Predictive analysis of water resource carrying capacity based on system dynamics and improved fuzzy comprehensive evaluation method in Henan Province.

The water resource carrying capacity (WRCC) is a carrying capacity of natural resources. It affects the application and expansion of the carrying capacity of water resources. This subject involves various elements, such as water resources, the ecological environment system, humans and their economic and social systems, and a wider range of biological groups and their survival needs. Based on the objective recognition of the complex relationship between the water resource system, ecological environment system, and economic and social system, the support scale of water resources and the ecological environment for economic and social development is studied. Current research on the carrying capacity of water resources has mostly shifted from the previously limited support capacity of water resources to include factors such as the population, economy, and ecology, establishing the internal relationships between the economics, water resources, and ecological environment. This reflects the comprehensive carrying capacity of the entire region (or river basin) of water resources and the ecological environment system on an overall economic and social scale. Based on the conceptual connotation of the WRCC and the actual problems facing water resources in Henan Province, the paper uses a system dynamics method to develop information feedback between the four subsystems of Henan Province: economic, population, water resource, and water environment subsystems. The index system of the WRCC in Henan Province is also determined. The weight of each index is comprehensively determined by a combination weighting method of the analytic hierarchy process and an entropy weight method, and then a fuzzy comprehensive evaluation method is used to evaluate the WRCC of Henan Province under four different development models. The validation period of the model is 2010-2020, and the forecast period is 2021-2030. The results indicate that during the period 2021-2030, the WRCC of Henan Province showed a slight upward trend overall under the four models, but the increase rates were different under the different models. Among the four models, the comprehensive model's benefit was the best, which not only maintained the healthy and stable development of the economy and society but also improved the pressure on the water resources and the quality of the water environment.

Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet.

BACKGROUND & AIMS: Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21, FGF21, a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis. METHODS: We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 nontumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (KrasG12D/+ mice) and fElasCreERT mice (controls). KrasG12D/+ mice were placed on an HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative polymerase chain reaction, and immunohistochemistry. We measured markers of inflammation in the pancreas, liver, and adipose tissue. Activity of RAS was measured based on the amount of bound guanosine triphosphate. RESULTS: Pancreatic tissues of mice expressed high levels of FGF21 compared with liver tissues. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed KrasG12D/+ had significantly lower expression of Fgf21 messenger RNA compared with acinar cells from control mice, partly due to down-regulation of PPARG expression-a transcription factor that activates Fgf21 transcription. Pancreata from KrasG12D/+ mice on a control diet and given injections of rhFGF21 had reduced pancreatic inflammation, infiltration by immune cells, and acinar-to-ductal metaplasia compared with mice given injections of vehicle. HFD-fed KrasG12D/+ mice given injections of vehicle accumulated abdominal fat, developed extensive inflammation, pancreatic cysts, and high-grade pancreatic intraepithelial neoplasias (PanINs); half the mice developed PDAC with liver metastases. HFD-fed KrasG12D/+ mice given injections of rhFGF21 had reduced accumulation of abdominal fat and pancreatic triglycerides, fewer pancreatic cysts, reduced systemic and pancreatic markers of inflammation, fewer PanINs, and longer survival-only approximately 12% of the mice developed PDACs, and none of the mice had metastases. Pancreata from HFD-fed KrasG12D/+ mice given injections of rhFGF21 had lower levels of active RAS than from mice given vehicle. CONCLUSIONS: Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on an HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the guanosine triphosphate binding capacity of RAS. FGF21 might be used in the prevention or treatment of pancreatic cancer.

Risk Factors and Nomogram for Pancreatic Stone Formation in Chronic Pancreatitis over a Long-Term Course: A Cohort of 2,153 Patients.

BACKGROUND: Pancreatic stones are pathognomonic of chronic pancreatitis (CP). This study aimed to determine the incidence, identify risk factors, and develop a nomogram for pancreatic stones in CP patients. METHODS: Patients with CP admitted to our center from January 2000 to December 2013 were enrolled. Cumulative rates of pancreatic stones after the onset of CP and after the diagnosis of CP were calculated. Patients were randomly assigned, in a 2:1 ratio, to the training and validation cohort. Based on the training cohort, risk factors were identified through Cox proportional hazards regression model, and nomogram was developed. Internal and external validations were performed based on the training and validation cohort, respectively. RESULTS: With a total of 2,153 CP patients, pancreatic stones were detected in 1,626 (75.5%) patients, with a median follow-up of 7.8 years. Age at the onset of CP, body mass index, smoking, diabetes mellitus, pancreatic pseudocyst, biliary stricture, severe acute pancreatitis, and type of pain were identified risk factors for pancreatic stones development. The nomogram with these 8 factors achieved good accuracy. CONCLUSIONS: The nomogram achieved an individualized prediction of pancreatic stones development in CP. It may help the management of pancreatic stones.

Obesogenic high-fat diet heightens aerobic glycolysis through hyperactivation of oncogenic KRAS.

Oncogenic KRAS plays a vital role in controlling tumor metabolism by enhancing aerobic glycolysis. Obesity driven by chronic consumption of high-fat diet (HFD) is a major risk factor for oncogenic KRAS-mediated pancreatic ductal adenocarcinoma (PDAC). However, the role of HFD in KRAS-mediated metabolic reprogramming has been obscure. Here, by using genetically engineered mouse models expressing an endogenous level of KRASG12D in pancreatic acinar cells, we demonstrate that hyperactivation of KRASG12D by obesogenic HFD, as compared to carbohydrate-rich diet, is responsible for enhanced aerobic glycolysis that associates with critical pathogenic responses in the path towards PDAC. Ablation of Cox-2 attenuates KRAS hyperactivation leading to the reversal of both aggravated aerobic glycolysis and high-grade dysplasia under HFD challenge. Our data highlight a pivotal role of the cooperative interaction between obesity-ensuing HFD and oncogenic KRAS in driving the heightened aerobic glycolysis during pancreatic tumorigenesis and suggest that in addition to directly targeting KRAS and aerobic glycolysis pathway, strategies to target the upstream of KRAS hyperactivation may bear important therapeutic value.

Risk Factors and Nomogram for Common Bile Duct Stricture in Chronic Pancreatitis: A Cohort of 2153 Patients.

GOALS: To identify the risk factors and develop nomograms for common bile duct (CBD) stricture in chronic pancreatitis (CP) patients. BACKGROUND: CBD stricture is a common complication in CP and has a variable clinical presentation ranging from asymptomatic to overt jaundice and cholangitis. STUDY: Patients with CP admitted to Changhai Hospital (Shanghai, China) from January 2000 to December 2013 were enrolled. Cumulative rates of CBD stricture after onset and diagnosis of CP were calculated. Patients were randomly assigned, in a 2:1 ratio, to the training and validation cohort. On the basis of the training cohort, risk factors for CBD stricture and symptomatic CBD stricture were identified through Cox proportional hazards regression model, and nomograms was developed, respectively. Internal and external validations were performed based on the training and validation cohort, respectively. RESULTS: With a total of 2153 patients, the median duration of follow-up was 7.0 years. CBD strictures were detected in 340 (15.8%) patients, whereas 159 of them were symptomatic. Male gender, age at onset of CP, smoking, body mass index, and morphology of main pancreatic duct were identified risk factors for CBD stricture development. Age at onset of CP, body mass index, and type of pain were identified risk factors for symptomatic CBD stricture development. Both nomograms achieved good concordance indexes with well-fitted calibration curves. CONCLUSIONS: The nomogram achieved an individualized prediction of symptomatic CBD stricture development in CP patients. It may help the early diagnosis and intervention of symptomatic CBD stricture and reduce the rates of severe adverse events.

Autoantibody detection is not recommended for chronic pancreatitis: a cross-sectional Study of 557 patients.

BACKGROUND: Autoimmune factor was regarded as one of the risk factors in the pathogenesis of chronic pancreatitis (CP), especially for autoimmune pancreatitis (AIP). However, whether autoimmune factor plays a role in non-AIP CP or not was unknown. METHODS: Hospitalized patients with non-AIP CP from January 2010 to October 2016 were detected for 22 autoantibodies at the time of hospital admission. Autoantibodies with frequency > 0.5% were enrolled to calculate the frequency in historial healthy controls through literature search in PubMed. Differentially expressed autoantibodies were determined between patients and historial healthy controls, and related factors were identified by multivariate logistic regression analysis. RESULTS: In a total of 557 patients, 113 cases were detected with 19 kinds of positive autoantibodies, among them anti-ß2-glycoprotein I (ß2-GPI) antibody was most frequent (9.16%). Compared with historial healthy controls, the frequencies of serum ß2-GPI and anti SS-B antibody in patients were significantly higher, while frequencies of anti-smooth muscle antibody and anticardiolipin antibody were significantly lower (all P < 0.05). Multivariate logistic regression analysis result showed that diabetes mellitus (OR = 2.515) and common bile duct stricture (OR = 2.844) were the risk factors of positive ß2-GPI antibody in patients while diabetes mellitus in first-/second-/third-degree relatives (OR = 0.266) was the protective factor. There were no related factors for other three differentially expressed autoantibodies. CONCLUSIONS: Four autoantibodies were expressed differentially between patients with non-AIP CP and historial healthy controls. Due to limited significance for diagnosis and treatment of chronic pancreatitis, autoantibodies detection is not recommended conventionally unless suspected of AIP.

Risk factor for steatorrhea in pediatric chronic pancreatitis patients.

BACKGROUND: Pediatric patients always suffer from chronic pancreatitis (CP), especially those with steatorrhea. This study aimed to identify the incidence of and risk factors for steatorrhea in pediatric CP. To our best knowledge, there is no pediatric study to document the natural history of steatorrhea in CP. METHODS: CP patients admitted to our center from January 2000 to December 2013 were enrolled. Patients were assigned to the pediatric (< 18 years old) and adult group according to their age at onset of CP. Cumulative rates of steatorrhea in both groups were calculated. Risk factors for both groups were identified, respectively. RESULTS: The median follow-up duration for the whole cohort was 7.6 years. In a total of 2153 patients, 13.5% of them were pediatrics. The mean age at the onset and the diagnosis of CP in pediatrics were 11.622 and 19.727, respectively. Steatorrhea was detected in 46 patients (46/291, 15.8%) in the pediatric group and in 447 patients (447/1862, 24.0%) in the adult group. Age at the onset of CP (hazard ratio [HR], 1.121), diabetes mellitus (DM, HR, 51.140), and severe acute pancreatitis (SAP, HR, 13.946) was identified risk factor for steatorrhea in the pediatric group. CONCLUSIONS: Age at the onset of CP, DM and SAP were identified risk factors for the development of steatorrhea in pediatric CP patients. The high-risk populations were suggested to be followed up closely. They may benefit from a full adequate pancreatic exocrine replacement therapy.

Extracorporeal shock wave lithotripsy is safe and effective for pediatric patients with chronic pancreatitis.

Background and aims Pancreatic extracorporeal shock wave lithotripsy (P-ESWL) is recommended as the first-line treatment for pancreatic stones. However, how well P-ESWL performs in pediatric patients remains unclear. We aimed to evaluate the safety and efficacy of P-ESWL for pediatric patients with chronic pancreatitis. Methods This prospective observational study was conducted in patients with painful chronic pancreatitis who underwent P-ESWL. Patients aged under 18 years were included in the pediatric group; patients aged over 18 years who underwent P-ESWL in the same period were assigned to the control group. For investigation of long-term follow-up, the pediatric group were matched with patients from the control group in a 1:1 ratio. The primary outcomes were P-ESWL complications and pain relief. The secondary outcomes included: stone clearance, physical and mental health, quality of life score, and growth and developmental state. Results From March 2011 to March 2015, P-ESWL was performed in 1135 patients (72 in the pediatric group, 1063 in the control group). No significant differences were observed in the occurrence of P-ESWL complications between the two groups (11.1 % vs. 12.8 %; P = 0.68). Among the 67 pediatric patients (93.1 %) who underwent follow-up for 3.0 years (range 1.3 - 5.2), complete pain relief was achieved in 52 patients (52 /67; 77.6 %); this value was not significantly different from that of the matched controls (55 /69; 79.7 %; P = 0.94). Conclusions P-ESWL is safe and effective for pediatric patients with chronic pancreatitis. It can promote significant pain relief and stone clearance, and can benefit growth and development.

Risk factors and nomogram for pancreatic pseudocysts in chronic pancreatitis: A cohort of 1998 patients.

BACKGROUND AND AIM: Pancreatic pseudocyst is a common complication of chronic pancreatitis. The identification of risk factors and development of a nomogram for pancreatic pseudocysts in chronic pancreatitis patients may contribute to the early diagnosis and intervention of pancreatic pseudocysts. METHODS: Patients with chronic pancreatitis admitted to our center from January 2000 to December 2013 were enrolled. Cumulative rates of pancreatic pseudocysts after the onset of chronic pancreatitis and after the diagnosis of chronic pancreatitis were calculated. Patients were randomly assigned, in a 2:1 ratio, to the training and validation cohort. Based on the training cohort, risk factors were identified through Cox proportional hazards regression model, and nomogram was developed. Internal and external validations were performed based on the training and validation cohort, respectively. RESULTS: With a total of 1998 patients, pancreatic pseudocysts were detected in 228 (11.41%) patients. Age at the onset of chronic pancreatitis, smoking, and severe acute pancreatitis were identified risk factors for pancreatic pseudocysts development while steatorrhea and pancreatic stones were protective factors. Incorporating these five factors, the nomogram achieved good concordance indexes of 0.735 and 0.628 in the training and validation cohorts, respectively, with well-fitted calibration curves. CONCLUSION: The nomogram achieved an individualized prediction of pancreatic pseudocysts development in chronic pancreatitis. It may help the early diagnosis and management of pancreatic pseudocysts.

A long-term follow-up study on the prognosis of endoscopic submucosal dissection for colorectal laterally spreading tumors.

BACKGROUND AND AIMS: Colorectal laterally spreading tumors (LSTs) are divided into homogeneous (LST-G-H), nodular mixed (LST-G-M), flat elevated (LST-NG-F), and pseudodepressed (LST-NG-PD) subtypes. We hypothesized that based on the rates of advanced histology, the recurrence rates of the LST-NG-PD and LST-G-M groups may be higher than those of the other subgroups. METHODS: Endoscopic submucosal dissection (ESD) was performed in 156 patients with a total of 177 LSTs. The clinicopathological features and long-term prognosis of ESD according to specific subtype were investigated. RESULTS: LSTs were most commonly found in the rectum, and the highest percentage of rectal lesions was observed in the LST-G-M group (71.1% vs overall 55.4%, P = .032). The LST-G-M lesions were larger (60 ± 22 mm vs 40 ± 33 mm, P = .034) than the LST-G-H lesions. The LST-G-M group also demonstrated more high-grade intraepithelial neoplasias (32.2% vs 10.8%, P = .003) and submucosal carcinomas (13.6% vs 1.5%, P = .010) compared with the LST-G-H group. The LST-NG-PD group exhibited the highest incidence of submucosally invasive cancer (16.7%). The overall perforation rate was 2.3%. The perforation rate in the LST-NG group was higher than that in the LST-G group (5.7% vs 0.8%, P = .047). All recurrences (7.7%) were found by colonoscopy without any detection of cancers, and no difference was found among the subtypes. CONCLUSIONS: No significant differences were observed among subgroups with 44.4 ± 16.3 months of follow-up. Considering that all recurrences were discovered by colonoscopy and most could be cured by repeated ESD, the LSTs of all subgroups require more intensive follow-up compared with smaller adenomatous lesions.

Extracorporeal shock wave lithotripsy is a safe and effective treatment for pancreatic stones coexisting with pancreatic pseudocysts.

BACKGROUND AND AIMS: We aimed to investigate outcomes of pancreatic extracorporeal shock wave lithotripsy (P-ESWL) for the removal of large pancreatic stones coexisting with pancreatic pseudocysts (PPCs) in chronic pancreatitis (CP). METHODS: This is a prospective study performed in CP patients with at least 1 stone (≥5 mm). Patients were divided into the PPC group (stones coexisting with PPCs) or the control group (stones alone). Patients were initially subjected to successive P-ESWL treatments, followed by ERCP. Primary outcomes were P-ESWL adverse events, and secondary outcomes were stone clearance, long-term pain relief, improved quality-of-life scores, and PPC regression. RESULTS: A total of 849 patients (59 in the PPC group and 790 in the control group) was subjected to P-ESWL between March 2011 and October 2013. Occurrences of P-ESWL adverse events were similar between the PPC group and the control group (11.86% vs 12.41%, P = .940). After the treatment of initial P-ESWL combined with ERCP, the complete, partial, and nonclearance of stones occurred in 67.24%, 20.69%, and 12.07%, respectively, of patients in PPC group, with no significant difference from the control group (complete, partial, and nonclearance: 83.17%, 10.40%, and 11.39%, respectively; P = .106). Fifty-five of 59 patients (93.22%) with PPCs were followed for a median period of 21.9 months (range, 12.0-45.1). PPCs disappeared in 56.36% (31/55) and 76.36% (42/55) of patients after 3 months and 1 year of follow-up visits, respectively. Moreover, complete and partial pain relief were achieved in 63.64% (35/55) and 25.45% (14/55) of patients, respectively. The scores for quality of life (P < .001), physical health (P < .001), and weight loss (P < .001) improved. CONCLUSIONS: In our multispecialty tertiary center, initial P-ESWL followed by ERCP was safe in patients with coexisting pancreatic stones and PPCs and effective for stone clearance, main pancreatic duct drainage, and pain relief.

Potential application of miRNAs as diagnostic and therapeutic tools in chronic pancreatitis.

Chronic pancreatitis (CP) is a progressive inflammatory disease typified by end-stage fibrosis. This disease can also increase the risk of pancreatic cancer. The associated diagnosis, pain and other complications further add to the burden of disease management. In recent years, significant progress has been achieved in identifying miRNAs and their physiological functions, including mRNA repression and protein expression control. Given the extensive effort made on miRNA research, a close correlation has been discovered between certain types of miRNAs and disease progression, particularly for tissue fibrosis. Designing miRNA-related tools for disease diagnosis and therapeutic treatments presents a novel and potential research frontier. In the current review, we discuss various miRNAs closely interacting with CP, as well as the possible development of targeted miRNA therapies in managing this disease.

Risk factors for complications of pancreatic extracorporeal shock wave lithotripsy.

BACKGROUND AND STUDY AIMS: Extracorporeal shock wave lithotripsy is recommended as treatment for stones in chronic pancreatitis. The aim of this study was to investigate the risk factors for complications of pancreatic extracorporeal shock wave lithotripsy (P-ESWL). PATIENTS AND METHODS: Patients with painful chronic pancreatitis and pancreatic stones (> 5 mm diameter) who were treated with P-ESWL between March 2011 and June 2013 were prospectively included. Adverse events after P-ESWL were classified as complications and transient adverse events, depending on severity. The major complications of P-ESWL included post-ESWL pancreatitis, bleeding, infection, steinstrasse, and perforation. Multivariate analyses based on univariate analysis were performed to detect risk factors of overall and moderate-to-severe complications. RESULTS: A total of 634 patients underwent 1470 P-ESWL procedures. The overall complication rate was 6.7 % of all procedures. Complications occurred in 62 patients (9.8 %) after the first ESWL procedure. The risk factors for complications were pancreas divisum (odds ratio [OR] 1.28) and the interval between diagnosis of chronic pancreatitis and P-ESWL (OR 1.28). Protective factors were male sex (OR 0.50), diabetes (OR 0.45), and steatorrhea (OR 0.43). Male sex, the only identified predictor for moderate-to-severe complications, was a protective factor (OR 0.19). For the second P-ESWL procedure, complications occurred in 22/409 patients (5.4 %). Complication and asymptomatic hyperamylasemia after the first ESWL session were significantly associated with higher risk for complications after the second ESWL session (P < 0.05). CONCLUSIONS: Patient-related factors were important in determining a high risk of P-ESWL complications when no procedure-related factors were identified. Patients suffering from complications after the first ESWL session were also likely to experience complications in subsequent P-ESWL sessions.

Differential Effects of Dietary Macronutrients on the Development of Oncogenic KRAS-Mediated Pancreatic Ductal Adenocarcinoma.

KRAS mutations are prevalent in patients with pancreatic ductal adenocarcinoma (PDAC) and are critical to fostering tumor growth in part by aberrantly rewiring glucose, amino acid, and lipid metabolism. Obesity is a modifiable risk factor for pancreatic cancer. Corroborating this epidemiological observation, mice harboring mutant KRAS are highly vulnerable to obesogenic high-fat diet (HFD) challenges leading to the development of PDAC with high penetrance. However, the contributions of other macronutrient diets, such as diets rich in carbohydrates that are regarded as a more direct source to fuel glycolysis for cancer cell survival and proliferation than HFD, to pancreatic tumorigenesis remain unclear. In this study, we compared the differential effects of a high-carbohydrate diet (HCD), an HFD, and a high-protein diet (HPD) in PDAC development using a mouse model expressing an endogenous level of mutant KRASG12D specifically in pancreatic acinar cells. Our study showed that although with a lower tumorigenic capacity than chronic HFD, chronic HCD promoted acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions with increased inflammation, fibrosis, and cell proliferation compared to the normal diet (ND) in KrasG12D/+ mice. By contrast, chronic HPD showed no significant adverse effects compared to the ND. Furthermore, ablation of pancreatic acinar cell cyclooxygenase 2 (Cox-2) in KrasG12D/+ mice abrogated the adverse effects induced by HCD, suggesting that diet-induced pancreatic inflammation is critical for promoting oncogenic KRAS-mediated neoplasia. These results indicate that diets rich in different macronutrients have differential effects on pancreatic tumorigenesis in which the ensuing inflammation exacerbates the process. Management of macronutrient intake aimed at thwarting inflammation is thus an important preventive strategy for patients harboring oncogenic KRAS.

Clinical characteristics of smoking-related chronic pancreatitis.

Objective: The pathogenesis of chronic pancreatitis (CP) is not completely clear. With further studies, smoking is toxic to the pancreas. This study classified smoking-related CP as a new etiology of CP and defined the cutoff of smoking. Design: Patients with CP admitted from January 2000 to December 2013 were included in the study. The characteristics were compared between smoking patients, drinking patients, and a group of patients who never smoke or drink (control group). The cumulative rates of steatorrhea, diabetes mellitus (DM), pancreatic pseudocyst (PPC), pancreatic stone, and biliary stricture after the onset of CP were calculated, respectively. Results: A total of 1,324 patients were included. Among them, 55 were smoking patients, 80 were drinking patients, and 1,189 were controls. The characteristics of smokers are different from the other two groups, especially in age at the onset and diagnosis of CP, initial manifestation, and type of pain. The development of DM (P = 0.011) and PPC (P = 0.033) was significantly more common and earlier in the smokers than in the other two groups. Steatorrhea also developed significantly more in the smokers than in the controls (P = 0.029). Smokers tend to delay the formation of pancreatic stones and steatorrhea. Conclusion: The clinical characteristics of smoking-related CP is different from CP of other etiologies. A new type of CP, smoking-related CP, was put forward. Smoking-related CP should be separated from idiopathic CP and defined as a new independent subtype of CP different from alcoholic CP or idiopathic CP.

Selective killing of cancer cells harboring mutant RAS by concomitant inhibition of NADPH oxidase and glutathione biosynthesis.

Oncogenic RAS is a critical driver for the initiation and progression of several types of cancers. However, effective therapeutic strategies by targeting RAS, in particular RASG12D and RASG12V, and associated downstream pathways have been so far unsuccessful. Treatment of oncogenic RAS-ravaged cancer patients remains a currently unmet clinical need. Consistent with a major role in cancer metabolism, oncogenic RAS activation elevates both reactive oxygen species (ROS)-generating NADPH oxidase (NOX) activity and ROS-scavenging glutathione biosynthesis. At a certain threshold, the heightened oxidative stress and antioxidant capability achieve a higher level of redox balance, on which cancer cells depend to gain a selective advantage on survival and proliferation. However, this prominent metabolic feature may irrevocably render cancer cells vulnerable to concurrent inhibition of both NOX activity and glutathione biosynthesis, which may be exploited as a novel therapeutic strategy. In this report, we test this hypothesis by treating the HRASG12V-transformed ovarian epithelial cells, mutant KRAS-harboring pancreatic and colon cancer cells of mouse and human origins, as well as cancer xenografts, with diphenyleneiodonium (DPI) and buthionine sulfoximine (BSO) combination, which inhibit NOX activity and glutathione biosynthesis, respectively. Our results demonstrate that concomitant targeting of NOX and glutathione biosynthesis induces a highly potent lethality to cancer cells harboring oncogenic RAS. Therefore, our studies provide a novel strategy against RAS-bearing cancers that warrants further mechanistic and translational investigation.

Risk factor for diabetes mellitus in pediatric chronic pancreatitis patients.

Pediatric patients suffer from chronic pancreatitis (CP), especially those with diabetes mellitus (DM). This study aimed to identify the incidence of and risk factors for DM in pediatric CP.CP patients admitted to our center from January 2000 to December 2013 were assigned to the pediatric (<18 years old) and adult group according to their age at onset of CP. Cumulative rates of DM and risk factors for both groups were calculated and identified.The median follow-up duration for the whole cohort was 7.6 years. In these 2153 patients, 13.5% of them were pediatrics. The mean age at the onset and the diagnosis of CP in pediatrics were 11.622 and 19.727, respectively. DM was detected in 13.1% patients and 31.0% patients in the pediatric group and adult group, respectively. Age at the onset of CP, smoking history, body mass index (BMI), and etiology of CP were identified risk factors for DM in pediatrics.DM was detected in 13.1% pediatric patients. Age at the onset of CP, smoking history, BMI, and etiology of CP were identified risk factors for the development of DM in pediatric CP patients. The high-risk populations were suggested to be monitored frequently. They could also benefit from a lifestyle modification.

Extracorporeal Shock Wave Lithotripsy for Chronic Pancreatitis Patients With Stones After Pancreatic Surgery.

OBJECTIVES: The objective of this study was to evaluate the safety and efficacy of pancreatic extracorporeal shock wave lithotripsy (P-ESWL) in chronic pancreatitis (CP) patients with pancreatic stones after previous pancreatic surgery. METHODS: This is a single-center study prospectively conducted in pained CP patients undergoing P-ESWL. Patients with a pancreatic surgery history (PSH) were included in the PSH group, and patients without a PSH during the same period were assigned to the control group. The primary outcomes included complications associated with P-ESWL and pain relief. Secondary outcomes included stone clearance and improved quality-of-life scores. RESULTS: From March 2011 to October 2014, P-ESWLs were performed on 1017 patients (50 in the PSH group, 967 in the control group). No significant difference was observed in the frequency of occurrence of P-ESWL complications between the PSH group and control group (14.0% vs 13.2%, P = 0.877). At follow-up (2.6 years; range, 1.0-4.5 years), pain relief was achieved in 36 patients (75.0%), and 37 patients (77.1%) experienced complete stone clearance. No significant differences were observed between these patients and the matched controls. CONCLUSIONS: For CP patients who develop painful stones after pancreatic surgery, P-ESWL safely achieves significant pain relief and stone clearance, preventing the need for a repeat surgery.

The different course of alcoholic and idiopathic chronic pancreatitis: A long-term study of 2,037 patients.

BACKGROUND: Chronic pancreatitis (CP) is a chronic inflammatory disease of the pancreas. This study aimed to compare the natural course of alcoholic chronic pancreatitis (ACP) and idiopathic chronic pancreatitis (ICP). METHODS: CP patients admitted to our center from January 2000 to December 2013 were enrolled. Characteristics were compared between ACP and ICP patients. Cumulative rates of diabetes mellitus (DM), steatorrhea, pancreatic stone, pancreatic pseudocyst, biliary stricture, and pancreatic cancer after the onset and the diagnosis of CP were calculated, respectively. The cumulative rates of DM and steatorrhea after diagnosis of pancreatic stone were also calculated. RESULTS: A total of 2,037 patients were enrolled. Among them, 19.8% (404/2,037) were ACP and 80.2% (1,633/2,037) were ICP patients. ACP and ICP differs in many aspects, especially in gender, age, smoking, complications, morphology of pancreatic duct, and type of pain. The development of DM, steatorrhea, PPC, pancreatic stone, and biliary stricture were significantly earlier and more common in ACP patients. No significant difference was observed for pancreatic cancer development. There was a rather close correlation between exocrine/endocrine insufficiency and pancreatic stone in ACP patients, which was much less correlated in ICP patients. CONCLUSION: The long-term profile of ACP and ICP differs in some important aspects. ACP patients usually have a more severe course of CP. These differences should be recognized in the diagnosis and treatment of CP.