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Figure S1-S5

DNA repair mechanisms are crucial for cell survival. It increases the cancer cell's ability to resist DNA damage. FEN1 is involved in DNA replication and repair, specifically long-patch base excision repair. Although the gene function and post-translational modification of FEN1 are well studied, the regulatory mechanism of FEN1 by upstream signal pathways remains unclear. In this article, we have identified AKT as a regulator of FEN1 activity in lung cancer cells. Sustained activation of AKT can phosphorylate nuclear transcription factor NF-κB/p65. NF-κB/p65 directly binds to FEN1 promoter to promote a high transcription level of FEN1, revealing the contribution of the AKT signaling pathway to drug resistance of cancer cells. The combination of an AKT inhibitor and cisplatin efficiently suppressed lung cancer cell growth both in vitro and in vivo. Our study illustrated an upstream regulatory mechanism of FEN1, which will contribute to the development of effective lung cancer therapies.These findings identified AKT as a regulator of FEN1 activity and revealed the AKT signaling pathway's contribution to drug resistance, which will contribute to the development of effective lung cancer therapy.

Objective The aim of this study was to analyze the predictive role of serum gastrin-17 (G-17) for oral mucositis in head and neck carcinoma (HNC) patients receiving radiotherapy. Methods Serum G-17 were detected in patients before and after radiotherapy. Patients were divided into high G-17 group (baseline serum G-17 ≥ 5pmol/L) and low G-17 group (baseline serum G-17

Camptothecin has been used in tumor therapy for a long time but its antitumor effect is rather limited due to the side effect and the drug resistance. FEN1, a major component of DNA repair systems, plays important roles in maintaining genomic stability via DNA replication and repair. Here we found that FEN1 inhibitor greatly sensitizes cancer cells to low-dose camptothecin. The combinative treatment of FEN1 inhibitor and 1 nM camptothecin induced a synthetic lethal effect, which synergistically suppressed cancer cell proliferation and significantly mediated apoptosis both in vitro and in vivo. Our study suggested that targeting FEN1 could be a potent strategy for tumor-targeting cancer therapy.

DNA repair mechanisms are crucial for cell survival. It increases the cancer cell's ability to resist DNA damage. FEN1 is involved in DNA replication and repair, specifically long-patch base excision repair. Although the gene function and post-translational modification of FEN1 are well studied, the regulatory mechanism of FEN1 by upstream signal pathways remains unclear. In this article, we have identified AKT as a regulator of FEN1 activity in lung cancer cells. Sustained activation of AKT can phosphorylate nuclear transcription factor NF-κB/p65. NF-κB/p65 directly binds to FEN1 promoter to promote a high transcription level of FEN1, revealing the contribution of the AKT signaling pathway to drug resistance of cancer cells. The combination of an AKT inhibitor and cisplatin efficiently suppressed lung cancer cell growth both in vitro and in vivo. Our study illustrated an upstream regulatory mechanism of FEN1, which will contribute to the development of effective lung cancer therapies. These findings identified AKT as a regulator of FEN1 activity and revealed the AKT signaling pathway's contribution to drug resistance, which will contribute to the development of effective lung cancer therapy.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme involved in energy metabolism. Recently, GAPDH has been suggested to have extraglycolytic functions in DNA repair, but the underlying mechanism for the GAPDH response to DNA damage remains unclear. Here, we demonstrate that the tyrosine kinase Src is activated under DNA damage stress and phosphorylates GAPDH at Tyr41. This phosphorylation of GAPDH is essential for its nuclear translocation and DNA repair function. Blocking the nuclear import of GAPDH by suppressing Src signaling or through a GAPDH Tyr41 mutation impairs its response to DNA damage. Nuclear GAPDH is recruited to DNA lesions and associates with DNA polymerase β (Pol β) to function in DNA repair. Nuclear GAPDH promotes Pol β polymerase activity and increases base excision repair (BER) efficiency. Furthermore, GAPDH knockdown dramatically decreases BER efficiency and sensitizes cells to DNA damaging agents. Importantly, the knockdown of GAPDH in colon cancer SW480 cells and xenograft models effectively enhances their sensitivity to the chemotherapeutic drug 5-FU. In summary, our findings provide mechanistic insight into the new function of GAPDH in DNA repair and suggest a potential therapeutic target in chemotherapy.

Objective This study aimed to evaluate the incidence and risk factors for acute cholecystitis (AC) in the late phase of severe acute pancreatitis (SAP). Methods A review of patients with SAP from January 2008 to December 2009 was performed. Clinical characteristics were compared between patients with AC in the late phase and those without. Risk factors for AC were analyzed using a logistic regression analysis. Receiver operating characteristic curve was used to estimate the predictive value of the risk factors. Results A total of 269 cases were included. Twenty-seven episodes of AC in the late phase were identified. Patients with AC had higher computed tomography severity index and Acute Physiology and Chronic Health Evaluation (APACHE) II score, as well as higher rate of intraabdominal hypertension, infective pancreatic necrosis (IPN) of the pancreas head, fistula, abdominal bleeding, mechanical ventilation, and prolonged enteral nutrition (EN) via jejunal tube. Independent risk factors for AC, based on the results of logistic regression analysis, included higher APACHE II score, prolonged EN via jejunal tube, and IPN of the pancreas head. Conclusions Approximately 10% of patients with SAP will develop AC in the late phase. Risk factors include higher APACHE II score, prolonged EN via jejunal tube, and IPN of the pancreas head.

The aim of this study was to investigate the role of hypertriglyceridemia for acute kidney injury (AKI) in the course of acute pancreatitis.Patients with acute pancreatitis were retrospectively divided into four groups according to admission triglyceride: normal group, mild HTG group, moderate HTG group and severe HTG group. Clinical characteristics were compared among these groups. Wild type (WT) mice and Human ApoC III transgenic (ApoCIIItg) mice were used in the next animal experiments. Severe acute pancreatitis (SAP) model was established by retrograde injection of 0.5% sodium taurocholate (0.1 ml/100 g) from duodenum to pancreatic duct. Histological scores, serum amylase, creatinine, usea nitrogen were compared between WT mice and ApoCIIItg mice.Two hundred and sixty-two patients were classified into 4 groups: normal TG (104, 39.7%), mild HTG (72, 27.5%), moderate HTG (47, 17.9%), and severe HTG (39, 14.9%) groups. The proportions of AKI were 13.5% (14/104, normal), 13.9% (10/72, mild), 21.3% (10/47, moderate), and 38.5% (15/39, severe), respectively. After establishing SAP model, the levels of serum amylase (P 0.05) and pancreatic histological score (P 0.05) of ApoCIII-SAP-9h group were significantly higher than that of WT-SAP-9h group, respectively. ApoCIII-SAP-9h group had significantly higher levels of serum creatinine (P 0.001), usea nitrogen (P 0.001), and kidney histological score (P 0.05) than that of WT-SAP-9h group, respectively.Mild HTG has little adverse impact on disease severity of acute pancreatitis; severe HTG can aggravate kidney injury in the course of acute pancreatitis. ApoCIII-SAP mice have more serious pancreatic damage and kidney injury than WT-SAP mice.

Sphingosine-1-phosphate type-1 receptor (S1P1) agonists have the potential to inhibit the egress of lymphocytes, and have been demonstrated to provide protective effects on some acute inflammatory diseases. However, the value of S1P1 agonists on acute pancreatitis (AP) remains unclear. The aim of this study was to explore the effect of SEW2871, a S1P1-selective agonist, on caerulein-induced AP in mice. AP was induced by giving eight intraperitoneal injections of caerulein (50 µg/kg/h) at hourly intervals. SEW2871 was administered by gavage, at a dose of 20 mg/kg, at 0 h and 12 h after the first intraperitoneal injection of caerulein. The mice were sacrificed at 24 h. Severity of AP, serum amylase and lipase activity, levels of serum cytokines, pancreatic myeloperoxidase (MPO) activity, CD45+CD4+ T lymphocytes in blood, CD4+ T cell infiltration in the pancreas, and proinflammatory cytokine production were assessed. Furthermore, the expression of signal transducer and activator of transcription (STAT) 3 and phospho-STAT3 (p-STAT3) in the pancreas was also evaluated. The results revealed that the administration of SEW2871 ameliorated the severity of AP, by a reduction of serum pancreatic enzyme activity and levels of cytokines, decreased pancreatic MPO activity, depletion of CD4+CD45+ T lymphocytes in the blood and a reduction of CD4+ T cell infiltration in the pancreas. Furthermore, the expression of proinflammatory cytokines mRNA and p-STAT3 were also suppressed by SEW2871 treatment. These results suggest that SEW2871 treatment attenuates the severity of caerulein-induced AP in mice, which may provide a new therapeutic approach for AP therapy.

Critical acute pancreatitis (CAP) has recently emerged as the most ominous severity category of acute pancreatitis (AP). As such there have been no studies specifically designed to evaluate predictors of CAP. In this study, we aimed to evaluate the accuracy of 4 parameters (Acute Physiology and Chronic Health Evaluation [APACHE] II score, C-reactive protein [CRP], D-dimer, and intra-abdominal pressure [IAP]) for predicting CAP early after hospital admission. During the study period, data on patients with AP were prospectively collected and D-dimer, CRP, and IAP levels were measured using standard methods at admission whereas the APACHE II score was calculated within 24 hours of hospital admission. The receiver-operating characteristic (ROC) curve analysis was applied and the likelihood ratios were calculated to evaluate the predictive accuracy. A total of 173 consecutive patients were included in the analysis and 47 (27%) of them developed CAP. The overall hospital mortality was 11% (19 of 173). APACHE II score ≥11 and IAP ≥13 mm Hg showed significantly better overall predictive accuracy than D-dimer and CRP (area under the ROC curve—0.94 and 0.92 vs 0.815 and 0.667, correspondingly). The positive likelihood ratio of APACHE II score is excellent (9.9) but of IAP is moderate (4.2). The latter can be improved by adding CRP (5.8). In conclusion, of the parameters studied, APACHE II score and IAP are the best available predictors of CAP within 24 hours of hospital admission. Given that APACHE II score is rather cumbersome, the combination of IAP and CRP appears to be the most practical way to predict critical course of AP early after hospital admission.

The aim of this study was to investigate the risk factors for acute kidney injury (AKI) in patients with acute pancreatitis (AP).Patients with AP were retrospectively divided into AKI group and non-AKI group. To investigate the risk factors for AKI, logistic regression analysis was performed with demography, etiologies, and comorbidities. Mortalities of patients with different body mass indexes were compared.There were 43 patients with AKI and 202 patients without AKI. The risk factor for AKI in AP was hypertriglyceridemia (odds ratio, 2.964; 95% confidence interval, 1.485-5.915; P = 0.007). Forty-two patients developed AKI within the first 48 hours. The mortalities of normal weight, overweight, and obese groups in patients with AKI were 16.7%, 17.4%, and 62.5%, respectively. All the 4 patients who died in the non-AKI group were of normal weight.Hypertriglyceridemia is an independent risk factor for AKI in the early phase of AP. Obesity does not increase mortality of patients without AKI. We hypothesize that the role of pancreatic enzymes on triglyceride accumulated in renal may be an explanation for AKI in the early phase of AP.

To explore early (within 72 h) vs delayed enteral nutrition (EN) therapy for patients with acute pancreatitis (AP). A total of 93 patients were allocated to two groups: early enteral nutrition (EEN) group (started within 72 h after onset) and delayed enteral nutrition (DEN) group (started beyond 72 h but within 7 days after onset). Baseline parameters and scores were recorded on admission and on day 3 after the initiation of EN therapy, as were the clinical outcome variables. Hospital mortality, length of stay, number of patients requiring mechanical ventilation and incidence of pancreatic infection in the EEN group were significantly lower than those in the DEN group; all six reported deaths were in the DEN group. In the DEN group, more patients suffered from sepsis, shock or acute kidney injury, and more patients required surgical intervention or continuous renal replacement therapy. On day 3 after EN therapy was initiated, the acute physiology and chronic health evaluation II scores, sequential organ failure assessment scores, C-reactive protein levels and the incidence of bowel wall thickening were lower in the EEN group than in the DEN group. The time when EN therapy was initiated was a prognostic variable for pancreatic infection (odds ratio, 24.08; P=0.014). Compared with the DEN therapy, EEN therapy can accelerate the recovery of disturbed homeostasis, reduce the incidence of pancreatic infection and improve the clinical outcomes of AP patients. For AP patients, EN therapy should be initiated within 72 h after onset.