HYAL-1-induced autophagy facilitates pancreatic fistula for patients who underwent pancreaticoduodenectomy.

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.

Sodium butyrate inhibits the production of HMGB1 and attenuates severe burn plus delayed resuscitation-induced intestine injury via the p38 signaling pathway.

BACKGROUND: Inflammatory response triggered by high mobility group box-1 (HMGB1) protein and oxidative stress play critical roles in the intestinal injury after severe burn. Sodium butyrate, a histone deacetylase inhibitor, has potential anti-inflammatory properties, inhibiting the expression of inflammatory mediators such as HMGB1 in diverse diseases. This study was designed to investigate the effects of sodium butyrate on severe burn plus delayed resuscitation-induced intestine injury, intestinal expressions of HMGB1 and intracellular adhesion molecule-1 (ICAM-1), oxidative stress, and signal transduction pathway changes in rats. MATERIALS AND METHODS: Fifty-six Sprague-Dawley rats were divided into 3 groups randomly: (1) sham group, animals underwent sham burn; (2) burn group, rats subjected to full-thickness burns of 30% total body surface area (TBSA) and received 2ml/kg/TBSA lactated Ringer solution for resuscitation at 6, 12, and 36h after burn injury; (3) burn plus sodium butyrate (burn+SB) group, animals received burn injury and lactated Ringer solution with sodium butyrate inside for resuscitation in the same manner. Diamine oxidase (DAO) concentration in plasma was measured by enzyme-linked immunosorbent assay. Intestinal fatty acid binding protein (I-FABP) and ICAM-1 expressions in the intestine were analyzed by immunohistochemical method. HMGB1 and p38 mitogen-activated protein kinase (MAPK) expressions in the intestine tissues were examined by Western blot. The intestinal concentration of malondialdehyde (MDA) was also determined. RESULTS: Intestinal HMGB1 expression was significantly increased in burn group compared with sham group. Sodium butyrate administration significantly inhibited the HMGB1 expression in the intestine, decreased the DAO concentration in plasma, reduced the intestinal I-FABP expression, and improved the intestinal histologic changes induced by burn injury plus delayed resuscitation. Sodium butyrate treatment also markedly reduced the increase of intestinal ICAM-1 expression and MDA content, and inhibited p38 MAPK activity in the intestine of severely burned rats with delayed resuscitation. CONCLUSIONS: Sodium butyrate inhibits HMGB1 expression which could be attributed to p38 MAPK signal transduction pathway and decreases intestinal inflammatory responses and oxidative stress, thus attenuates burn plus delayed resuscitation-induced intestine injury.

Risk Factors for the Need of Surgical Necrosectomy After Percutaneous Catheter Drainage in the Management of Infection Secondary to Necrotizing Pancreatitis.

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.

RB1CC1-enhanced autophagy facilitates PSCs activation and pancreatic fibrogenesis in chronic pancreatitis.

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.

Early prediction of infected pancreatic necrosis secondary to necrotizing pancreatitis.

To assess the association between the clinical parameters within 48 hours of admission and the occurrence of infected pancreatic necrosis (IPN) during the late phase of necrotizing pancreatitis (NP).All patients were divided into 2 groups, the IPN and non-IPN groups. The clinical data were retrospectively analyzed. Univariate and multivariate logistic regression analyses were performed to evaluate the relationship between clinical parameters and IPN secondary to NP. The performance of each independent variable was plotted by the receiver-operating characteristic (ROC) curve. Consequently, the cut-off level of each independent variable with its sensitivity and specificity was calculated.A total of 215 patients were enrolled in our study. Among them, 87 (40.5%) patients developed IPNs after a median of 13.5 (9.5-23.0) days from admission. Multivariate analysis indicated that the level of hematocrit (HCT) from 40% to 50% (P=.012, odds ratio (OR) = 2.407), HCT over 50% (P < .009, OR = 6.794), blood urea nitrogen (BUN) (P = .040, OR = 1.894), C-reactive protein (CRP) (P = .043, OR = 1.837), and procalcitonin (PCT) (P = .002, OR = 2.559) were independent risk factors of IPN secondary to NP. The ROC cures revealed that the area under the ROC (AUC) of the maximum level of HCT, BUN, CRP, and PCT within 48 hours of admission was 0.687, 0.620, 0.630, and 0.674 respectively. Furthermore, the combination of these 4 individual parameters contributes to a more preferable AUC of 0.789 with a sensitivity of 67.8% and specificity of 77.3%.The maximum levels of PCT, CRP, HCT, and BUN within 48 hours of admission are independent factors of IPN and their combination might accurately predict the occurrence of IPN secondary to NP.

Plasma and tumor levels of Linc-pint are diagnostic and prognostic biomarkers for pancreatic cancer.

Long intergenic non-protein coding RNA, p53 induced transcript (Linc-pint) is a long noncoding RNA (lncRNA) that regulates tumor cell viability and proliferation. We used qRT-PCR and RNA FISH analysis to evaluate Linc-pint levels in the plasma and tumor tissues of pancreatic cancer (PCa) patients. Our data demonstrate that Linc-pint expression is lower in plasma samples from PCa patients than from healthy individuals, and indicate that plasma Linc-pint levels are more sensitive than CA19-9 for detecting PCa. Our data also show that Linc-pint levels are lower in PCa tumors than in adjacent tissues, carcinoma of the ampulla of Vater (CAV) and cholangiocarcinoma (CCA), and suggest that Linc-pint could be used for distinguishing the cause of malignant obstructive jaundice. Low plasma Linc-pint levels correlate with tumor recurrence, while low tumor Linc-pint levels correlate with poor prognosis for PCa patients after pancreatectomy. These results thus indicate that low plasma Linc-pint expression could serve as a minimally invasive biomarker for early PCa detection, and that low Linc-pint levels in PCa tumors could be used for predicting patient prognosis.