Citations

Abstract Despite much effort, pancreatic cancer survival rates are still dismally low. Novel therapeutics may hold the key to improving survival. YM155 is a small molecule inhibitor that has shown antitumor activity in a number of cancers by reducing the expression of survivin. The aim of our study is to understand the mechanisms by which YM155 functions in pancreatic cancer cells. We established the antitumor effect of YM155 with in vitro studies in cultured cells, and in vivo studies using a mouse xenograft model. Our data demonstrated that YM155 reduced the expression of survivin; however, downregulation of survivin itself is insufficient to induce apoptosis in pancreatic cancer cells. We showed for the first time that treatment with YM155 increased death receptor 5 (DR5) expression in pancreatic cancer cells. We found that YM155 induced apoptosis by broad-spectrum inhibition of IAP family member proteins (e.g., CIAP1/2 and FLIP) and induced proapoptotic Bak protein upregulation and activation; the antitumor effect of YM155 treatment with either the DR5 agonist lexatumumab or gemcitabine on pancreatic cancer cells was synergistic. Our data also revealed that YM155 inhibits tumor growth in vivo, without apparent toxicity to the noncancerous human pancreatic ductal epithelial cell line. Together, these findings suggest that YM155 could be a novel therapeutic agent for pancreatic cancer. Mol Cancer Ther; 14(1); 80–89. ©2014 AACR.

Abstract Although myeloid-derived suppressor cells (MDSCs) are well known for their immunosuppressive function in several pathological conditions, the role of MDSCs in hepatitis B virus infection remains obscure. In this study, we investigated the frequency and function of MDSCs in the peripheral blood and liver of 91 chronic hepatitis B (CHB) patients. A higher percentage of MDSCs, defined as CD14+HLA-DR−/low, was detected in peripheral blood of CHB patients than that of the healthy controls. Moreover, high expression of programmed death 1 (PD-1) and secretion of IL-10 in this population were determined. The frequency of MDSCs was positively correlated with serum viral load, but it was negatively correlated with liver inflammatory injury. These cells were also abundant in liver tissue of CHB patients and were related to necroinflammatory activity. Furthermore, we found that these cells could suppress hepatitis B virus–specific CD8+ T cell response, including reduced proliferation and IFN-γ production, and inhibit degranulation of CD8+ T cells, including reduced production of granzyme B and perforin. Importantly, PD-1–induced IL-10 production by MDSCs was responsible for the suppressive activity. To our knowledge, for the first time our study proved that CD14+HLA-DR–/lowPD-1+ MDSCs in CHB patients contribute to an inadequate immune response against the virus and lead to chronic infection, which represents a potential target for therapeutic intervention.

Background— Invasive hemodynamic exercise testing is commonly used in the evaluation of patients with suspected heart failure with preserved ejection fraction (HFpEF) or pulmonary hypertension. Saline loading has been suggested as an alternative provocative maneuver, but the hemodynamic changes induced by the 2 stresses have not been compared. Methods and Results— Twenty-six subjects (aged, 67±10 years; n=14 HFpEF; n=12 control) underwent right heart catheterization at rest, during supine exercise, and with acute saline loading in a prospective study. Exercise and saline each increased cardiac output and pressures in the right atrium, pulmonary artery, and pulmonary capillary wedge positions. Changes in heart rate, blood pressure, rate–pressure product, and cardiac output were greater with exercise compared with saline. In controls subjects, right atrial pressure, pulmonary arterial pressure, and pulmonary capillary wedge pressure increased similarly with saline and exercise, whereas in HFpEF subjects, exercise led to ≈2-fold greater increases in right atrial pressure (10±4 versus 6±3 mm Hg; P =0.02), pulmonary arterial pressure (22±8 versus 11±4 mm Hg; P =0.0001), and pulmonary capillary wedge pressure (18±5 versus 10±4 mm Hg; P <0.0001) compared with saline. Systolic reserve assessed by stroke work and cardiac power output was lower in HFpEF subjects with both exercise and saline. Systemic and pulmonary arterial compliances were enhanced with saline but reduced with exercise. Conclusions— Exercise elicits greater pulmonary capillary wedge pressure elevation compared with saline in HFpEF but not controls, suggesting that hemodynamic stresses beyond passive stiffness and increased venous return explain the development of pulmonary venous hypertension in HFpEF. Exercise testing is more sensitive than saline loading to detect hemodynamic derangements indicative of HFpEF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01418248.

SummarySphingomyelin metabolism has been linked to several diseases and to longevity. However, few epidemiological studies have quantified individual plasma sphingomyelin species (identified by acyl‐chain length and saturation) or their relationship between demographic factors and disease processes. In this study, we determined plasma concentrations of distinct sphingomyelin species in 992 individuals, aged 55 and older, enrolled in the Baltimore Longitudinal Study of Aging. Participants were followed, with serial measures, up to 6 visits and 38 years (3972 total samples). Quantitative analyses were performed on a high‐performance liquid chromatography‐coupled electrospray ionization tandem mass spectrometer. Linear mixed models were used to assess variation in specific sphingomyelin species and associations with demographics, diseases, medications or lifestyle factors, and plasma cholesterol and triglyceride levels. We found that most sphingomyelin species increased with age. Women had higher plasma levels of all sphingomyelin species and showed steeper trajectories of age‐related increases compared to men. African Americans also showed higher circulating sphingomyelin concentrations compared to Caucasians. Diabetes, smoking, and plasma triglycerides were associated with lower levels of many sphingomyelins and dihydrosphingomyelins. Notably, these associations showed specificity to sphingomyelin acyl‐chain length and saturation. These results demonstrate that longitudinal changes in circulating sphingomyelin levels are influenced by age, sex, race, lifestyle factors, and diseases. It will be important to further establish the intra‐individual age‐ and sex‐specific changes in each sphingomyelin species in relation to disease onset and progression.

ABSTRACT Insulin resistance causes diminished glucose uptake in similar regions of the brain in Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2). Brain tissue studies suggested that insulin resistance is caused by low insulin receptor signaling attributable to its abnormal association with more phospho (P)‐serine‐type 1 insulin receptor substrate (IRS‐1) and less P‐tyrosine‐IRS‐1. Plasma exosomes enriched for neural sources by immunoabsorption were obtained once from 26 patients with AD, 20 patients with DM2, 16 patients with frontotemporal dementia (FTD), and matched case control subjects. At 2 time points, they were obtained from 22 others when cognitively normal and 1 to 10 yr later when diagnosed with AD. Mean exosomal levels of extracted P‐serine 312‐IRS‐1 and P‐pan‐tyrosine‐IRS‐1 by ELISA and the ratio of P‐serine 312‐IRS‐1 to P‐pan‐tyrosine‐IRS‐1 (insulin resistance factor, R) for AD and DM2 and P‐serine 312‐IRS‐1 and R for FTD were significantly different from those for case control subjects. The levels of R for AD were significandy higher than those for DM2 or FTD. Stepwise discriminant modeling showed correct classification of 100% of patients with AD, 97.5% of patients with DM2, and 84% of patients with FTD. In longitudinal studies of 22 patients with AD, exosomal levels of P‐serine 312‐IRS‐1, P‐pan‐tyrosine‐IRS‐1, and R were significantly different 1 to 10 yr before and at the time of diagnosis compared with control subjects. Insulin resistance reflected in R values from this blood test is higher for patients with AD, DM2, and FTD than case control subjects; higher for patients with AD than patients with DM2 or FTD; and accurately predicts development of AD up to 10 yr prior to clinical onset.—Kapogiannis, D., Boxer, A., Schwartz, J. B., Abner, E. L., Biragyn, A., Masharani, U., Frassetto, L., Petersen, R. C., Miller, B. L., Goetzl, E. J. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural‐derived blood exosomes of preclinical Alzheimer's disease. FASEB J . 29, 589‐596 (2015). www.fasebj.org