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1.
Support Care Cancer ; 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34981197

RESUMO

PURPOSE: Sarcopenia is an independent risk factor for poor prognosis of cancers. The nutritional risk screening 2002 (NRS2002) and patient-generated subjective global assessment (PG-SGA) tools are widely used tools for nutrition risk screening and assessing. The purpose of this study was to investigate whether NRS2002 and PG-SGA scores are associated with sarcopenia in gastrointestinal cancers. METHODS: A consecutive cohort comprised of 432 gastrointestinal cancer patients was conducted. We used NRS2002 and PG-SGA to assess their nutrition status. Sarcopenia was diagnosed with CT scan at the third lumber vertebra level. The correlations of nutritional scores with SMI, nutritional categories with sarcopenia were assessed by Spearman's correlation test and point biserial correlation. The cut-off value of nutritional scores for identifying sarcopenia was obtained by maximum Youden index. Logistic regression was used to confirm the associations. RESULTS: Sarcopenia patients had higher NRS2002 (2.63 ± 1.16 vs. 2.15 ± 1.20, p < 0.001) and PG-SGA (8.69 ± 1.16 vs. 5.56 ± 3.28, p < 0.001) scores. The NRS2002 (r = -0.198, p < 0.001) and PG-SGA (r = -0.409, p < 0.001) scores were significantly and negatively correlated with skeletal muscle mass index. The cut-off value of PG-SGA score for predicting sarcopenia was 7. In multivariate logistic regression, the PG-SGA exceeded 7 score (OR = 7.489, 95% CI: 4.122-13.608, p < 0.001) was significantly associated with increased risk of sarcopenia, while NRS2002 score showed no significant association with sarcopenia. CONCLUSIONS: PG-SGA ≥ 7 was associated with increased risk of sarcopenia and could serve as a useful criterion for capturing sarcopenia in gastrointestinal cancers. Routine PG-SGA evaluation for patient with gastrointestinal cancers is important.

2.
Int Immunopharmacol ; 101(Pt A): 108329, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34749293

RESUMO

BACKGROUNDS: Berberine (BBR), a compound long used in traditional Chinese medicine, has been reported to have therapeutic effects in treating ulcerative colitis (UC), attributed to its anti-inflammatory properties and restorative potential of tight junctions (TJs). However, the mechanism by which BBR affects intestinal bacteria and immunity is still unclear. METHODS: This study investigated the effects of BBR on intestinal bacteria and the inflammatory response in dextran sulfate sodium (DSS)-induced colitis mice. Immunohistochemistry (IHC) and electron microscopy were used to detect intestinal TJs. Microflora analysis was used to screen for bacteria regulated by BBR. RESULTS: The results showed that BBR had increased colonic epithelium zonula occludens proteins-1 (ZO-1) and occludin expression and reduced T-helper 17/T regulatory ratio in DSS-induced mice. Mechanically, BBR eliminated DSS-induced intestinal flora disturbances in mice, particularly increased Bacteroides fragilis (B. fragilis) in vivo and in vitro. B. fragilis decreased the interleukin-6 induced by dendritic cells through some heat-resistant component rather than nucleic acids or proteins. CONCLUSIONS: Overall, these data suggest that BBR had a moderating effect on DSS-induced colitis. This compound may regulate intestinal immune cell differentiation by affecting the growth of B. fragilis, providing new insights into the potential application of BBR in UC.

3.
Gastrointest Endosc ; 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34736933

RESUMO

BACKGROUND AND AIMS: With the increasing incidence of small gastrointestinal stromal tumors (GISTs), endoscopic full-thickness resection (EFR) and cap-assisted EFR (EFR-C) have been suggested as 2 effective resection methods. We aimed to compare the outcomes of EFR and EFR-C for the treatment of small (≤ 1.5 cm) gastric GISTs. METHODS: This retrospective study included 67 patients who underwent EFR and 46 patients who underwent EFR-C at Nanjing Drum Tower Hospital. Clinicopathological features, adverse events and outcomes were compared between the 2 groups. Univariate and multivariate linear and logistic regressions were used to analyze the effects of the procedure on the therapeutic outcomes of patients and adjusted for covariates in multivariate analysis. RESULTS: The tumor size in the EFR group tended to be larger (P = 0.005). The resection time in the EFR-C group was shorter than that in the EFR group (38.3 ± 20.7 min vs 15.0 ± 11.8 min, P < 0.001), which retained statistical significance with adjustment for the covariates (adjusted mean difference: 22.2; 95% CI, 15.0-29.4, P < 0.001). The R0 resection rate of the EFR group was 94.0%, and for the EFR-C group, it was 97.8% (P = 0.355). The EFR-C group was superior to the EFR group in terms of perioperative therapeutic outcomes, adverse events and postoperative recovery. No recurrence occurred in the EFR and EFR-C groups. CONCLUSION: EFR-C was found to be the preferable technique for small (≤1.5 cm) gastric GISTs with shorter operation times, lower adverse events, faster postoperative recovery, and shorter hospitalization times as compared with those with EFR.

4.
Front Pharmacol ; 12: 769647, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790132

RESUMO

Emerging evidences demonstrate that metabolic reprogramming is a hallmark of malignancies, including gastric cancer (GC). Abnormal expression of metabolic rate-limiting enzymes, as the executive medium of energy metabolism, drives the occurrence and development of cancer. However, a comprehensive model of metabolic rate-limiting enzymes associated with the development and progression of GC remains unclear. In this research, we identified a rate-limiting enzyme, sterol O-acyltransferase 1 (SOAT1), was highly expressed in cancerous tissues, which was associated with advanced tumor stage and lymph node metastasis, leading to the poor prognosis of GC. It was shown that knockdown of SOAT1 or pharmacological inhibition of SOAT1 by avasimibe could suppress GC cell proliferation, cholesterol ester synthesis, and lymphangiogenesis. However, overexpression of SOAT1 promoted these biological processes. Mechanistically, SOAT1 regulated the expression of cholesterol metabolism genes SREBP1 and SREBP2, which could induce lymphangiogenesis via increasing the expression of VEGF-C. In conclusion, our results indicated that SOAT1 promotes gastric cancer lymph node metastasis through lipid synthesis, which suggested that it may be a promising prognostic biomarker for guiding clinical management and treatment decisions.

5.
Cancer Manag Res ; 13: 7649-7661, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34675662

RESUMO

Background: Circulating tumor cells (CTCs) were a promising liquid biopsy for pancreatic cancer (PC) but circulate in low counts in peripheral blood. We evaluated the diagnostic and prognostic values of portal vein (PoV) CTCs in PC patients. Methods: PoV was aspirated under EUS guidance from 40 patients with suspected pancreaticobiliary cancers. Epithelial-mesenchymal-transition-related subtypes of CTCs were identified via immunofluorescence using EpCAM and Twist antibodies. The diagnostic and prognostic performance of PoV CTCs was investigated by receiver-operating characteristic (AUC) curve and Kaplan-Meier survival analysis. Results: In total, 40 patients including 31 with PC, 4 with non-pancreatic periampullary cancer and 5 with benign pancreatic diseases (BPD) were enrolled. CTCs were detected more in PoV compared with peripheral blood. PoV CTC numbers in BPD patients were lower than in PC patients. The number of PoV CTCs, especially mesenchymal-CTCs (M-CTCs), was positively correlated with the tumor burden, instead of epithelial-CTCs (E-CTCs). The combination of PoV CTC numbers and CA19-9 demonstrated better diagnostic efficiency (AUC value 0.987) than either alone in differentiating PC with BPD. Moreover, the diagnostic efficacy of PoV CTCs and M-CTCs were obviously better than that of E-CTCs and CA19-9 in distinguishing early and late stage PC. Lastly, high PoV CTC and M-CTC numbers were both associated with shorter overall survival. Conclusion: Acquisition of the PoV samples in PC patients via EUS-guided procedures has been proved safe and feasible. PoV CTCs, especially M-CTCs, have great potentials in diagnosing and predicting the prognosis of PC, especially in combination with CA19-9.

6.
Clin Transl Gastroenterol ; 12(8): e00393, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34346911

RESUMO

INTRODUCTION: This study aims to construct a real-time deep convolutional neural networks (DCNNs) system to diagnose early esophageal squamous cell carcinoma (ESCC) with white light imaging endoscopy. METHODS: A total of 4,002 images from 1,078 patients were used to train and cross-validate the DCNN model for diagnosing early ESCC. The performance of the model was further tested with independent internal and external validation data sets containing 1,033 images from 243 patients. The performance of the model was then compared with endoscopists. The accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and Cohen kappa coefficient were measured to assess performance. RESULTS: The DCNN model had excellent performance in diagnosing early ESCC with a sensitivity of 0.979, a specificity of 0.886, a positive predictive value of 0.777, a negative predictive value of 0.991, and an area under curve of 0.954 in the internal validation data set. The model also depicted a tremendously generalized performance in 2 external data sets and exhibited superior performance compared with endoscopists. The performance of the endoscopists was markedly elevated after referring to the predictions of the DCNN model. An open-accessed website of the DCNN system was established to facilitate associated research. DISCUSSION: A real-time DCNN system, which was constructed to diagnose early ESCC, showed good performance in validation data sets. However, more prospective validation is needed to understand its true clinical significance in the real world.

7.
Cancer Lett ; 519: 315-327, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34343634

RESUMO

Recent studies suggest that RRP15 (Ribosomal RNA Processing 15 Homolog) might be a potential target for cancer therapy. However, the role of RRP15 in hepatocarcinogenesis remains poorly delineated. In this study, we aimed to evaluate the expression and biological function of RRP15 in human hepatocellular carcinoma (HCC). We show that RRP15 was up regulated in HCC cell lines and tumours. Up-regulation of RRP15 in HCC tumours was also correlated with unfavorable prognosis. We further show that the frequent up-regulation of RRP15 in HCCs is at least partly driven by recurrent gene copy gain at chromosome 1q41. Functional studies indicated that RRP15 knockdown suppresses HCC proliferation and growth both in vitro and in vivo. Mechanistically, RRP15 depletion in p53-wild-type HepG2 cells induced senescence via activation of the p53-p21 signalling pathway through enhanced interaction of RPL11 with MDM2, as well as inhibition of SIRT1-mediated p53 deacetylation. Moreover, RRP15 depletion in p53-mutant PLC5 and p53-deleted Hep3B cells induced metabolic shift from the glycolytic pentose-phosphate to mitochondrial oxidative phosphorylation via regulating a series of key genes such as HK2 and TIGAR, and thus, promoted the generation of ROS and apoptosis. Taken together, our findings provide evidence for an important role of the RRP15 gene in hepatocarcinogenesis through regulation of HCC proliferation and growth, raising the possibility that targeting RRP15 may represent a potential therapeutic strategy for HCC treatment.

8.
Cell Prolif ; 54(10): e13117, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34423480

RESUMO

OBJECTIVES: Abnormal expression of metabolic rate-limiting enzymes drives the occurrence and progression of hepatocellular carcinoma (HCC). This study aimed to elucidate the comprehensive model of metabolic rate-limiting enzymes associated with the prognosis of HCC. MATERIALS AND METHODS: HCC animal model and TCGA project were used to screen out differentially expressed metabolic rate-limiting enzyme. Cox regression, least absolute shrinkage and selection operation (LASSO) and experimentally verification were performed to identify metabolic rate-limiting enzyme signature. The area under the receiver operating characteristic curve (AUC) and prognostic nomogram were used to assess the efficacy of the signature in the three HCC cohorts (TCGA training cohort, internal cohort and an independent validation cohort). RESULTS: A classifier based on three rate-limiting enzymes (RRM1, UCK2 and G6PD) was conducted and serves as independent prognostic factor. This effect was further confirmed in an independent cohort, which indicated that the AUC at year 5 was 0.715 (95% CI: 0.653-0.777) for clinical risk score, whereas it was significantly increased to 0.852 (95% CI: 0.798-0.906) when combination of the clinical with signature risk score. Moreover, a comprehensive nomogram including the signature and clinicopathological aspects resulted in significantly predict the individual outcomes. CONCLUSIONS: Our results highlighted the prognostic value of rate-limiting enzymes in HCC, which may be useful for accurate risk assessment in guiding clinical management and treatment decisions.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/fisiologia , Células Hep G2 , Humanos , Estimativa de Kaplan-Meier , Camundongos , Camundongos Endogâmicos C57BL , Nomogramas , Prognóstico , Curva ROC
9.
Ann Transl Med ; 9(8): 646, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33987344

RESUMO

Background: Our study aims to analyze the association between Lauren's classification and gastric adenocarcinoma prognosis using comprehensive statistical analyses. Methods: According to the selection criteria, patients were included from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression, propensity score matching, and a multivariate competing risk model were used to investigate the association between Lauren's classification and prognosis. Subgroup analysis was used to investigate the role of confounding factors on the association between Lauren types and prognosis. Results: After exclusion, a total of 20,218 patients from the SEER database were included, with 14,374 intestinal types and 5,844 diffuse types. The univariate Cox regression analysis revealed that the diffuse type had a poorer cancer-specific survival (CSS) rate [hazard ratio (HR), 1.44; 95% confidence interval (CI), 1.38-1.50]. After adjusting for confounding variables, the diffuse type also showed a higher risk of cancer-specific death (HR, 1.20; 95% CI, 1.15-1.20). Sensitivity analysis showed that after propensity score matching, the diffuse type had a poorer CSS rate (HR, 1.23; 95% CI, 1.10-1.36), and the competing risk model further validated these results [subdistribution HR (SHR), 1.32; 95% CI, 1.23-1.41]. Moreover, subgroup analysis demonstrated stable results in the subgroups, except for patients with T1 stage (HR, 1.06; 95% CI, 0.87-1.28) and a tumor size <2 cm (HR, 1.00; 95% CI, 0.83-1.21). Conclusions: Diffuse-type gastric adenocarcinoma had an overall poorer prognosis compared to the intestinal type. However, in patients with T1 stage and tumor size <2 cm, the diffuse type had a comparable survival rate with the intestinal type.

10.
Front Oncol ; 11: 628346, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34026608

RESUMO

Background: Pancreatic cancer (PC) has a dismal prognosis due to its insidious early symptoms and poor early detection rate. Exosomes can be released by various cell types and tend to be a potential novel biomarker for PC detection. In this study, we explored the proteomic profiles of plasma exosomes collected from patients with PC at different stages and other pancreatic diseases. Methods: Plasma samples were collected from six groups of patients, including PC at stage I/II, PC at stage III/IV, well-differentiated pancreatic neuroendocrine tumor (P-NET), pancreatic cystic lesions (PCLs), chronic pancreatitis (CP), and healthy controls (HCs). Plasma-derived exosomes were isolated by ultracentrifugation and identified routinely. Isobaric tags for relative and absolute quantification (iTRAQ) based proteomic analysis along with bioinformatic analysis were performed to elucidate the biological functions of proteins. The expression of exosomal ALIX was further confirmed by enzyme-linked immunosorbent assay in a larger cohort of patients. Furthermore, receiver operating characteristic curve analysis was applied to evaluate the potential of ALIX as a novel diagnostic biomarker. Results: The proteomic profile revealed a total of 623 proteins expressed among the six groups, and 16 proteins with differential degrees of abundance were found in PC vs. other pancreatic diseases (including P-NET, PCLs, and CP). Based on the results of proteomic and bioinformatic analyses, exosomal ALIX was subsequently selected as a novel biomarker for PC detection and validated in another clinical cohort. We noticed that ALIX expression was elevated in PC patients compared with patients with other pancreatic diseases or HC, and it was also closely associated with TNM stage and distant metastasis. Interestingly, the combination of exosomal ALIX and serum CA199 has greater values in differentiating both early vs. late PC (AUC value 0.872) and PC vs. other pancreatic diseases (AUC value 0.910) than either ALIX or CA199 alone. Conclusion: In summary, our study demonstrated that based on proteomic profiling, proteins isolated from the plasma-derived exosomes may function as ideal non-invasive biomarkers for the clinical diagnosis of PC. Importantly, exosomal ALIX combined with CA199 has great potentials in detection of PC, especially in distinguishing PC patients at early stages from advanced stages.

11.
Front Oncol ; 11: 622827, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33959495

RESUMO

Background and Aims: Prediction of intramucosal gastric cancer (GC) is a big challenge. It is not clear whether artificial intelligence could assist endoscopists in the diagnosis. Methods: A deep convolutional neural networks (DCNN) model was developed via retrospectively collected 3407 endoscopic images from 666 gastric cancer patients from two Endoscopy Centers (training dataset). The DCNN model's performance was tested with 228 images from 62 independent patients (testing dataset). The endoscopists evaluated the image and video testing dataset with or without the DCNN model's assistance, respectively. Endoscopists' diagnostic performance was compared with or without the DCNN model's assistance and investigated the effects of assistance using correlations and linear regression analyses. Results: The DCNN model discriminated intramucosal GC from advanced GC with an AUC of 0.942 (95% CI, 0.915-0.970), a sensitivity of 90.5% (95% CI, 84.1%-95.4%), and a specificity of 85.3% (95% CI, 77.1%-90.9%) in the testing dataset. The diagnostic performance of novice endoscopists was comparable to those of expert endoscopists with the DCNN model's assistance (accuracy: 84.6% vs. 85.5%, sensitivity: 85.7% vs. 87.4%, specificity: 83.3% vs. 83.0%). The mean pairwise kappa value of endoscopists was increased significantly with the DCNN model's assistance (0.430-0.629 vs. 0.660-0.861). The diagnostic duration reduced considerably with the assistance of the DCNN model from 4.35s to 3.01s. The correlation between the perseverance of effort and diagnostic accuracy of endoscopists was diminished using the DCNN model (r: 0.470 vs. 0.076). Conclusions: An AI-assisted system was established and found useful for novice endoscopists to achieve comparable diagnostic performance with experts.

12.
Genome Biol ; 22(1): 104, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849634

RESUMO

BACKGROUND: Although using a blockade of programmed death-ligand 1 (PD-L1) to enhance T cell immune responses shows great promise in tumor immunotherapy, the immune-checkpoint inhibition strategy is limited for patients with solid tumors. The mechanism and efficacy of such immune-checkpoint inhibition strategies in solid tumors remains unclear. RESULTS: Employing qRT-PCR, Sanger sequencing, and RNA BaseScope analysis, we show that human lung adenocarcinoma (LUAD) all produce a long non-coding RNA isoform of PD-L1 (PD-L1-lnc) by alternative splicing, regardless if the tumor is positive or negative for the protein PD-L1. Similar to PD-L1 mRNA, PD-L1-lnc in various lung adenocarcinoma cells is significantly upregulated by IFNγ. Both in vitro and in vivo studies demonstrate that PD-L1-lnc increases proliferation and invasion but decreases apoptosis of lung adenocarcinoma cells. Mechanistically, PD-L1-lnc promotes lung adenocarcinoma progression through directly binding to c-Myc and enhancing c-Myc transcriptional activity. CONCLUSIONS: In summary, the PD-L1 gene can generate a long non-coding RNA through alternative splicing to promote lung adenocarcinoma progression by enhancing c-Myc activity. Our results argue in favor of investigating PD-L1-lnc depletion in combination with PD-L1 blockade in lung cancer therapy.

13.
J Cell Mol Med ; 25(8): 3991-4000, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33682267

RESUMO

Pancreatic cancer (PC) has been the fourth cancer-related death worldwide, diagnosed at an unresectable stage due to its rapid progression and few symptoms of this disease at early stages. The aim of this study was to determine the association between the diversity of T-cell receptor (TCR) repertoire and clinicopathological characteristics of patients with PC and other benign pancreatic diseases. In order to make a comprehensive analysis the TCR repertoire, high-throughput sequencing was used to differentiate complementarity determining region 3 (CDR3) of the TCR ß chain in peripheral blood samples from 3 PC, 3 chronic pancreatitis, 3 pancreatic cystic lesions and 3 pancreatic neuroendocrine tumour patients. We found that there were significant differences related to TCR repertoire between PC and other pancreatic diseases, and PC is a relatively immunosuppressive tumour. Changes of peripheral TCR repertoire may be used to predict the progression of PC and the response to immunotherapy. And there may exist novel-specific antigens in PC patients which could be used to design targeting immunotherapy in the nearly future.


Assuntos
Biomarcadores/metabolismo , Carcinoma Neuroendócrino/patologia , Regulação da Expressão Gênica , Cisto Pancreático/patologia , Neoplasias Pancreáticas/patologia , Pancreatite Crônica/patologia , Receptores de Antígenos de Linfócitos T/metabolismo , Adulto , Idoso , Carcinoma Neuroendócrino/sangue , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/metabolismo , Regiões Determinantes de Complementaridade/genética , Regiões Determinantes de Complementaridade/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cisto Pancreático/sangue , Cisto Pancreático/genética , Cisto Pancreático/metabolismo , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Pancreatite Crônica/sangue , Pancreatite Crônica/genética , Pancreatite Crônica/metabolismo , Prognóstico , Receptores de Antígenos de Linfócitos T/genética , Estudos Retrospectivos
14.
BMC Gastroenterol ; 21(1): 119, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33711944

RESUMO

BACKGROUND: Endoscopic submucosal dissection (ESD) has been accepted as a standard treatment for early gastric cardiac cancer (EGCC). Here, we investigate the clinical outcomes of the EGCC patients who underwent ESD in different indications. METHODS: From January 2011 to October 2019, we enrolled 502 EGCC lesions from 495 patients which were resected by ESD at our center. We retrospectively analyzed the short-term and long-term clinical outcomes among different indication groups. RESULTS: The number of the patients in the absolute indication (AI), expanded indication (EI) and beyond the expanded indication (BEI) groups was 265, 137 and 93, respectively. The en bloc resection rate was 100%, 100% and 98.9% (P = 0.185). The complete resection rate was 99.3%, 98.5% and 74.5%, respectively (P < 0.001). During a median follow-up of 48.1 months, the lymph node metastasis rate was 0%, 0% and 2.3% (P < 0.001). The distant metastasis rate was 0.4%, 0% and 2.3% (P = 0.150). The five-year disease-specific survival rate in the BEI group was 96.6% (P = 0.016), compared to 99.6% in the AI group and 100% in the EI group. CONCLUSION: The efficacy for ESD patients in EI group was almost equal to the AI group. Patients in the BEI group showed generally favorable clinical outcomes and needed to be carefully checked after ESD. ESD may be an optional treatment for patients unsuitable for gastrectomy.


Assuntos
Ressecção Endoscópica de Mucosa , Neoplasias Cardíacas , Neoplasias Gástricas , Ressecção Endoscópica de Mucosa/efeitos adversos , Mucosa Gástrica/cirurgia , Humanos , Estudos Retrospectivos , Neoplasias Gástricas/cirurgia , Resultado do Tratamento
15.
J Cell Physiol ; 236(10): 6868-6883, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33629745

RESUMO

Gemcitabine is first-line chemotherapy for pancreatic cancer, however, the development of resistance limits its effectiveness. The tripartite motif-containing 11 (TRIM11) protein plays crucial roles in tumor development and undergoes auto-polyubiquitination to promote interactions in selective autophagy. Therefore, Understanding whether TRIM11 is involved in ferritinophagy and gemcitabine resistance in pancreatic cancer is critical in developing pancreatic cancer therapeutics. TRIM11 expression was validated by Western blot analysis, real-time polymease chain reaction, and immunohistochemical staining. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Colony formation assays were performed to investigate pancreatic ductal adenocarcinomas (PDAC) cell viability. Mouse xenograft model of PDAC cells was established to verify the role of TRIM11 in vivo. Coimmunoprecipitation was used to identify the reciprocal regulation between TRIM11 and UBE2N. In this study, we found that TRIM11 expression were higher in PDAC cells and tissues. TRIM11 overexpression promotes PDAC cell proliferation in vitro and tumor growth in vivo. Decreased expression of TRIM11 in PDAC patients is associated with decreased UBE2N and increased TAX1BP1 expression. Coimmunoprecipitation established that TRIM11 interacts and colocalizes with UBE2N. Mechanistically, TRIM11 promoted gemcitabine resistance and suppressed ferritinophagy through UBE2N-TAX1BP1 signaling. Our findings identify TRIM11 as a key regulator of TAX1BP1 signaling with a crucial role in ferritinophagy and gemcitabine resistance in PDAC.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Ferroptose/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas com Motivo Tripartido/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Transdução de Sinais , Proteínas com Motivo Tripartido/genética , Carga Tumoral/efeitos dos fármacos , Enzimas de Conjugação de Ubiquitina/genética , Ubiquitina-Proteína Ligases/genética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Dis Esophagus ; 34(10)2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-33442745

RESUMO

Endoscopic submucosal dissection (ESD) is widely used for early stage esophageal cancer and precancerous lesions. Non-cardiac chest pain (NCCP) is a frequent complication of ESD. However, little is known about its incidence and associated factors. This study investigated the pain incidence and predictive factors for pain development after ESD for esophageal neoplasms. We enrolled a total of 309 patients with esophageal neoplasms, who underwent ESD in our center from January 2018 to June 2019. Sociodemographic and clinicopathological information for all patients was collected, and patients were divided into either a pain-free group (n = 156) or a pain group (n = 153) according to whether there was onset of NCCP 24-48 hours after surgery. We made comparisons between groups using Student's t test or the χ2 test. Logistic-regression analysis was used to screen for risk factors. There were statistically significant differences in histories of previous surgery (P = 0.039), lesion size (P = 0.026), operation time (P = 0.009), and postoperative fever (P = 0.001). History of previous surgery (P = 0.043) and postoperative fever (P = 0.007) were independent risk factors for chest pain after esophageal ESD treatment. Chest pain and fever prolonged postoperative hospitalization time (P = 0.005, P = 0.001) and increased hospitalization cost (P = 0.034, P < 0.001). A history of previous surgery and postoperative fever was associated with the occurrence of NCCP after ESD in patients with esophageal neoplasms. NCCP and fever after esophageal ESD increased both hospitalization time and cost.


Assuntos
Ressecção Endoscópica de Mucosa , Neoplasias Esofágicas , Estudos de Casos e Controles , Dor no Peito/epidemiologia , Dor no Peito/etiologia , Ressecção Endoscópica de Mucosa/efeitos adversos , Neoplasias Esofágicas/cirurgia , Humanos , Estudos Retrospectivos , Resultado do Tratamento
17.
Clin Epigenetics ; 13(1): 18, 2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33499904

RESUMO

BACKGROUND: Hypoxia is a characteristic of the tumor microenvironments within pancreatic cancer (PC), which has been linked to its malignancy. Recently, hypoxia has been reported to regulate the activity of important carcinogenic pathways by changing the status of histone modification. NOX4, a member of NADPH oxidase (NOX), has been found to be activated by hypoxia and promote cancer progression in several cancers. But whether it is involved in the epigenetic changes of tumor cells induced by hypoxia is still unclear, and its biological roles in PC also need to be explored. METHODS: A hypoxic-related gene signature and its associated pathways in PC were identified by analyzing the pancreatic cancer gene expression data from GEO and TCGA database. Candidate downstream gene (NOX4), responding to hypoxia, was validated by RT-PCR and western blot. Then, we evaluated the relationship between NOX4 expression and clinicopathologic parameters in 56 PC patients from our center. In vitro and in vivo assays were preformed to explore the phenotype of NOX4 in PC. Immunofluorescence, western blot and chromatin immunoprecipitation assays were further applied to search for a detailed mechanism. RESULTS: We quantified hypoxia and developed a hypoxia signature, which was associated with worse prognosis and elevated malignant potential in PC. Furthermore, we found that NADPH oxidase 4 (NOX4), which was induced by hypoxia and upregulated in PC in a HIF1A-independent manner, caused inactivation of lysine demethylase 5A (KDM5A), increased the methylation modification of histone H3 and regulated the transcription of EMT-associated gene_ snail family transcriptional repressor 1 (SNAIL1). This served to promote the invasion and metastasis of PC. NOX4 deficiency repressed hypoxia-induced EMT, reduced expression of H3K4ME3 and impaired the invasion and metastasis of PC cells; however, knockdown of KDM5A reversed the poor expression of H3KEME3 induced by NOX4 deficiency, thereby promoting EMT. CONCLUSIONS: This study highlights the prognostic role of hypoxia-related genes in PC and strong correlation with EMT pathway. Our results also creatively discovered that NOX4 was an essential mediator for hypoxia-induced histone methylation modification and EMT in PC cells.

18.
Gastrointest Endosc ; 93(3): 565-572, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32615178

RESUMO

BACKGROUND AND AIMS: EUS-guided portal pressure gradient (EUS-PPG) measurement is a novel method to evaluate portal hypertension severity. In this study, we determined the consistency between EUS-PPG and hepatic venous pressure gradient (HVPG) measurements in patients with acute or subacute portal hypertension. METHODS: Twelve patients were prospectively enrolled. EUS-PPG measurements were performed using a 22-gauge FNA needle and a central venous pressure measurement monitor. The HVPG measurements were performed using the transjugular approach. If an HVPG measurement was not attainable and the patient underwent transjugular intrahepatic portosystemic shunt (TIPS) treatment, a PPG was recorded as a reference standard during the procedure. We assessed the feasibility and safety of EUS-PPG and calculated the correlation between the 2 measurements. RESULTS: EUS-PPG measurements were successful in 11 patients (91.7%). Subsequent HVPG measurements failed in 2 patients with Budd-Chiari syndrome (hepatic vein occlusion subtype), 1 of whom underwent TIPS treatment to obtain transjugular PPG data. A small shunt was found during 1 HVPG measurement that introduced inaccuracy. Nine patients were included in the statistical analysis. Mean EUS-PPG and HVPG/PPG (transjugular) were 18.07 ± 4.32 mm Hg and 18.82 ± 3.43 mm Hg, respectively. Pearson's correlation coefficient between the 2 methods was .923 (P < .001). CONCLUSIONS: EUS-PPG measurement using a 22-gauge FNA needle was a safe and accurate method to evaluate portal hypertension and has the potential to supplement the measurement of HVPG in liver diseases. (Clinical trial registration number: ChiCTR1800017317.).


Assuntos
Hipertensão Portal , Derivação Portossistêmica Transjugular Intra-Hepática , Endossonografia , Veias Hepáticas , Humanos , Hipertensão Portal/complicações , Pressão na Veia Porta
19.
Int Immunopharmacol ; 90: 107212, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33310666

RESUMO

BACKGROUND: The pathogenesis of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC) has not been fully elucidated. However, a strong correlation between IBD and high T helper 17 (Th17) levels has been found. Sirtuin 2 (SIRT2) has recently been found to play an important role in metabolic reprogramming, but its potential anti-inflammatory properties remain unclear. METHODS: The expression levels of SIRT2 and glucose metabolism-related proteins in peripheral blood mononuclear cells (PBMCs) of IBD patients and healthy volunteers were detected. Human PBMCs were differentiated into Th17 cells in vitro and were treated with TM simultaneously. The ratio of Th17 cells and apoptotic cells and the production of Interleukin (IL)-17A and the expression levels of transcription factors of classical signaling pathway related to Th17 differentiation were determined. The acetylation of LDHA and glucose metabolism was assessed. Subsequently, C57BL/6J colitis mice induced by 2.5% dextran sulfatesodiumsalt (DSS) were treated with or without TM, Disease activity index, T cell subsets in the mice spleen, relevant inflammatory cytokines in serum, specific mRNA, and proteins in mice colon were evaluated respectively. RESULTS: SIRT2 and glucose metabolism-related proteins in PBMCs of patients were overexpressed. Compared with the positive control group, human PBMCs treated with TM had lower levels of IL-17A, percentage of Th17 cells, levels of phospho-signal transducer and activator of transcription (p-STAT) 3 and phospho-nuclear transcription factor-κB (p-NF-κB), but higher levels of acetylated LDHA. Compared with colitis mice, TM-treated colitis mice had longer colons, reduced weight-losses, and lower disease activity index and histopathologic scores. Interestingly, although the expression levels of interferon (IFN)-γ, IL-17A, and retinoic acid receptor-related orphan receptor (ROR)-γt were inhibited in the colons of TM-treated colitis mice, the expression of forkhead box protein P3 (FOXP3) didn't change. Consistently, relative to the high percentage of splenic Th17 cells in colitis mice, the percentage of splenic Th17 cells in TM-treated colitis mice was as normal as PBS-treated mice, while the percentage of Treg cells was not affected. Additionally, the TM group had reduced levels of IL-23 and hypoxiainduciblefactor-1α (HIF-1α), and an increased level of IL-10 in the colon, compared with the colitis group. CONCLUSION: Our results indicate that TM reduces UC progression by reducing metabolic reprogramming and T cell differentiation. Specifically, TM prevented Th17 differentiation by reducing the expression of related transcription factors and promoting acetylation of LDHA (weakening glycolysis). SIRT2 may be a potential target for IBD treatment.


Assuntos
Anti-Inflamatórios/farmacologia , Diferenciação Celular/efeitos dos fármacos , Reprogramação Celular/efeitos dos fármacos , Colite/prevenção & controle , Colo/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Sirtuína 2/metabolismo , Células Th17/efeitos dos fármacos , Acetilação , Animais , Apoptose/efeitos dos fármacos , Estudos de Casos e Controles , Células Cultivadas , Colite/enzimologia , Colite/imunologia , Colite/patologia , Colo/enzimologia , Colo/imunologia , Colo/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , L-Lactato Desidrogenase/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sirtuína 2/genética , Células Th17/enzimologia , Células Th17/imunologia
20.
Endosc Int Open ; 8(11): E1690-E1697, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33140026

RESUMO

Background and study aims Gastric outlet obstruction (GOO) is common in the late stage of many malignant tumors of the digestive system. Endoscopic ultrasound (EUS)-guided gastroenterostomy (EUS-GE) is commonly used for palliative treatment of malignant GOO. The objective of this study was to investigate the safety, efficacy, and prognosis of EUS-GE in treatment of malignant GOO in Chinese patients. Patients and methods This was a retrospective, single-center study with 36 consecutive patients with malignant GOO who were treated with EUS-GE. The main outcome measures were technical success rate, clinical success rate, incidence of adverse events (AEs), and median survival time. Results A total of 36 patients with malignant GOO underwent double-balloon-assisted EUS-GE between March 2017 and June 2019 in our hospital. GOO occurred mainly in elderly men (mean age 69.0 years, M:F 0.89). The most common etiology of GOO was pancreatic cancer (41.7 %). The most common obstruction site was the second part of the duodenum (63.9 %). The technical success rate was 100 % (36/36). The clinical success rate was 94.4 % (34/36). Median time for the total procedure was 52 minutes (range 34 - 156 min). Median time for determination of puncture site was 20 minutes (range 15 - 28 min). Median time between puncture and successful delivery of the stent was 38 minutes (range 19 - 128 min). The GOOSS score was 0.2 before EUS-GE. The GOO Scoring System (GOOSS) score was 2.2 at 15 days after the EUS-GE ( P  = 0.001). The GOOSS score was still higher than 2 during a median follow-up period of 89 days. AEs were observed in nine patients (25.0 %) and 13 total AEs occurred. One patient died as a result of delayed stent migration and bleeding. Mean length of hospital stay was 5.8 ±â€Š4.7 days. The median survival period was 103 days. The rate of GOO recurrence was 2.7 % (1/36). Conclusion EUS-GE was associated with increased safety and efficacy for treatment of malignant GOO in Chinese Mainland.

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