Epithelial neutrophil-activating peptide-78 (CXCL5), a member of the CXC chemokine family, has been shown to be involved in angiogenesis, tumor growth, and metastasis. The objective of this study was to determine the relationship between CXCL5 expression and tumor progression in human pancreatic cancer and to elucidate the mechanism underlying CXCL5-mediated tumor angiogenesis and cancer growth. We report herein that CXCL5 is overexpressed in human pancreatic cancer compared with paired normal pancreas tissue. Overexpression of CXCL5 is significantly correlated with poorer tumor differentiation, advanced clinical stage, and shorter patient survival. Patients with pancreatic cancer and CXCL5 overexpression who underwent resection of cancer had a mean survival time 25.5 months shorter than that of patients who did not overexpress CXCL5. Blockade of CXCL5 or its receptor CXCR2 by small-interfering RNA knockdown or antibody neutralization attenuated human pancreatic cancer growth in a nude mouse model. Finally, we demonstrated that CXCL5 mediates pancreatic cancer-derived angiogenesis through activation of several signaling pathways, including protein kinase B (Akt), extracellular signal-regulated kinase (ERK), and signal transducer and activator of transcription (STAT) in human endothelial cells. These data suggest that CXCL5 is an important mediator of tumor-derived angiogenesis and that it may serve as a survival factor for pancreatic cancer. Blockade of either CXCL5 or CXCR2 may be a critical adjunct antiangiogenic therapy against pancreatic cancer.

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Background Neoadjuvant treatment has proven beneficial for many GI malignancies, but no phase III trials have been completed examining this approach in pancreatic cancer. This meta-analysis examines the best available phase II trials using neoadjuvant treatment for resectable and borderline/unresectable pancreatic adenocarcinoma. Methods Phase II trials were identified using a MEDLINE search, and the Cochrane Central Register of Controlled Trials from 1960 to July 2010. Patients were divided into two groups: patients with initially resectable tumors (Group A), and patients with borderline/unresectable tumors (Group B). Primary outcome measures were rate of resection and survival. Pooled proportions and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. Results A total of 14 phase II clinical trials including 536 patients were analyzed. Following treatment, resectability was 65.8% (95% CI 55.4%–75.6%) compared with 31.6% in Group B (95% CI 14.0%–52.5%). A significant partial response was observed in patients with borderline/unresectable tumors; 31.8 (95% CI 24.2%–39.8%) in Group B, and 9.5% (95% CI 2.9%–19.4%) in Group A (p=0.003). Progressive disease was seen in 17.0% (95% CI 11.9%–22.7) of patients in Group A versus 21.8% (95% CI 10.1%–36.5%) in Group B (p=0.006). Median survival in resected patients was 23 months for Group A, and 22.3 months for Group B. Conclusion Neoadjuvant treatment appears to have some activity in patients with borderline/unresectable pancreatic adenocarcinoma. Nearly one-third of tumors initially deemed marginal for operative intervention were ultimately able to be resected following treatment. Until more effective targeted chemotherapeutics are developed, the only group of patients with pancreatic cancer that may benefit from neoadjuvant treatment are those with locally advanced disease.

Objectives The flavonoid quercetin holds promise as an anti-tumor agent in several preclinical animal models. However, the efficacy of oral administration of quercetin in a pancreatic cancer mouse model is unknown. Methods The anti-proliferative effects of quercetin alone or in combination with gemcitabine were tested in two human pancreatic cancer cell lines using cell count and MTT assays. Apoptosis was evaluated by flow cytometry. Tumor growth in vivo was investigated in an orthotopic pancreatic cancer animal model using bioluminescence. Quercetin was administered orally in the diet. Results Quercetin inhibited the growth of pancreatic cancer cell lines, which was caused by an induction of apoptosis. In addition, dietary supplementation of quercetin attenuated the growth of orthotopically transplanted pancreatic xenografts. The combination of gemcitabine and quercetin had no additional effect compared to quercetin alone. In vivo quercetin caused significant apoptosis and reduced tumor cell proliferation. Conclusions Our data provide evidence that oral administration of quercetin was capable of inhibiting growth of orthotopic pancreatic tumors in a nude mouse model. These data suggest a possible benefit of quercetin in patients with pancreatic cancer.

Background: It is increasingly recognized that cancer progression induces systemic immune changes in the host. Alterations in number and function of immune cells have been identified in cancer patients' peripheral blood and lymphoid organs. Recently, we found dysregulated cytokine signaling in peripheral blood T cells from breast cancer (BC) patients, even those with localized disease. Methods: We used phosphoflow cytometry to determine the clinical significance of cytokine signaling responsiveness in peripheral blood monocytes from non-metastatic BC patients at diagnosis. We also examined the correlation between cytokine signaling in peripheral monocytes and the number of tumor-infiltrating macrophages in paired breast tumors. Findings: Our results show that cytokine (IFNg) signaling may also be dysregulated in peripheral blood monocytes at diagnosis, specifically in BC patients who later relapsed. Some patients exhibited concurrent cytokine signaling defects in monocytes and lymphocytes at diagnosis, which predict the risk of future relapse in two independent cohorts of BC patients. Moreover, IFNg signaling negatively correlates with expression of CSF1R on monocytes, thus modulating their ability to infiltrate into tumors. Interpretation: Our results demonstrate that tumor-induced systemic immune changes are evident in peripheral blood immune cells for both myeloid and lymphoid lineages, and point to cytokine signaling responsiveness as important biomarkers to evaluate the overall immune status of BC patients.

Telomere length (TL) has been implicated in the pathogenesis of age-related disorders. However, there are no prospective studies directly investigating the role of TL and relevant genes in diabetes development. In the multiethnic Women’s Health Initiative, we identified 1,675 incident diabetes case participants in 6 years of follow-up and 2,382 control participants matched by age, ethnicity, clinical center, time of blood draw, and follow-up duration. Leukocyte TL at baseline was measured using quantitative PCR, and Mendelian randomization analysis was conducted to test whether TL is causally associated with diabetes risk. After adjustment for matching and known diabetes risk factors, odds ratios per 1-kilobase increment were 1.00 (95% CI 0.90–1.11) in whites, 0.95 (0.85–1.06) in blacks, 0.96 (0.79–1.17) in Hispanics, and 0.88 (0.70–1.10) in Asians. Of the 80 single nucleotide polymorphisms (SNPs) in nine genes involved in telomere regulation, 14 SNPs were predictive of TL, but none were significantly associated with diabetes risk. Using ethnicity-specific SNPs as randomization instruments, we observed no statistically significant association between TL and diabetes risk (P = 0.52). Although leukocyte TL was weakly associated with diabetes risk, this association was not independent of known risk factors. These prospective findings indicate limited clinical utility of TL in diabetes risk stratification among postmenopausal women.

PurposeTo evaluate the association between cigarette smoking and glaucoma in the United States population.Patients and methodsUS civilian, non-institutionalized population from 2005 to 2008 administrations of the National Health and Nutrition Examination Survey that were ≥40 years of age with visual fields and optic disc photographs were included. Diagnosis of glaucoma was based on the Rotterdam criteria. Logistic regression modeling was performed to assess the association between glaucoma and smoking history, while controlling for age, gender, ethnicity, household income, alcohol consumption, diabetes, and hypertension.ResultsIn 3864 participants, 212 (5.5%) had glaucoma (corresponds to a population weighted glaucoma prevalence of 3.7% in a total of 83 570 127 subjects). Population weighted proportion of current smokers was 20.6% and ex-smokers was 28.3%. Participants with glaucoma were older (63.0±11.6 vs 56.1±11.2, P=0.002), likely to be male (57.1% vs 49.2%, P=0.03), to be Black (36.3% vs 20.7%, P<0.001), and to have diabetes (18.9% vs 12.4%, P=0.006) and hypertension (50.5% vs 39.7%, P=0.003). Current smokers had a lower odds of glaucoma compared to non-smokers (OR=0.61, 95% CI=0.41-0.88, P=0.009), and ex-smokers (OR=0.46, 95% CI=0.28-0.76, P=0.002). The effect estimates were similar in adjusted models, but not statistically significant. Among smokers, greater pack/day of smoking history was associated with statistically significantly higher odds of glaucoma (OR=1.70, 95% CI=1.08-2.67, P=0.02).ConclusionsAmong cigarette smokers, heavy smoking defined by greater number of pack of cigarettes smoked per day is associated with higher odds of glaucoma. Health care providers should include this association when counseling patients on their smoking habit.

word count (limit 250): 250 Body word count (limit 5000): 3495 Figures and tables (limit 6): 6 References (limit 50): 40 Disclosure of potential conflicts of interest: Research. on March 6, 2020. AbstractPurpose: GDC-0084 is an oral, brain-penetrant small molecule inhibitor of phosphoinositide 3kinase (PI3K) and mammalian target of rapamycin (mTOR). A first-in-human, Phase I study was conducted in patients with recurrent high-grade glioma.Experimental design: GDC-0084 was administered orally, once-daily to evaluate safety, pharmacokinetics (PK) and activity. Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed to measure metabolic responses.