number was ≤ 6, > 6 but ≤ 12, and > 12, respectively. RESULTS: Both initial and best ORRs interacted with tumor burden. Initial and best ORRs could equivalently predict and correlate with OS in low (adjusted HR, 2.55 and 2.95, respectively, both p < 0.001; R = 0.84, p = 0.035, and R = 0.97, p = 0.002, respectively) and intermediate strata (adjusted HR, 1.81 and 2.22, respectively, both p < 0.001; R = 0.74, p = 0.023, and R = 0.9, p = 0.002, respectively). For high strata, only best ORR exhibited qualified surrogacy (adjusted HR, 2.61, p < 0.001; R = 0.70, p = 0.035), whereas initial ORR was not significant (adjusted HR, 1.08, p = 0.357; R = 0.22, p = 0.54). CONCLUSIONS: ORR as surrogacy of OS is associated with tumor burden. For patients with low/intermediate tumor burden, initial ORR should be preferred in its early availability upon similar sensitivity, whereas for patients with high tumor burden, best ORR has optimal sensitivity. Timing of OR assessment should be tailored according to tumor burden. KEY POINTS: • This is the first study utilizing individual patient data to comprehensively analyze the surrogacy of ORR with a long follow-up period. • Optimal timing of ORR assessment for predicting survival should be tailored according to tumor burden. • For patients with low and intermediate tumor burden, initial ORR is optimal for its timeliness upon similar sensitivity with best ORR. For patients with high tumor burden, best ORR has optimal sensitivity.

7.
J Med Chem ; 65(8): 5902-5925, 2022 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-35412827

RESUMO

Protein S-nitrosation (SNO), a posttranslational modification (PTM) of cysteine (Cys) residues elicited by nitric oxide (NO), regulates a wide range of protein functions. As a crucial form of redox-based signaling by NO, SNO contributes significantly to the modulation of physiological functions, and SNO imbalance is closely linked to pathophysiological processes. Site-specific identification of the SNO protein is critical for understanding the underlying molecular mechanisms of protein function regulation. Although careful verification is needed, SNO modification data containing numerous functional proteins are a potential research direction for druggable target identification and drug discovery. Undoubtedly, SNO-related research is meaningful not only for the development of NO donor drugs but also for classic target-based drug design. Herein, we provide a comprehensive summary of SNO, including its origin and transport, identification, function, and potential contribution to drug discovery. Importantly, we propose new views to develop novel therapies based on potential protein SNO-sourced targets.


Assuntos
Cisteína , Proteína S , Cisteína/química , Óxido Nítrico/metabolismo , Nitrosação , Processamento de Proteína Pós-Traducional , Proteína S/metabolismo , Proteínas/metabolismo
8.
Front Mol Biosci ; 9: 840412, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35355509

RESUMO

Background: Hepatocellular carcinoma (HCC) is a tumor with high morbidity and mortality worldwide. lysine acetylation regulators (LARs) dynamically regulate Lysine acetylation modification which plays an important regulatory role in cancer. Therefore, we aimed to explore the potential clinical prognostic value of LARs in HCC. Methods: Differentially expressed LARs in normal liver and HCC tissues were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. To identify genes with prognostic value and establish the risk characteristics of LARs, consensus clustering was employed. We used univariate Cox regression survival analysis and LASSO Cox regression based on LARs to determine the independent prognostic signature of HCC. CIBERSORT and Gene Set Enrichment Analysis (GSEA) were used to estimate immune infiltration and functional enrichment analysis respectively. The expression of LAR was detected by Real-time quantitative polymerase chain reaction (RT-qPCR). statistical analyses were conducted using SPSS and R software. Results: In this study, the 33 LARs expression data and corresponding clinical information of HCC were obtained using TCGA and ICGC datasets. We found majority of the LARs were differentially expressed. Consensus cluster analysis was carried out based on the TCGA cohort, and three HCC subtypes (cluster 1, 2, and 3) were obtained. The LA3 subgroup had the worst clinical outcomes. Nine key LARs were identified to affect prognosis. The results showed that LARs signature has a strong independent prognostic value in HCC patients, whether in the training datasets or in the testing datasets. GSEA results showed that various tumor-related processes and pathways were abundant in the high-risk groups. RT-qPCR results showed that HAT1, HDAC1, HDAC2, HDAC4, and HDAC11 were highly expressed in HCC cells. Conclusion: Our results suggest that LARs play critical roles in HCC and are helpful for individual prognosis monitoring and clinical decision-making of HCC.

9.
Front Oncol ; 12: 763842, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35280776

RESUMO

Background: The presence of microvascular invasion (MVI) is considered an independent prognostic factor associated with early recurrence and poor survival in hepatocellular carcinoma (HCC) patients after resection. Artificial intelligence (AI), mainly consisting of non-deep learning algorithms (NDLAs) and deep learning algorithms (DLAs), has been widely used for MVI prediction in medical imaging. Aim: To assess the diagnostic accuracy of AI algorithms for non-invasive, preoperative prediction of MVI based on imaging data. Methods: Original studies reporting AI algorithms for non-invasive, preoperative prediction of MVI based on quantitative imaging data were identified in the databases PubMed, Embase, and Web of Science. The quality of the included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) scale. The pooled sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) were calculated using a random-effects model with 95% CIs. A summary receiver operating characteristic curve and the area under the curve (AUC) were generated to assess the diagnostic accuracy of the deep learning and non-deep learning models. In the non-deep learning group, we further performed meta-regression and subgroup analyses to identify the source of heterogeneity. Results: Data from 16 included studies with 4,759 cases were available for meta-analysis. Four studies on deep learning models, 12 studies on non-deep learning models, and two studies compared the efficiency of the two types. For predictive performance of deep learning models, the pooled sensitivity, specificity, PLR, NLR, and AUC values were 0.84 [0.75-0.90], 0.84 [0.77-0.89], 5.14 [3.53-7.48], 0.2 [0.12-0.31], and 0.90 [0.87-0.93]; and for non-deep learning models, they were 0.77 [0.71-0.82], 0.77 [0.73-0.80], 3.30 [2.83-3.84], 0.30 [0.24-0.38], and 0.82 [0.79-0.85], respectively. Subgroup analyses showed a significant difference between the single tumor subgroup and the multiple tumor subgroup in the pooled sensitivity, NLR, and AUC. Conclusion: This meta-analysis demonstrates the high diagnostic accuracy of non-deep learning and deep learning methods for MVI status prediction and their promising potential for clinical decision-making. Deep learning models perform better than non-deep learning models in terms of the accuracy of MVI prediction, methodology, and cost-effectiveness. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php? RecordID=260891, ID:CRD42021260891.

10.
Front Oncol ; 11: 754881, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34692541

RESUMO

BACKGROUND: Microsatellite stability (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is resistant to immune checkpoint inhibitors. Studies have shown that antiangiogenic drugs combined with programmed death receptor-1 (PD-1) inhibitors can improve immunosuppression. The purpose of this study was to compare the efficacy of fruquintinib combined with PD-1 inhibitor (FP) and regorafenib combined with PD-1 inhibitor (RP) in the treatment of advanced mCRC with MSS or pMMR. MATERIALS AND METHODS: We retrospectively collected advanced MSS or pMMR mCRC patient data from The Second Affiliated Hospital of Nanchang, China, from June 2019 to March 2021. Then, we analyzed and compared the efficacy and safety of FP and RP. RESULTS: A total of 51 patients who met the criteria were divided into FP (n = 28) and RP groups (n = 23). The overall response rate of the FP and RP groups was 7.1% and 8.7% and the disease control rate was 89.3% and 56.5%, respectively. The median progression-free survival (PFS) time was higher in the FP group than in the RP group (6.4 vs. 3.9 months, respectively; P = 0.0209). Patients with no liver metastasis, KRAS wild type, and left colon tumor may benefit from FP. Eight patients (15.7%) had grade 3 toxicity related to treatment. Cox multivariate regression analysis showed that the treatment method was an independent risk factor for median PFS time. CONCLUSION: Our study indicates that FP could improve PFS time of patients with advanced mCRC compared with RP.

12.
J Med Chem ; 64(15): 10919-10933, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34292749

RESUMO

The treatment of ischemic stroke (IS) remains a big challenge in clinics, and it is urgently needed to develop novel, safe, and effective medicines against IS. Here, we report the design, synthesis, and biological evaluation of organic NO2- donors as potential agents for the treatment of IS. The representative compound 4a was able to slowly generate low concentrations of NO2- by reaction with a thiol-containing nucleophile, and the NO2- was selectively converted into NO under ischemic/hypoxia conditions to protect primary rat neurons from oxygen-glucose deprivation and recovery (OGD/R)-induced cytotoxicity by enhancing the Nrf2 signaling and activating the NO/cGMP/PKG pathway. Treatment with 4a at 2 h before or after ischemia mitigated the ischemia/reperfusion-induced brain injury in middle cerebral artery occlusion (MCAO) rats by producing NO and enhancing Nrf2 signaling. Furthermore, 4a significantly promoted endothelial cell proliferation and angiogenesis within the ischemic penumbra. Our findings suggest that this type of NO2- donors, like 4a, may be valuable to fight IS and other ischemic diseases.


Assuntos
Desenho de Fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Nitritos/farmacologia , Animais , Relação Dose-Resposta a Droga , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Estrutura Molecular , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Nitritos/síntese química , Nitritos/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
13.
Curr Top Med Chem ; 21(24): 2213-2229, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34218787

RESUMO

Biofilms are among the most important causes of nosocomial and recurrent infections as biofilms confer antibiotic resistance to pathogenic bacteria and protect them from the host's immune system. Thus, it is imperative to investigate effective therapeutic agents to counteract biofilms. As an important signaling molecule, Nitric Oxide (NO) plays a crucial role in various biological and pathological processes. NO could disperse biofilm and restore the drug sensitivity by reducing intracellular cyclic-diguanosine monophosphate (c-di-GMP) levels. This review highlights recent advances on antibacterial and antibiofilm effects of NO when NO was co-administered with other antimicrobial agents. A significant improvement in drug permeability and biofilm cell targeting and reduced cytotoxicity could be attained with this strategy. In this review, we briefly lay out challenges and propose future directions in this appealing avenue of research on NO-based therapy for biofilm eradication.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Óxido Nítrico/farmacologia , Animais , Antibacterianos/uso terapêutico , Humanos , Óxido Nítrico/uso terapêutico
14.
Front Mol Biosci ; 8: 690151, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34307456

RESUMO

The actin-related protein 2/3 complex (Arp2/3) is a major actin nucleator that has been widely reported and plays an important role in promoting the migration and invasion of various cancers. However, the expression patterns and prognostic values of Arp2/3 subunits in hepatocellular carcinoma (HCC) remain unclear. In this study, The Cancer Genome Atlas (TCGA) and UCSC Xena databases were used to obtain mRNA expression and the corresponding clinical information, respectively. The differential expression and Arp2/3 subunits in HCC were analyzed using the "limma" package of R 4.0.4 software. The prognostic value of each subunit was evaluated using Kaplan-Meier survival analysis and Cox proportional hazards regression analyses. The results revealed that mRNA expression of Arp2/3 members (ACTR2, ACTR3, ARPC1A, APRC1B, ARPC2, ARPC3, ARPC4, ARPC5, and ARPC5L) was upregulated in HCC. Higher expression of Arp2/3 members was significantly correlated with worse overall survival (OS) and shorter progression-free survival (PFS) in HCC patients. Cox proportional hazards regression analyses demonstrated that ACTR3, ARPC2, and ARPC5 were independent prognostic biomarkers of survival in patients with HCC. The relation between tumor immunocyte infiltration and the prognostic subunits was determined using the TIMER 2.0 platform and the GEPIA database. Gene set enrichment analysis (GSEA) was performed to explore the potential mechanisms of prognostic subunits in the carcinogenesis of HCC. The results revealed that ACTR3, ARPC2, and ARPC5 were significantly positively correlated with the infiltration of immune cells in HCC. The GSEA results indicated that ACTR3, ARPC2, and ARPC5 are involved in multiple cancer-related pathways that promote the development of HCC. In brief, various analyses indicated that Arp2/3 complex subunits were significantly upregulated and predicted worse survival in HCC, and they found that ACTR3, ARPC2, and ARPC5 could be used as independent predictors of survival and might be applied as promising molecular targets for diagnosis and therapy of HCC in the future.

15.
Lancet Oncol ; 22(7): 977-990, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143971

RESUMO

BACKGROUND: China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2-3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. METHODS: This randomised, open-label, phase 2-3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab-bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. FINDINGS: Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8-46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab-bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached-not reached] vs 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). The most common grade 3-4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab-bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab-bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab-bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). INTERPRETATION: Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. FUNDING: Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Medicamentos Biossimilares/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , China , Progressão da Doença , Feminino , Hepatite B/virologia , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Sorafenibe/efeitos adversos , Fatores de Tempo , Adulto Jovem
16.
World J Surg Oncol ; 19(1): 168, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112190

RESUMO

BACKGROUND: Sorafenib was reported as a useful adjuvant treatment in patients with hepatocellular carcinoma who underwent surgical resection. However, its therapeutic value remains controversial. This meta-analysis examined the available data regarding the efficacy and safety of sorafenib in patients with hepatocellular carcinoma after radical surgery. METHODS: The meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was registered in advance with PROSPERO (CRD42021233868). We searched PubMed, Embase, Cochrane Library, and Web of Science to identify eligible studies. Overall survival, recurrence-free survival, and recurrence rates were analyzed, and adverse events were reviewed. Hazard ratios or pooled risk ratios with 95% CIs were collected and analyzed using STATA version 12.0 in a fixed-effects or random-effects meta-analysis model. RESULTS: In total, 2655 patients from 13 studies were ultimately included in this meta-analysis. The combined results illustrated that sorafenib was associated with better overall survival than the control (hazard ratio = 0.71, 95% CI = 0.59-0.86; P < 0.001). Similarly, the drug also improved recurrence-free survival (hazard ratio = 0.68, 95% CI = 0.54-0.86, P = 0.001). Combined data revealed that patients treated with sorafenib after resection had a lower recurrence rate (pooled risk ratio = 0.78, 95% CI = 0.68-0.90, P < 0.001). The primary adverse events were hand-foot skin reaction, fatigue, and diarrhea of mild-to-moderate severity, whereas grade 4 adverse events were rare (< 1%). CONCLUSIONS: This meta-analysis demonstrated that adjuvant sorafenib therapy after resection in patients with hepatocellular carcinoma could prolong overall survival and recurrence-free survival and reduce recurrence rates without intolerable side effects. However, more evidence is needed before reaching a definitive conclusion.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/cirurgia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/tratamento farmacológico , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Prognóstico , Sorafenibe/uso terapêutico , Resultado do Tratamento
17.
Drug Des Devel Ther ; 15: 1653-1666, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33935492

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is an incurable disease that urgently needs therapeutic approaches. Based on the therapeutic effects of fasudil and dichloroacetate (DCA) on PAH, we aimed to explore the effects and potential mechanism of a new salt, fasudil dichloroacetate (FDCA), in a SU5416 plus hypoxia (SuHx)-induced rat model of PAH. METHODS: The rat model of PAH was established by a single subcutaneous injection of SU5416 (20 mg/kg) followed by hypoxia (10% O2) exposure for 3 weeks. FDCA (15, 45, or 135 mg/kg i.g. daily) or the positive control, bosentan (100 mg/kg i.g. daily), were administered from the first day after SU5416 injection. After 3-week hypoxia, hemodynamic parameters, and histological changes of the pulmonary arterial vessels and right ventricle (RV) were assessed. Additionally, in vitro, the effects of FDCA (50 µM), compared with equimolar doses of fasudil, DCA, or fasudil+DCA, on the proliferation, migration, and contraction of human pulmonary arterial smooth muscle cell (PASMC) under hypoxia (1% O2) were evaluated. RESULTS: FDCA dose-dependently attenuated SuHx-induced PAH, with significant reductions in RV systolic pressure, pulmonary artery wall thickness, pulmonary vessel muscularization, perivascular fibrosis, as well as RV hypertrophy and fibrosis. In vitro, FDCA inhibited hypoxia-induced PASMC proliferation, migration, and contraction to a greater degree than fasudil or DCA alone by restoring mitochondrial function, reducing intracellular Ca2+, and inhibiting calcium/calmodulin-dependent kinase (Ca2+/CaMK) activity as well as Rho-kinase activity. CONCLUSION: FDCA ameliorates hypoxia-induced PASMC dysfunction by inhibiting both Ca2+/CaMK and Rho-kinase signaling pathways, as well as maintaining mitochondrial homeostasis, thus alleviating SuHx-induced PAH.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Ácido Dicloroacético/farmacologia , Hipóxia/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Indóis , Masculino , Miócitos de Músculo Liso/patologia , Hipertensão Arterial Pulmonar/induzido quimicamente , Artéria Pulmonar/patologia , Pirróis , Ratos , Ratos Sprague-Dawley
18.
Biomater Sci ; 9(5): 1816-1825, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33458722

RESUMO

Bond cleavage bioorthogonal chemistry has been widely employed to restore or activate proteins or prodrugs. Nitric oxide (NO), as a free radical molecule, has joined the clinical arena of cancer therapy, since high levels of NO could produce a cancer cell growth inhibitory effect. However, the spatiotemporal controlled release of NO remains a great challenge, and bioorthogonal chemistry may open a new window. Herein, we described a class of O2-3-isocyanopropyl diazeniumdiolates 3a-f as new bioorthogonal NO precursors, which can be effectively uncaged via tetrazine-mediated bond cleavage reactions to liberate NO and acrolein in living cancer cells, exhibiting potent antiproliferative activity. Furthermore, 3a and tetrazine BTZ were respectively encapsulated into two liposomes. It was found that simultaneous administrations of the two liposomes could specifically release large amounts of NO in the implanted cancer cells in zebrafish, thus generating potent tumor suppression activity in vivo. Our findings indicate that the TZ-labile NO precursors could serve to expand the NO-based smart therapeutics and the scope of bioorthogonal chemistry utility in vivo in the near future.


Assuntos
Compostos Heterocíclicos , Pró-Fármacos , Animais , Preparações de Ação Retardada , Óxido Nítrico , Peixe-Zebra
19.
J Mol Diagn ; 23(2): 223-233, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33271368

RESUMO

RNA sequencing (RNA-seq) is a well-validated tool for detecting gene fusions in fresh-frozen tumors; however, RNA-seq is much more challenging to use with formalin-fixed, paraffin-embedded (FFPE) tumor samples. We evaluated the performance of RNA-seq to detect gene fusions in clinical FFPE tumor samples. Our assay identified all 15 spiked-in NTRK fusions from RNA reference material and six known fusions from five cancer cell lines. Limit of detection for the assay was assessed with a series of dilutions of RNA from the cell line H2228. These fusions can be detected when the dilution is down to 10%. Good intra-assay and interassay reproducibility was observed in three specimens. For clinical validation, the assay detected 10 of 12 fusions initially identified by a DNA panel (covering 23 gene fusions) in clinical specimens (83.3% sensitivity), whereas one fusion (MET fusion) was identified in another 34 fusion-negative tumor specimens as determined by the DNA panel (negative prediction value of 94.3%). This MET fusion was confirmed by RT-PCR and Sanger sequencing, which found that this is a false-negative result for the DNA panel. The assay also identified 26 extra fusions not covered by the DNA panel, 20 (76.9%) of which were validated by RT-PCR and Sanger sequencing. Therefore, this RNA assay has reasonable performance and could complement DNA-based next-generation sequencing assays.


Assuntos
Formaldeído/química , Fusão Gênica , Neoplasias/genética , Inclusão em Parafina , Análise de Sequência de RNA , Fixação de Tecidos , Sequência de Bases , Humanos , Reprodutibilidade dos Testes
20.
Front Mol Biosci ; 8: 781307, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35004851

RESUMO

Introduction: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with poor prognosis. The tumor microenvironment (TME) plays a vital role in HCC progression. Thus, this research was designed to analyze the correlation between the TME and the prognosis of HCC patients and to construct a TME-related long noncoding RNA (lncRNA) signature to determine HCC patients' prognosis and response to immunotherapy. Methods: We assessed the stromal-immune-estimate scores within the HCC microenvironment using the ESTIMATE (Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression Data) algorithm based on The Cancer Genome Atlas database, and their associations with survival and clinicopathological parameters were also analyzed. Thereafter, differentially expressed lncRNAs were filtered out according to the immune and stromal scores. Cox regression analysis was performed to build a TME-related lncRNA risk signature. Kaplan-Meier analysis was used to explore the prognostic value of the risk signature. Furthermore, we explored the biological functions and immune microenvironment features in the high- and low-risk groups. Lastly, we probed the association of the risk model with treatment responses to immune checkpoint inhibitors (ICIs) in HCC. Results: The stromal, immune, and estimate scores were obtained utilizing the ESTIMATE algorithm for patients with HCC. Kaplan-Meier analysis showed that high scores were significantly correlated with better prognosis in HCC patients. Six TME-related lncRNAs were screened to construct the prognostic model. The Kaplan-Meier curves suggested that HCC patients with low risk had better prognosis than those with high risk. Receiver operating characteristic (ROC) curve and Cox regression analyses indicated that the risk model could predict HCC survival exactly and independently. Functional enrichment analysis revealed that some tumor- and immune-related pathways were activated in the high-risk group. We also revealed that some immune cells, which were important in enhancing immune responses toward cancer, were significantly increased in the low-risk group. In addition, there was a close correlation between ICIs and the risk signature, which can be used to predict the treatment responses of HCC patients. Conclusion: We analyzed the influence of the stromal, immune, and estimate scores on the prognosis of HCC patients. A novel TME-related lncRNA risk model was established, which could be effectively applied as an independent prognostic biomarker and predictor of ICIs for HCC patients.

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