Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 95
Filter
1.
Neurochem Res ; 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38837093

ABSTRACT

Neuroinflammation is being increasingly recognized as a vital factor in the development of various neurological and neuropsychiatric diseases. Lipopolysaccharides (LPS), an outer membrane component of gram-negative bacteria, can trigger innate immune responses, resulting in neuroinflammation and subsequent cognitive deficits. The expression of glutamate receptors (GluRs) on glial cells can induce glial activation. Therefore, we hypothesized that repeated LPS exposure can increase GluR levels, promoting microglial activation and ultimately affecting synaptic plasticity and cognitive function. In this study, C57/BL6 mice were repeatedly exposed to LPS to construct a neuroinflammation animal model. The levels of GluRs, inflammatory cytokines, ionized calcium-binding adaptor molecule 1, postsynaptic density protein 95, synaptophysin 38, NMDA receptor 2 A, and NMDA receptor 2B (GluN2B) were measured in the hippocampi. Furthermore, dendritic spine density in the CA1 hippocampal region was determined. Repeated LPS exposure induced cognitive impairments and microglial activation and increased GluR1 and GluR2 levels. This was accompanied by a significant decrease in GluN2B expression and dendritic spine density in the hippocampi. However, CFM-2, an α-amino-3- hydroxy-5-methyl-4-isoxazolepropionate receptor antagonist, reversed these anomalies. Furthermore, minocycline, a microglial inhibitor, reversed these anomalies and downregulated GluR2 but not GluR1 expression. In summary, we demonstrated that GluR2 plays an essential role in microglia-induced neuroinflammation, resulting in synaptic plasticity and cognitive impairment induced by repeated exposure to LPS.

2.
Cell Prolif ; : e13659, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38773866

ABSTRACT

Aberrant A-to-I RNA editing, mediated by ADAR1 has been found to be associated with increased tumourigenesis and the development of chemotherapy resistance in various types of cancer. Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive malignancy with a poor prognosis, and overcoming chemotherapy resistance poses a significant clinical challenge. This study aimed to clarify the roles of ADAR1 in tumour resistance to cisplatin in iCCA. We discovered that ADAR1 expression is elevated in iCCA patients, particularly in those resistant to cisplatin, and associated with poor clinical outcomes. Downregulation of ADAR1 can increase the sensitivity of iCCA cells to cisplatin treatment, whereas its overexpression has the inverse effect. By integrating RNA sequencing and Sanger sequencing, we identified BRCA2, a critical DNA damage repair gene, as a downstream target of ADAR1 in iCCA. ADAR1 mediates the A-to-I editing in BRCA2 3'UTR, inhibiting miR-3157-5p binding, consequently increasing BRCA2 mRNA and protein levels. Furthermore, ADAR1 enhances cellular DNA damage repair ability and facilitates cisplatin resistance in iCCA cells. Combining ADAR1 targeting with cisplatin treatment markedly enhances the anticancer efficacy of cisplatin. In conclusion, ADAR1 promotes tumour progression and cisplatin resistance of iCCA. ADAR1 targeting could inform the development of innovative combination therapies for iCCA.

3.
Cancer Lett ; 585: 216640, 2024 Mar 31.
Article in English | MEDLINE | ID: mdl-38290659

ABSTRACT

Gemcitabine, a pivotal chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC), frequently encounters drug resistance, posing a significant clinical challenge with implications for PDAC patient prognosis. In this study, employing an integrated approach involving bioinformatic analyses from multiple databases, we unveil CSNK2A1 as a key regulatory factor. The patient-derived xenograft (PDX) model further substantiates the critical role of CSNK2A1 in gemcitabine resistance within the context of PDAC. Additionally, targeted silencing of CSNK2A1 expression significantly enhances sensitivity of PDAC cells to gemcitabine treatment. Mechanistically, CSNK2A1's transcriptional regulation is mediated by H3K27 acetylation in PDAC. Moreover, we identify CSNK2A1 as a pivotal activator of autophagy, and enhanced autophagy drives gemcitabine resistance. Silmitasertib, an established CSNK2A1 inhibitor, can effectively inhibit autophagy. Notably, the combinatorial treatment of Silmitasertib with gemcitabine demonstrates remarkable efficacy in treating PDAC. In summary, our study reveals CSNK2A1 as a potent predictive factor for gemcitabine resistance in PDAC. Moreover, targeted CSNK2A1 inhibition by Silmitasertib represents a promising therapeutic strategy to restore gemcitabine sensitivity in PDAC, offering hope for improved clinical outcomes.


Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Gemcitabine , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Autophagy , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics
4.
J Robot Surg ; 18(1): 1, 2024 Jan 04.
Article in English | MEDLINE | ID: mdl-38175325

ABSTRACT

AIM: Robotic-assisted pancreatectomy has been widely used. Organ-preserving pancreatectomy (OPP) and parenchymal-sparing pancreatectomy (PSP) has been gradually adopted for pancreatic benign or low-grade malignant tumors. This study aimed to evaluate the safety and efficacy of robotic-assisted OPP/PSP in our institute. METHODS: Patients undergoing robotic-assisted OPS/PSP at First Affiliated Hospital of Sun Yat-sen University between July 2015 and October 2021 were included in this study. The short-term and long-term outcomes of patients were retrospectively analyzed. RESULTS: Seventy-two patients were enrolled, including spleen-preserving distal pancreatectomy, central pancreatectomy, duodenum-preserving pancreatic head resection, and enucleation. Patients included were more likely to be young female (female: 46/72, median age: 47 years old). The median intraoperative blood loss and operation time was 50 ml and 255 min, respectively. Clinically relevant postoperative pancreatic fistula was 20.8% (grade B: 15/72, 20.8%; no grade C). The overall complication rate was 22.2% with the median postoperative length-of-stay of 8 days. At a median follow-up time of 28.5 months, the 5-year overall survival and recurrence-free survival rate were 100.0% and 100.0%, respectively. CONCLUSION: The short-term and long-term outcomes of patients receiving robotic-assisted OPP/PSP were acceptable. Robotic-assisted OPP/PSP was a feasible and safe technique for pancreatic benign or low-grade malignant lesions.


Subject(s)
Neoplasms , Robotic Surgical Procedures , Humans , Female , Middle Aged , Pancreatectomy , Retrospective Studies , Robotic Surgical Procedures/methods , Pancreas/surgery , Postoperative Complications/epidemiology
5.
Eur Radiol ; 34(3): 1994-2005, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37658884

ABSTRACT

OBJECTIVES: To develop a computed tomography (CT) radiomics-based interpretable machine learning (ML) model to predict the pathological grade of pancreatic neuroendocrine tumors (pNETs) in a non-invasive manner. METHODS: Patients with pNETs who underwent contrast-enhanced abdominal CT between 2010 and 2022 were included in this retrospective study. Radiomics features were extracted, and five radiomics-based ML models, namely logistic regression (LR), random forest (RF), support vector machine (SVM), XGBoost, and GaussianNB, were developed. The performance of these models was evaluated using a time-independent testing set, and metrics such as sensitivity, specificity, accuracy, and the area under the receiver operating characteristic curve (AUC) were calculated. The accuracy of the radiomics model was compared to that of needle biopsy. The Shapley Additive Explanation (SHAP) tool and the correlation between radiomics and biological features were employed to explore the interpretability of the model. RESULTS: A total of 122 patients (mean age: 50 ± 14 years; 53 male) were included in the training set, whereas 100 patients (mean age: 48 ± 13 years; 50 male) were included in the testing set. The AUCs for LR, SVM, RF, XGBoost, and GaussianNB were 0.758, 0.742, 0.779, 0.744, and 0.745, respectively, with corresponding accuracies of 73.0%, 70.0%, 77.0%, 71.9%, and 72.9%. The SHAP tool identified two features of the venous phase as the most significant, which showed significant differences among the Ki-67 index or mitotic count subgroups (p < 0.001). CONCLUSIONS: An interpretable radiomics-based RF model can effectively differentiate between G1 and G2/3 of pNETs, demonstrating favorable interpretability. CLINICAL RELEVANCE STATEMENT: The radiomics-based interpretable model developed in this study has significant clinical relevance as it offers a non-invasive method for assessing the pathological grade of pancreatic neuroendocrine tumors and holds promise as an important complementary tool to traditional tissue biopsy. KEY POINTS: • A radiomics-based interpretable model was developed to predict the pathological grade of pNETs and compared with preoperative needle biopsy in terms of accuracy. • The model, based on CT radiomics, demonstrated favorable interpretability. • The radiomics model holds potential as a valuable complementary technique to preoperative needle biopsy; however, it should not be considered a replacement for biopsy.


Subject(s)
Neuroectodermal Tumors, Primitive , Neuroendocrine Tumors , Pancreatic Neoplasms , Humans , Male , Adult , Middle Aged , Neuroendocrine Tumors/diagnostic imaging , Radiomics , Retrospective Studies , Pancreatic Neoplasms/diagnostic imaging
6.
BMC Surg ; 23(1): 382, 2023 Dec 19.
Article in English | MEDLINE | ID: mdl-38114974

ABSTRACT

AIM: Splenic vessel-preserving spleen-preserving distal pancreatectomy (SVP-SPDP) has a lower risk of splenic infarction than the splenicvessel-sacrificing SPDP, but it is more technically demanding. Learning curve of robotic-assisted SVP-SPDP (RSVP-SPDP) remains unreported. This study sought to analyze the perioperative outcomes and learning curve of RSVP-SPDP by one single surgeon. METHODS: Seventy-four patients who were intended to receive RSVP-SPDP at the First Affiliated Hospital of Sun Yat-sen University between May 2015 and January 2023 were included. The learning curve were retrospectively analyzed by using cumulative sum (CUSUM) analyses. RESULTS: Sixty-two patients underwent RSVP-SPDP (spleen preservation rate: 83.8%). According to CUSUM curve, the operation time (median, 318 vs. 220 min; P < 0.001) and intraoperative blood loss (median, 50 vs. 50 mL; P = 0.012) was improved significantly after 16 cases. Blood transfusion rate (12.5% vs. 3.4%; P = 0.202), postoperative major morbidity rate (6.3% vs. 3.4%; P = 0.524), and postoperative length-of-stay (median, 10 vs. 8 days; P = 0.120) improved after 16 cases but did not reach statistical difference. None of the patients had splenic infarction or abscess postoperatively. CONCLUSION: RSVP-SPDP was a safe and feasible approach for selected patients after learning curve. The improvement of operation time and intraoperative blood loss was achieved after 16 cases.


Subject(s)
Laparoscopy , Pancreatic Neoplasms , Robotic Surgical Procedures , Splenic Infarction , Surgeons , Humans , Pancreatectomy , Retrospective Studies , Blood Loss, Surgical , Splenic Infarction/etiology , Splenic Infarction/surgery , Learning Curve , Treatment Outcome , Splenic Artery/surgery , Pancreatic Neoplasms/surgery
8.
BMC Cancer ; 23(1): 826, 2023 Sep 05.
Article in English | MEDLINE | ID: mdl-37670280

ABSTRACT

BACKGROUND: Hypertension is a risk factor for cholangiocarcinoma (CCA). The effect of anti-hypertensive drugs on the prognosis of CCA is not clear. METHODS: This is a retrospective study of 102 patients (56.9% males, median age 66 years) diagnosed with CCA and hypertension concurrently and received radical surgery (R0), with a median follow-up of 36.7 months. Kaplan-Meier analysis, Cox regressions, and propensity score (PS) matching were applied for statistical analysis. RESULTS: Results of multivariable cox analysis showed that renin-angiotensin system inhibitors (RASis) usage was a protective factor for progression-free survival (PFS) (hazard ratio [HR] = 0.55, 95% confidence interval [95% CI]: 0.32-0.96) and overall survival (OS) (HR = 0.40, 95% CI: 0.20-0.79), respectively. Calcium channel blockers, diuretics, and ß-blockers didn't show significant associations. The association of RASis usage and PFS and OS was derived by PS matching, with a cohort of 28 RASis users and 56 RASis non-users. The median PFS and OS of RASis users (PFS, 17.6 months (9.2-34.4); OS, 24.8 months (16.5-42.3)) were longer than RASis non-users (PFS, 10.5 months (4.1-24.1); OS, 14.6 months (10.6-28.4)). The 1 year, 2 years, and 3 years' survival rates of RASis users (89.1%, 77.0%, and 65.5%) were higher than RASis non-users (70.9%, 54.0%, and 40.0%). CONCLUSIONS: RASis usage improves the survival of patients with CCA and hypertension concurrently.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Hypertension , Male , Humans , Aged , Female , Antihypertensive Agents , Cohort Studies , Retrospective Studies , Propensity Score , Renin-Angiotensin System , Enzyme Inhibitors , Bile Ducts, Intrahepatic
9.
World J Gastroenterol ; 29(32): 4815-4830, 2023 Aug 28.
Article in English | MEDLINE | ID: mdl-37701136

ABSTRACT

The robotic liver resection (RLR) has been increasingly applied in recent years and its benefits shown in some aspects owing to the technical advancement of robotic surgical system, however, controversies still exist. Based on the foundation of the previous consensus statement, this new consensus document aimed to update clinical recommendations and provide guidance to improve the outcomes of RLR clinical practice. The guideline steering group and guideline expert group were formed by 29 international experts of liver surgery and evidence-based medicine (EBM). Relevant literature was reviewed and analyzed by the evidence evaluation group. According to the WHO Handbook for Guideline Development, the Guidance Principles of Development and Amendment of the Guidelines for Clinical Diagnosis and Treatment in China 2022, a total of 14 recommendations were generated. Among them were 8 recommendations formulated by the GRADE method, and the remaining 6 recommendations were formulated based on literature review and experts' opinion due to insufficient EBM results. This international experts consensus guideline offered guidance for the safe and effective clinical practice and the research direction of RLR in future.


Subject(s)
Robotic Surgical Procedures , Humans , Robotic Surgical Procedures/adverse effects , Hepatectomy/adverse effects , China , Consensus , Liver/surgery
10.
Gastroenterol Rep (Oxf) ; 11: goad042, 2023.
Article in English | MEDLINE | ID: mdl-37502197

ABSTRACT

Background: Robotic-assisted pancreatoduodenectomy (RPD) has been routinely performed in a few of centers worldwide. This study aimed to evaluate the perioperative outcomes and the learning curves of resection and reconstruction procedures in RPD by one single surgeon. Methods: Consecutive patients undergoing RPD by a single surgeon at the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) between July 2016 and October 2022 were included. The perioperative outcomes and learning curves were retrospectively analysed by using cumulative sum (CUSUM) analyses. Results: One-hundred and sixty patients were included. According to the CUSUM curve, the times of resection and reconstruction procedures were shortened significantly after 30 cases (median, 284 vs 195 min; P < 0.001) and 45 cases (median, 138 vs 120 min; P < 0.001), respectively. The estimated intraoperative blood loss (median, 100 vs 50 mL; P < 0.001) and the incidence of clinically relevant post-operative pancreatic fistula (29.2% vs 12.5%; P = 0.035) decreased significantly after 20 and 120 cases, respectively. There were no significant differences in the total number of lymph nodes examined, post-operative major complications, or post-operative length-of-stay between the two groups. Conclusions: Optimization of the resection procedure and the acquisition of visual feedback facilitated the performance of RPD. RPD was a safe and feasible procedure in the selected patients.

11.
Cell Death Differ ; 30(7): 1742-1756, 2023 07.
Article in English | MEDLINE | ID: mdl-37188742

ABSTRACT

In the past few decades, advances in the outcomes of patients suffering from pancreatic ductal adenocarcinoma (PDAC) have lagged behind these gained in the treatment of many other malignancies. Although the pivotal role of the SUMO pathway in PDAC has been illustrated, the underlying molecule drivers have yet to be fully elucidated. In the present study, we identified SENP3 as a potential suppressor of PDAC progression through an in vivo metastatic model. Further studies revealed that SENP3 inhibited PDAC invasion in a SUMO system dependent fashion. Mechanistically, SENP3 interacted with DKC1 and, as such, catalyzed the deSUMOylation of DKC1, which accepted SUMO3 modifiers at three lysine residues. SENP3-mediated deSUMOylation caused DKC1 instability and disruption of the interaction between snoRNP proteins, which contributed to the impaired migration ability of PDAC. Indeed, overexpression of DKC1 abated the anti-metastasis effect of SENP3, and DKC1 was elevated in PDAC specimens and associated with a poor prognosis in PDAC patients. Collectively, our findings shed light on the essential role of SENP3/DKC1 axis in the progression of PDAC.


Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Cell Movement , Pancreatic Neoplasms/pathology , Carcinoma, Pancreatic Ductal/pathology , Peptide Hydrolases/metabolism , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Cell Proliferation , Nuclear Proteins/metabolism , Cell Cycle Proteins/metabolism , Cysteine Endopeptidases/genetics , Cysteine Endopeptidases/metabolism , Pancreatic Neoplasms
12.
Gastroenterol Rep (Oxf) ; 11: goad018, 2023.
Article in English | MEDLINE | ID: mdl-37051578

ABSTRACT

Background: The application of robotic-assisted radical resection in perihilar cholangiocarcinoma (pCCA) remains poorly defined. This study aimed to evaluate the safety and efficacy of robotic-assisted radical resection for pCCA in our institute. Methods: Between July 2017 and July 2022, pCCA patients undergoing robotic-assisted and open radical resection at First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) were included. The short-term outcomes were compared by using propensity-scored matching (PSM) analysis. Results: Eighty-six pCCA patients were enrolled. After PSM at a ratio of 1:2, 10 and 20 patients were assigned to the robotic-assisted and open groups, respectively. There were no significant disparities in the clinicopathological features between the two groups. The robotic-assisted group had significantly longer operation time (median: 548 vs 353 min, P = 0.004) and larger total number of lymph nodes examined (median: 11 vs 5, P = 0.010) than the open group. The robotic-assisted group tended to have a lower intraoperative blood loss (median: 125 vs 350 mL, P = 0.067), blood transfusion rates (30.0% vs 70.0%, P = 0.056), and post-operative overall morbidities (30.0% vs 70.0%, P = 0.056) than the open group, even though the differences were not statistically significant. There were no significant differences in the negative resection margin, post-operative major morbidities, or post-operative length-of-stay between the robotic-assisted and open groups (all P > 0.05). Conclusions: Robotic-assisted radical resection of pCCA may get a larger total number of lymph nodes examined than open surgery. Provided robotic-assisted surgery may be a feasible and safe technique for selected pCCA patients.

13.
Clin Transl Med ; 13(3): e1213, 2023 03.
Article in English | MEDLINE | ID: mdl-36855786

ABSTRACT

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy characterized by massive fibrosis and has ineffective adjuvant therapies. Here, we demonstrate the potential of angiotensin receptor blockers (ARBs) in targeting iCCA. METHODS: Masson's trichrome staining was used to assess the effect of ARBs in iCCA specimens, CCK8 and gel contraction assays in vitro and in xenograft models in vivo. RNA-seq and ATAC-seq were used for mechanistic investigations. RESULTS: Patients with iCCA who were administered ARBs had a better prognosis and a lower proportion of tumour stroma, indicating alleviated fibrosis. The presence of AGTR1, the ARBs receptor, is associated with a poor prognosis of iCCA and is highly expressed in tumour tissues and cancer-associated fibroblasts (CAFs). The ARBs strongly attenuated the viability of AGTR1+ CAFs in vitro and retarded tumour progression and fibrosis in xenograft models of co-cultured CAFs and iCCA cells. Still, they did not have a significant effect on AGTR1- CAFs. Moreover, ARBs decreased the secretion of AGTR1+ CAF-derived MFAP5 via the Hippo pathway, weakened the interaction between CAFs and iCCA cells, and impaired the aggressiveness of iCCA cells by attenuating the activation of the Notch1 pathway in iCCA cells. CONCLUSIONS: ARBs exhibit anti-fibrotic function by inhibiting the viability of AGTR1+ CAFs. These findings support using ARBs as a novel therapeutic option for targeting iCCA.


Subject(s)
Bile Duct Neoplasms , Cancer-Associated Fibroblasts , Cholangiocarcinoma , Animals , Humans , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors , Cholangiocarcinoma/drug therapy , Disease Models, Animal , Bile Duct Neoplasms/drug therapy , Bile Ducts, Intrahepatic , Receptor, Angiotensin, Type 1/genetics
14.
Gastroenterol Rep (Oxf) ; 11: goad010, 2023.
Article in English | MEDLINE | ID: mdl-36911142

ABSTRACT

Background and objective: The value of debulking surgery for unresectable well-differentiated metastatic pancreatic neuroendocrine tumor (m-PNET) remains poorly defined. This study aimed to evaluate the outcomes of m-PNET following debulking surgery in our institute. Methods: Patients with well-differentiated m-PNET in our hospital between February 2014 and March 2022 were collected. Clinicopathological and long-term outcomes of patients treated with radical resection, debulking surgery, and conservative therapy were compared retrospectively. Results: Fifty-three patients with well-differentiated m-PNET were reviewed, including 47 patients with unresectable m-PNET (debulking surgery, 25; conservative therapy, 22) and 6 patients with resectable m-PNET (radical resection). Patients undergoing debulking surgery had a post-operative Clavien-Dindo ≥ III complication rate of 16.0% without mortality. The 5-year overall survival (OS) rate of patients treated with debulking surgery was significantly higher than that of those treated with conservative therapy alone (87.5% vs 37.8%, log-rank P = 0.022). Besides, the 5-year OS rate of patients treated with debulking surgery was comparable to that of patients with resectable m-PNET undergoing radical resection (87.5% vs 100%, log-rank P = 0.724). Conclusions: Patients with unresectable well-differentiated m-PNET who underwent resection had better long-term outcomes than those who received conservative therapy alone. The 5-year OS of patients undergoing debulking surgery and radical resection were comparable. Debulking surgery could be considered for patients with unresectable well-differentiated m-PNET if no contraindication exists.

15.
J Neuroinflammation ; 20(1): 69, 2023 Mar 11.
Article in English | MEDLINE | ID: mdl-36906561

ABSTRACT

BACKGROUND: Microglial activation-mediated neuroinflammation is one of the essential pathogenic mechanisms of sepsis-associated encephalopathy (SAE). Mounting evidence suggests that high mobility group box-1 protein (HMGB1) plays a pivotal role in neuroinflammation and SAE, yet the mechanism by which HMGB1 induces cognitive impairment in SAE remains unclear. Therefore, this study aimed to investigate the mechanism of HMGB1 underlying cognitive impairment in SAE. METHODS: An SAE model was established by cecal ligation and puncture (CLP); animals in the sham group underwent cecum exposure alone without ligation and perforation. Mice in the inflachromene (ICM) group were continuously injected with ICM intraperitoneally at a daily dose of 10 mg/kg for 9 days starting 1 h before the CLP operation. The open field, novel object recognition, and Y maze tests were performed on days 14-18 after surgery to assess locomotor activity and cognitive function. HMGB1 secretion, the state of microglia, and neuronal activity were measured by immunofluorescence. Golgi staining was performed to detect changes in neuronal morphology and dendritic spine density. In vitro electrophysiology was performed to detect changes in long-term potentiation (LTP) in the CA1 of the hippocampus. In vivo electrophysiology was performed to detect the changes in neural oscillation of the hippocampus. RESULTS: CLP-induced cognitive impairment was accompanied by increased HMGB1 secretion and microglial activation. The phagocytic capacity of microglia was enhanced, resulting in aberrant pruning of excitatory synapses in the hippocampus. The loss of excitatory synapses reduced neuronal activity, impaired LTP, and decreased theta oscillation in the hippocampus. Inhibiting HMGB1 secretion by ICM treatment reversed these changes. CONCLUSIONS: HMGB1 induces microglial activation, aberrant synaptic pruning, and neuron dysfunction in an animal model of SAE, leading to cognitive impairment. These results suggest that HMGB1 might be a target for SAE treatment.


Subject(s)
Cognitive Dysfunction , HMGB1 Protein , Sepsis-Associated Encephalopathy , Sepsis , Animals , Mice , Cognitive Dysfunction/metabolism , Disease Models, Animal , Hippocampus/metabolism , HMGB1 Protein/metabolism , Neuroinflammatory Diseases , Sepsis/complications , Sepsis-Associated Encephalopathy/metabolism
16.
Transl Androl Urol ; 12(2): 286-299, 2023 Feb 28.
Article in English | MEDLINE | ID: mdl-36915886

ABSTRACT

Background: Tumor-derived exosomes are involved in the process of tumor metastasis and angiogenesis. MicroRNAs (miRNAs) are the most widely investigated factors in exosomes. Therefore, we hope to find a new therapeutic target in bladder cancer (BLCA), which has high incidence rate and mortality. Methods: Exosomal microRNA(miR)-93-5p expression level, downstream target molecules, and biological functions were examined with bioinformatics technology. Exosomes were extracted by sequential differential centrifugation and verified by transmission electron microscopy. The exosomal miR-93-5p on cell proliferation, invasion, and angiogenesis abilities in 5637 and T24 cells was determined by Cell Counting Kit 8 (CCK-8), colony-forming assay, Transwell assay, and vascular ring formation assay. A mouse xenograft model with intratumor injection was adopted to evaluate the correlation between BLCA-derived exosomes and tumor growth in vivo. Results: The results revealed that exosomes play an important role in the biological progression of BLCA, with miR-93-5p being a particularly important molecule. Compared to normal cells, more malignant cells release more exosomal miR-93-5p, and tumor-derived exosomal miR-93-5p could significantly promote cell proliferation, invasion, and angiogenesis in vitro and in vivo. We identified phosphatase and tensin homolog (PTEN) as the most significant target of miR-93-5p in BLCA and human umbilical vein endothelial cells. Conclusions: Our study successfully revealed the biological role and mechanism of BLCA-derived exosomes in tumor progression. Target at tumor exosomes and exosomal miR-93-5p may be an effective treatment in BLCA.

17.
Clin Res Hepatol Gastroenterol ; 47(3): 102089, 2023 03.
Article in English | MEDLINE | ID: mdl-36707046

ABSTRACT

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a dismal prognosis. Cuproptosis, a novel mechanism mediated by protein lipoylation, results in acute proteotoxic stress and ultimately cell death. However, the clinical impacts of cuproptosis-associated genes and their relationship with immune status in PDAC have not been documented. In this study, we aimed at constructing a cuproptosis- and immune-associated prognostic signature to stratify and predict the prognosis for PDAC patients. METHODS: The gene expression profiles of 176 PDAC patients from The Cancer Genome Atlas and 167 normal pancreas tissues from the Genotype-Tissue Expression Project were analyzed for differentially expressed genes (DEGs) between PDAC and normal tissues. Pearson correlation analyses were performed to screen out cuproptosis- and immune-associated DEGs. The risk signature of DEGs was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis, which was validated in the Gene Expression Omnibus (GEO) cohort (n = 114). The immune characteristics in the two risk groups were evaluated using single-sample gene set enrichment analysis and ESTIMATE algorithms. RESULTS: A total of 91 cuproptosis- and immune-associated DEGs were screened out, and eight prognostic-related genes were identified using LASSO Cox regression. The prognostic-related genes were then used to construct a risk scoring model, which stratified patients into low- and high-risk groups and were further verified in the external GEO database. The patients in the high-risk group had significantly shorter overall survival than those in the low-risk group. A nomogram based on the risk signature was then constructed. Immune infiltration evaluation suggested that immune status was more activated in the low-risk group. The mutation spectrum also differed between high- and low-risk groups. CONCLUSIONS: Our cuproptosis- and immune-associated genetic risk signature could be a prognostic biomarker for PDAC. Cuproptosis might be a promising therapeutic target for PDAC.


Subject(s)
Apoptosis , Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/genetics , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/genetics , Prognosis , Risk Factors , Copper , Pancreatic Neoplasms
18.
Mol Ther ; 31(2): 503-516, 2023 02 01.
Article in English | MEDLINE | ID: mdl-36384875

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis. Gemcitabine-based chemotherapy has become one of the main modalities of its management. However, gemcitabine resistance frequently occurs, leading to failure of PDAC therapy. Platelet-derived growth factors (PDGFs) and their receptors play important roles in cancer progression and chemoresistance. We aimed to investigate the biological function and therapeutic significance of platelet-derived growth factor C (PDGFC) in drug-resistant PDAC. Our study showed that PDGFC was abnormally highly expressed in gemcitabine-resistant PDAC. Silencing PDGFC expression can enhance the therapeutic effect of gemcitabine on PDAC. Mechanistically, the transcription of PDGFC is mediated by H3K27 acetylation, and PDGFC promotes gemcitabine resistance by activating the PDGFR-PI3K-AKT signaling pathway. The PDGFR inhibitor imatinib inhibits the PDGFR pathway. Imatinib and gemcitabine have a synergistic effect on the treatment of PDAC, and imatinib can significantly enhance the anti-tumor effect of gemcitabine in a drug-resistant PDAC patient-derived xenograft model. In conclusion, PDGFC is a potential predictor of gemcitabine-resistant PDAC. Imatinib inhibits PDGFR activation to promote gemcitabine sensitivity in PDAC. Combined modality regimen of imatinib and gemcitabine is likely to translate into clinical trial for the treatment of PDGFC-associated gemcitabine-resistant patients.


Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Gemcitabine , Imatinib Mesylate/pharmacology , Imatinib Mesylate/therapeutic use , Deoxycytidine/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Cell Line, Tumor , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , Signal Transduction , Drug Resistance, Neoplasm/genetics
19.
Gastroenterol Rep (Oxf) ; 10: goac056, 2022.
Article in English | MEDLINE | ID: mdl-36263393

ABSTRACT

Background: The feasibility of spleen-preserving distal pancreatectomy (SPDP) to treat well-differentiated non-functioning pancreatic neuroendocrine tumors (NF-pNETs) located at the body and/or tail of the pancreas remains controversial. Distal pancreatectomy with splenectomy (DPS) has been widely applied in the treatment of NF-pNETs; however, it may increase the post-operative morbidities. This study aimed to evaluate whether SPDP is inferior to DPS in post-operative outcomes and survivals when being used to treat patients with NF-pNETs in our institute. Methods: Clinicopathological features of patients with NF-pNETs who underwent curative SPDP or DPS at the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) between January 2010 and January 2022 were collected. Short-term outcomes and 5-year survivals were compared between patients undergoing SPDP and those undergoing DPS. Results: Sixty-three patients (SPDP, 27; DPS, 36) with well-differentiated NF-pNETs were enrolled. All patients had grade 1/2 tumors. After identifying patients with T1-T2 NF-pNETs (SPDP, 27; DPS, 15), there was no disparity between the SPDP and DPS groups except for tumor size (median, 1.4 vs 2.6 cm, P = 0.001). There were no differences in operation time (median, 250 vs 295 min, P = 0.478), intraoperative blood loss (median, 50 vs 100 mL, P = 0.145), post-operative major complications (3.7% vs 13.3%, P = 0.287), clinically relevant post-operative pancreatic fistula (22.2% vs 6.7%, P = 0.390), or post-operative hospital stays (median, 9 vs 9 days, P = 0.750) between the SPDP and DPS groups. Kaplan-Meier curve showed no significant differences in the 5-year overall survival rate (100% vs 100%, log-rank P > 0.999) or recurrence-free survival (100% vs 100%, log-rank P > 0.999) between patients with T1-T2 NF-pNETs undergoing SPDP and those undergoing DPS. Conclusions: In patients with T1-T2 well-differentiated NF-pNETs, SPDP could achieve comparable post-operative outcomes and prognosis compared with DPS.

20.
Gastroenterol Rep (Oxf) ; 10: goac051, 2022.
Article in English | MEDLINE | ID: mdl-36196256

ABSTRACT

Background: Pyroptosis is an emerging form of programmed cell death associated with progression in malignancies. Yet, there are few studies reporting on the association between pancreatic ductal adenocarcinoma (PDAC) and pyroptosis. Therefore, we aimed to construct a pyroptosis-related genetic signature to predict the clinical outcome and immune status in PDAC patients. Methods: RNA-seq data of 176 PDAC patients from The Cancer Genome Atlas (TCGA) and 167 PDAC patients from the Genotype-Tissue Expression Project were analysed for pyroptosis-related differentially expressed genes (DEGs) between PDAC and normal pancreas. The risk signature of DEGs was analysed using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis and its accuracy was validated in the Gene Expression Omnibus (GEO) cohort (n = 190). Functional enrichment analyses were performed to explore the mechanisms of the DEGs. The immune characteristics were evaluated using single-sample gene set enrichment analysis and ESTIMATE algorithms for each group. Results: A nine-gene risk signature was generated from LASSO Cox regression analysis and classified PDAC patients into either a high- or low-risk group according to the median risk score. The high-risk group had significantly shorter overall survival than the low-risk group and it was verified in the external GEO database. A nomogram based on the risk signature was constructed and showed an ideal prediction performance. Functional enrichment analyses revealed that pyroptosis might regulate the tumor immune microenvironment in PDAC. Immune infiltration evaluation suggested that immune status was more activated in the low-risk group than in the high-risk group. Conclusion: The risk signature encompassing nine pyroptosis-related genes may be a prognostic marker for PDAC. Pyroptosis might affect the prognosis of PDAC patients via regulating the tumor immune microenvironment.

SELECTION OF CITATIONS
SEARCH DETAIL
...