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Objectives: A proteomic discovery study was performed to determine if urine possesses a unique biosignature that could form the basis for a noninvasive test able to predict intraductal papillary mucinous neoplasm (IPMN) dysplasia., Methods: Urine was collected from patients undergoing surgery for IPMN (72 low/moderate, 27 high-grade/invasive). Quantitative mass spectrometry-based proteomics was performed. Proteins of interest were identified by differential expression analysis followed by principal component analysis., Results: Proteomics identified greater than 4800 urinary proteins. Low/moderate and high-grade/invasive IPMN were distinguished by 188 proteins (P < 0.05). Following principal component analysis and heatmap visualization, vitamin D binding protein (DBP), apolipoprotein A1 (APOA1), and alpha-1 antitrypsin (A1AT) were selected. The proteomic abundance of DBP (median [interquartile range]) was significantly higher for high-grade/invasive than for low/moderate IPMN (219,735 [128,882-269,943] vs. 112,295 [77,905-180,773] normalized reporter ion intensity units; P = 0.001). Similarly, APOA1 was more abundant in the high-grade/invasive than low/moderate groups (235,420 [144,933-371,247] vs 150,095 [103,419-236,591]; P = 0.0007) as was A1AT (567,514 [358,544-774,801] vs 358,393 [260,850-477,882]; P = 0.0006)., Conclusions: Urinary DBP, APOA1, and A1AT represent potential biomarker candidates that may provide a noninvasive means of predicting IPMN dysplastic grade.

Objectives: We sought to determine if interleukin (IL)-1β and prostaglandin E2 (PGE2) (inflammatory mediators in pancreatic fluid) together with serum carbohydrate antigen (CA) 19-9 could better predict intraductal papillary mucinous neoplasm (IPMN) dysplasia than individual biomarkers alone., Methods: Pancreatic cyst fluid (n = 92) collected via endoscopy or surgery (2003-2016) was analyzed for PGE2 and IL-1β (enzyme-linked immunosorbent assay). Patients had surgical pathology-proven IPMN. Threshold values (PGE2 [>1100 pg/mL], IL-1β [>20 pg/mL], and serum CA 19-9 [>36 U/mL]) were determined., Results: Levels of IL-1β were higher in high-grade dysplasia (HGD)/invasive-IPMN (n = 42) compared with low/moderate IPMN (n = 37) (median [range], 54.6 [0-2671] vs 5.9 [0-797] pg/mL; P < 0.001; area under curve [AUC], 0.766). Similarly, PGE2 was higher in HGD/invasive IPMN (n = 45) compared with low/moderate IPMN (n = 47) (median [range], 1790 [20-15,180] vs. 140 [10-14,630] pg/mL; P < 0.001; AUC, 0.748). Presence of elevated PGE2 and IL-1β (AUC, 0.789) provided 89% specificity and 82% positive predictive value (PPV) for HGD/invasive IPMN. Elevated levels of all 3 provided 100% specificity and PPV for HGD/invasive IPMN., Conclusions: Cyst fluid PGE2, IL-1β, and serum CA 19-9 in combination optimize specificity and PPV for HGD/invasive IPMN and may help build a panel of markers to predict IPMN dysplasia.

Objective: To better understand the global response to HIV/AIDS, this study tracked development assistance for HIV/AIDS at a granular, program level., Methods: We extracted data from the Institute for Health Metrics and Evaluation's Financing Global Health 2015 report that captured development assistance for HIV/AIDS from 1990 to 2015 for all major bilateral and multilateral aid agencies. To build on these data, we extracted additional budget data, and disaggregated development assistance for HIV/AIDS into nine program areas, including prevention, treatment, and health system support., Results: Since 2000, $109.8 billion of development assistance has been provided for HIV/AIDS. Between 2000 and 2010, development assistance for HIV/AIDS increased at an annualized rate of 22.8%. Since 2010, the annualized rate of growth has dropped to 1.3%. Had development assistance for HIV/AIDS continued to climb after 2010 as it had in the previous decade, $44.8 billion more in development assistance would have been available for HIV/AIDS. Since 1990, treatment and prevention were the most funded HIV/AIDS program areas receiving $24.6 billion and $22.7 billion, respectively. Since 2010, these two program areas and HIV/AIDS health system strengthening have continued to grow, marginally, with majority support from the US government and the Global Fund. An average of $252.9 of HIV/AIDS development assistance per HIV/AIDS prevalent case was disbursed between 2011 and 2013., Conclusion: The scale-up of development assistance for HIV/AIDS from 2000 to 2010 was unprecedented. During this period, international donors prioritized HIV/AIDS treatment, prevention, and health system support. Since 2010, funding for HIV/AIDS has plateaued.

Objectives: Pancreatic cancer remains one of the deadliest diseases, with limited surgical and treatment options. Two targets of interest include the transcription factor nuclear factor-κB and cyclooxygenase-2, which are constitutively activated and overexpressed, respectively, in human pancreatic adenocarcinoma. We have previously shown that dimethylaminoparthenolide (DMAPT), a bioavailable nuclear factor-κB inhibitor, and the cyclooxygenase inhibitors sulindac and celecoxib have potential chemotherapeutic efficacy. The current study evaluates the efficacy of intervention with DMAPT and sulindac in the LSL-Kras(G12D);Pdx-1-Cre genetically engineered mouse model. Gemcitabine, traditionally a chemotherapeutic agent, has relatively low toxicity; thus, combinations with low-dose gemcitabine were also explored., Methods: LSL-Kras(G12D);Pdx-1-Cre mice at 7 months of age were randomized into placebo, DMAPT (40 mg/kg per day), sulindac (20 mg/kg per day), gemcitabine (50 mg/kg twice weekly), and combination treatment groups. After 3 months of treatment, the mice were killed., Results: The percentage of normal pancreatic ducts was significantly increased by the combinations of DMAPT/sulindac, DMAPT/gemcitabine, sulindac/gemcitabine, and DMAPT/sulindac/gemcitabine compared to placebo. Additionally, the percentage of mouse pancreatic intraepithelial neoplasia-2 lesions was significantly decreased by DMAPT/gemcitabine., Conclusions: Intervention with DMAPT and sulindac in combination with gemcitabine may delay or prevent progression of premalignant pancreatic lesions in the LSL-Kras(G12D);Pdx-1-Cre mouse model of pancreatic cancer.

Objectives: The aims of this study were to characterize the proteome of normal pancreatic juice, to analyze the effect of secretin on the normal proteome, and to compare these results with published data from patients with pancreatic cancer., Methods: Paired pancreatic fluid specimens (before and after intravenous secretin stimulation) were obtained during endoscopic pancreatography from 3 patients without significant pancreatic pathology. Proteins were identified and quantified by mass spectrometry-based protein quantification technology. The human RefSeq (NCBI) database was used to compare the data in samples from patients without pancreatic disease with published data from 3 patients with pancreatic cancer., Results: A total of 285 proteins were identified in normal pancreatic juice. Ninety had sufficient amino acid sequences identified to characterize the protein with a high level of confidence. All 90 proteins were present before and after secretin administration but with altered relative concentrations, usually by 1 to 2 folds, after stimulation. Comparison with 170 published pancreatic cancer proteins yielded an overlap of only 42 proteins., Conclusions: Normal pancreatic juice contains multiple proteins related to many biological processes. Secretin alters the concentration but not the spectrum of these proteins. The pancreatic juice proteome of patients without pancreatic disease and that of patients with pancreatic cancer differ markedly.

Unlabelled: To determine if the level of transforming growth factor α (TGF-α) in the pancreatic fluid (PF) can diagnose intraductal papillary mucinous neoplasm (IPMN) versus other cystic lesions of the pancreas in patients., Methods: Pancreatic fluid was prospectively obtained from patients during routine endoscopy and/or operation at Indiana University Hospital. Pancreatic fluid TGF-α levels were analyzed by enzyme-linked immunosorbent assay. Intraductal papillary mucinous neoplasm tissue was also analyzed by TGF-α immunohistochemistry., Results: Sixty-nine fluid samples from 58 patients with the following pathologically confirmed pancreatic disorders were analyzed: IPMN (26 patients), serous cystadenoma (6), mucinous cystic neoplasm (9), pseudocysts (5), non-IPMNY associated pancreatic ductal adenocarcinoma (6), and sphincter of Oddi dysfunction (6). There was no significant difference between the mean PF-TGF-α levels in each category or between different dysplastic grades of IPMN. However, of all the diagnoses examined, only IPMN demonstrated PF-TGF-α levels greater than 95 pg/mL. In low-grade IPMN specimens, TGF-α immunohistochemistry correlated with enzyme-linked immunosorbent assay levels., Conclusions: The mean PF-TGF-α levels are not significantly different in IPMN lesions compared with those in other cystic pancreatic lesions, pancreatic ductal adenocarcinoma, or sphincter of Oddi dysfunction. However, PF-TGF-α levels more than 95 pg/mL may be useful in diagnosing IPMN. This assertion requires prospective validation.

Objectives: Cancer of the exocrine pancreas is the fourth leading cause of cancer-related deaths in the United States. The efficacy of a novel bioavailable anticancer agent, dimethylamino-parthenolide (DMAPT), and the cyclooxygenase 2 inhibitor, celecoxib, was evaluated in a carcinogen-induced developmental model of pancreatic cancer., Methods: Syrian golden hamsters were injected with N-nitrosobis(2-oxopropyl)amine, once weekly for 6 weeks. Upon the first injection, hamsters were randomized as follows: placebo, low-/high-dose DMAPT (20 and 40 mg/kg per day), low-/high-dose celecoxib (10and 50 mg/kg per day), or combination DMAPT/celecoxib (low/low, high/high)., Results: The 32-week trial showed that 40 mg/kg DMAPT alone significantly decreased the size of gross pancreatic cancers relative to placebo. No significant difference in gross tumor number was observed between the treatment groups and placebo with the exception of 50 mg/kg celecoxib with a higher tumor incidence; this group also exhibited lower lymphotactin levels suggestive of decreased immune surveillance. Tumor invasion into adjacent organs and metastasis were not observed in the DMAPT/celecoxib treatment groups. Drug targets including prostaglandin E2, prostaglandin E2 metabolite and activated nuclear factor kappaB were significantly decreased., Conclusions: Dimethylamino-parthenolide and celecoxib have the potential to be novel chemotherapeutic agents for pancreatic cancer; however, further optimization or the use of other modalities may be required for chemoprevention.

Objectives: The MAP kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway is critical for cell growth and survival. In the current study, we examined the effect of inhibiting the MEK-ERK pathway in pancreatic tumor cells with the MEK-specific inhibitor U0126. In addition, we investigated whether the MEK-ERK pathway influenced the response of pancreatic cancer cells to nonsteroidal antiinflammatory drugs (NSAIDs)., Methods: Cell growth was monitored by a colorimetric proliferation assay and cell counts. Cell cycle analysis was performed using flow cytometry. Apoptosis was measured using a DNA fragmentation ELISA. Protein expression was detected by Western blot., Conclusion: Treatment with U0126 dose dependently inhibited the growth of 3 human pancreatic carcinoma cell lines (BxPC-3, PANC-1, and MIA PaCa-2). U0126 treatment resulted in cell-cycle alterations but did not induce apoptosis. Growth inhibitory concentrations of NSAIDs unexpectedly increased ERK phosphorylation in BxPC-3 and MIA PaCa-2 cells. We therefore evaluated the effect of treating pancreatic tumor cells with the combination of the NSAID sulindac and U0126. Treatment with U0126 complemented sulindac-induced growth inhibition in BxPC-3 and PANC-1 cells. The expression of several cell cycle (p21, p27, cyclin D1) and apoptotic (survivin, Bcl-xL) regulatory proteins was altered after U0126 and/or sulindac treatment. Our findings suggest that inhibition of the MEK-ERK signaling pathway may sensitize pancreatic tumor cells to NSAID therapy.