RESUMO
The main mechanism of hyaluronidase 1(HYAL-1) in the development of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD) was unknown. In this study, a comprehensive inventory of pre-, intra-, and postoperative clinical and biological data of two cohorts (62 pancreatic cancer [PCa] and 111 pancreatic ductal adenocarcinoma [PDAC]) which could induce POPF were retrospectively analyzed. Then, a total of 7644 genes correlated with HYAL-1 was predicted in PDAC tissues and the enriched pathway, kinase targets and biological process of those correlated genes were evaluated. Finally, a mouse pancreatic fistula (PF) model was first built and in vitro studies were performed to investigate the effects of HYAL-1 on PF progression. Our data indicated that preoperative serum HYAL-1 level, pancreatic fibrosis score, and pancreatic duct size were valuable factors for detecting POPF of Grade B and C. The serum HYAL-1 level of 2.07 mg/ml and pancreatic fibrosis score of 2.5 were proposed as the cutoff values for indicating POPF. The bioinformatic analysis and in vitro and in vivo studies demonstrated that HYAL-1 facilitates pancreatic acinar cell autophagy via the dephosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and signal transducers and activators of transcription 3 (STAT3) signaling pathways, which exacerbate pancreatic secretion and inflammation. In summary, the preoperative serum HYAL-1 was a significant predictor for POPF in patients who underwent PD. Tumor-induced HYAL-1 is one of core risk in accelerating PF and then promoting pancreatic secretion and acute inflammation response through the AMPK and STAT3-induced autophagy.
Assuntos
Autofagia/fisiologia , Hialuronoglucosaminidase/sangue , Fístula Pancreática/patologia , Pancreaticoduodenectomia , Adulto , Idoso , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Feminino , Humanos , Intestinos/patologia , Masculino , Pessoa de Meia-Idade , Pâncreas/patologia , Fístula Pancreática/diagnóstico , Fístula Pancreática/cirurgia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/métodos , Estudos Retrospectivos , Fatores de Risco , Neoplasias PancreáticasRESUMO
BACKGROUND Acute pancreatitis (AP) is a common digestive disorder. Its management depends on the severity; therefore, it is essential to stratify AP patients early. D-dimer, a coagulation indicator, appears to be associated with the pathogenesis of AP. The aim of this study was to evaluate D-dimer as an early predictor of the severity of AP. MATERIAL AND METHODS This was a single-center retrospective study of 1260 patients diagnosed based on the revised Atlanta classification. Only patients hospitalized within 24 h of onset were included, and 334 patients were enrolled. Blood was collected at admission and 3 times within 48 h of admission. Values at admission and average of the 3 blood samples were evaluated by univariate and multivariate analyses. Furthermore, the area under the receiver-operating characteristic curve (AUC) was used to estimate the validity of the predictor and to define optimal cut-off points for prediction. RESULTS We found that 53.3% of the patients had mild AP (MAP), 24.3% had moderately severe AP (MSAP), and 22.4% had severe AP (SAP). D-dimer at admission and the average D-dimer could distinguish MAP patients from MSAP and SAP patients, with cut-off values of 3.355 mg/L and 4.868 mg/L, respectively. No difference in the parameters at admission was observed in multivariate analysis in distinguishing SAP from MSAP, but the average D-dimer level was significantly different with a cut-off value of 7.268 mg/L by comparing Ranson score, APACHE II score, and D-dimer level. CONCLUSIONS The average value of D-dimer levels could be used as a predictor of severity of AP. In general, patients with an average D-dimer level <4.868 could be diagnosed with MAP, >7.268 would develop into SAP, and between 4.868 and 7.268 would be MSAP.
Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Pancreatite/metabolismo , APACHE , Doença Aguda , Adulto , China , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite/classificação , Plasma/química , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
Currently, preliminary results have confirmed the existence of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL)-dependent necroptosis of pancreatic acinar cells during early acute pancreatitis (AP), which might be a potential target for the effective regulation of necroinflammatory injury. However, the exact effect of receptor-interacting protein kinase 1 (RIPK1)-dependent regulated acinar cell necrosis on AP is still uncertain. In our study, we first explored the changes in the degree of local and systemic inflammation in AP rats when the activation of acinar cell RIPK1 was inhibited. The RIPK1 inhibitor Nec-1 was used to treat rats, and the levels of related inflammatory markers, necrosis indicators and apoptotic indicators were measured. Changes in pancreatic nuclear factor κB (NF-κB) and aquaporin 8 (AQP8) expression were noted. Next, the expression of AQP8 in AR42J cells was inhibited, and the degree of cell necrosis and inflammatory damage was found to be significantly reduced. Most importantly, we demonstrated that the RIPK1/NF-ĸB/AQP8 axis might be a potential regulatory pathway mediating RIPK1-dependent regulated acinar cell necrosis in early AP. Finally, we used the NF-κB inhibitor PDTC and Nec-1 to treat rats in different groups and measured the degree of pathological pancreatic injury, the activation of RIPK1, and the expression of NF-κB and AQP8. In summary, we hypothesized that there might be a RIPK1/NF-ĸB/AQP8 pathway controlling RIPK1-dependent regulated necrosis of acinar cells in AP, which might be a promising therapeutic target against AP-related injury.
Assuntos
Células Acinares/efeitos dos fármacos , Células Acinares/patologia , Imidazóis/farmacologia , Indóis/farmacologia , Pancreatite/prevenção & controle , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Aquaporinas/antagonistas & inibidores , Aquaporinas/genética , Aquaporinas/metabolismo , Linhagem Celular , Masculino , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Necrose/prevenção & controle , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pancreatite/patologia , Prolina/análogos & derivados , Prolina/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Wistar , Proteína Serina-Treonina Quinases de Interação com Receptores , Transdução de Sinais/efeitos dos fármacos , Tiocarbamatos/farmacologiaRESUMO
BACKGROUND: The objective of this study was to evaluate the surgical risk and prognosis between thyroid nodules of size <1 and ≥1 cm and to explore whether it is reasonable generally to ignore the diagnosis and treatment of thyroid nodules and thyroid carcinoma <1 cm in wide areas of China. METHODS: A retrospective observational study included all first-time thyroid surgery patients between January 2005 and December 2016 of the First Affiliated Hospital of Harbin Medical University. All patients were divided into two groups (group A: <1 cm, group B: ≥1 cm) according to the maximum diameter of the nodules and demographics, surgery procedure, pathology, postoperative complications, morbidity, and mortality were analyzed. RESULTS: A total of 6,317 patients were reviewed and 3,424 (54.20%) of them were malignant; 2,128 patients in group A and 4,189 in group B. Patients in group A had better pathological diagnosis, inferior extent of lymph node metastasis, less surgical complexity, fewer postoperative complications, and longer disease-free survival (DFS). CONCLUSIONS: Thyroid operations were safer and involved fewer postoperative complications when thyroid nodules were <1 cm and patients who were diagnosed with malignant thyroid disease had superior prognoses. Underdeveloped regions of China should diagnose and treat thyroid nodules <1 cm early.
RESUMO
OBJECTIVES: This study aimed to assess the need of surgical necrosectomy after percutaneous catheter drainage (PCD) for infected necrotizing pancreatitis. METHODS: The clinical data of documented/suspected patients who were treated with a step-up approach were extracted and analyzed. RESULTS: Of the 329 patients enrolled, the initial PCD was performed at 12 (interquartile range, 9-15) days since onset and 35.3% were cured by PCD alone. In the pre-PCD model, mean computed tomographic (CT) density of necrotic fluid collection (NFC; P < 0.001), and multiple-organ failure (MOF; P < 0.001) within 24 hours before the initial PCD were independent risk factors, and a combination of the previously mentioned 2 factors produced an area under the curve of 0.775. In the post-PCD model, mean CT density of NFC (P = 0.041), MOF (P = 0.002), and serum procalcitonin level (P = 0.035) 3 days after the initial PCD were independent risk factors, and a combination of these previously mentioned factors produced an area under the curve of 0.642. CONCLUSIONS: Both mean CT density of NFC and MOF are independent pre- and post-PCD risk factors for the need of necrosectomy after PCD. Post-PCD serum procalcitonin level might be a respondent factor that is correlated with the necessity of necrosectomy.
Assuntos
Drenagem/métodos , Infecções/cirurgia , Pancreatite Necrosante Aguda/cirurgia , Adulto , Líquidos Corporais/química , Catéteres , Feminino , Humanos , Infecções/etiologia , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/complicações , Insuficiência de Múltiplos Órgãos/diagnóstico por imagem , Necrose , Pancreatite Necrosante Aguda/complicações , Fatores de Risco , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Chronic pancreatitis (CP) is described as a progressive fibro-inflammatory disorder of the exocrine disease, which eventually leads to damage of the gland. Excessive activation of pancreatic stellate cells (PSCs) is a critical participant in the initiation of CP. Autophagy is involved in multiple degeneration and inflammation in acute pancreatitis and CP. In our study, we report that retinoblastoma coiled coil protein 1 (RB1CC1) expression and the autophagic level are elevated in activated PSCs. RB1CC1 is positively correlated with pancreatic fibrogenesis in tissues and plasma of CP patients. Knockdown of RB1CC1 restrains alpha smooth muscle actin (α-SMA) and collagen expressions, and autophagy in activated PSCs in vitro. Furthermore, we show that RB1CC1 induces PSC activation via binding to ULK1 promoter and the direct interaction with ULK1 protein. These suppress ULK1 expression and its kinase activity. In mice, knockdown of RB1CC1 blocks autophagy and then inhibits the pancreatic duct ligation-induced pancreatic fibrosis. Consequently, our study highlights that RB1CC1-mediated autophagy is a key event for the activation of PSCs. Inhibition of RB1CC1 alleviates autophagy, which plays a critical role in anti-fibrotic activation in PSCs and CP progression. RB1CC1 could be a novel strategy for the treatment of pancreatic fibrosis.