Amphiphilic polyanhydride-based recombinant MUC4β-nanovaccine activates dendritic cells

Mucin 4 (MUC4) is a high molecular weight glycoprotein that is differentially overexpressed in pancreatic cancer (PC), functionally contributes to disease progression, and correlates with poor survival. Further, due to its aberrant glycosylation and extensive splicing, MUC4 is a potential target for cancer immunotherapy. Our previous studies have demonstrated the utility of amphiphilic polyanhydride nanoparticles as a useful platform for the development of protein-based prophylactic and therapeutic vaccines. In the present study, we encapsulated purified recombinant human MUC4-beta (MUC4β) protein in polyanhydride (20:80 CPTEG:CPH) nanoparticles (MUC4β-nanovaccine) and evaluated its ability to activate dendritic cells and induce adaptive immunity. Immature dendritic cells when pulsed with MUC4β-nanovaccine exhibited significant increase in the surface expressions of MHC I and MHC II and costimulatory molecules (CD80 and CD86), as well as, secretion of pro-inflammatory cytokines (IFN-γ, IL-6, and IL-12) as compared to cells exposed to MUC4β alone or MUC4β mixed with blank nanoparticles (MUC4β+NP). Following immunization, as compared to the other formulations, MUC4β-nanovaccine elicited higher IgG2b to IgG1 ratio of anti-MUC4β-antibodies suggesting a predominantly Th1-like class switching. Thus, our findings demonstrate MUC4β-nanovaccine as a novel platform for PC immunotherapy

Urban American Indian Community Health Beliefs Associated with Addressing Cancer in the Northern Plains Region

American Indians residing in the Northern Plains region of the Indian Health Service experience some of the most severe cancer-related health disparities. We investigated ways in which the community climate among an American Indian population in an urban community in the Northern Plains region influences community readiness to address cancer. A Community Readiness Assessment, following the Community Readiness Model, conducted semi-structured interviews with eight educators, eight students, and eight community leaders from the American Indian community in Omaha’s urban American Indian population and established the Northern Plains region community at a low level of readiness to address cancer. This study reports on a subsequent qualitative study that analyzed all 24 interview transcriptions for emergent themes to help understand the prevailing attitude of the community toward cancer. A synthesis of six emergent themes revealed that the community’s perceptions of high levels of severity and barriers, paired with perceptions of low levels of susceptibility and benefits, lead to low levels of self-efficacy, all of which are reflected in minimal cues to action and little effort to address cancer. These findings, interpreted through the lens of the Health Belief Model, can inform the development of more community-based, comprehensive, and culturally appropriate approaches to address the multilevel determinants of health behaviors in relation to cancer among American Indians in the Northern Plains region

Amyloid Precursor-like Protein 2 Expression Increases during Pancreatic Cancer Development and Shortens the Survival of a Spontaneous Mouse Model of Pancreatic Cancer.

In the United States, pancreatic cancer is a major cause of cancer-related deaths. Although substantial efforts have been made to understand pancreatic cancer biology and improve therapeutic efficacy, patients still face a bleak chance of survival. A greater understanding of pancreatic cancer development and the identification of novel treatment targets are desperately needed. Our analysis of gene expression data from patient samples showed an increase in amyloid precursor-like protein 2 (APLP2) expression within primary tumor epithelium relative to pancreatic intraepithelial neoplasia (PanIN) epithelial cells. Augmented expression of APLP2 in primary tumors compared to adjacent stroma was also observed. Genetically engineered mouse models of spontaneous pancreatic ductal adenocarcinoma were used to investigate APLP2\u27s role in cancer development. We found that APLP2 expression intensifies significantly during pancreatic cancer initiation and progression in the LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mouse model, as shown by immunohistochemistry analysis. In studies utilizing pancreas-specific heterozygous and homozygous knockout of APLP2 in the KPC mouse model background, we observed significantly prolonged survival and reduced metastatic progression of pancreatic cancer. These results demonstrate the importance of APLP2 in pancreatic cancer initiation and metastasis and indicate that APLP2 should be considered a potential therapeutic target for this disease

Constraining the Evolution of Zz Ceti

We report our analysis of the stability of pulsation periods in the DAV star (pulsating hydrogen atmosphere white dwarf) ZZ Ceti, also called R548. On the basis of observations that span 31 years, we conclude that the period 213.13 s observed in ZZ Ceti drifts at a rate dP/dt ≤ (5:5 ± 1:9) x 10-15 s s-1, after correcting for proper motion. Our results are consistent with previous Ṗ values for this mode and an improvement over them because of the larger time base. The characteristic stability timescale implied for the pulsation period is ⎸P / Ṗ ⎸=⎹≥ 1:2 Gyr, comparable to the theoretical cooling timescale for the star. Our current stability limit for the period 213.13 s is only slightly less than the present measurement for another DAV, G117-B15A, for the period 215.2 s, establishing this mode in ZZ Ceti as the second most stable optical clock known, comparable to atomic clocks and more stable than most pulsars. Constraining the cooling rate of ZZ Ceti aids theoretical evolutionary models and white dwarf cosmochronology. The drift rate of this clock is small enough that we can set interesting limits on reflex motion due to planetary companions

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Are we overlooking alcohol use by younger children?

Alcohol use is a leading contributor to the burden of disease among youth. Early-onset use is associated with later life dependency, ill health and poor social functioning. Yet, research on and treatment opportunities for alcohol use among younger children are scarce. Despite knowledge that alcohol intake occurs in childhood, and the fact that children understand alcohol related norms and develop alcohol expectancies from age 4, younger children are rarely included in studies on alcohol use.Patterns of early alcohol use vary greatly across the globe and are part of complex interplays between sociocultural, economic and health-related factors. Family influence has proven important, but genetic factors do not seem to play a crucial role at this age. Stressful circumstances, including mental health problems and sociocultural factors can entice alcohol use to cope with difficult situations. The World Health Organization has developed guidelines for effective strategies to reduce the harmful use of alcohol, including preventative and treatment interventions, but important gaps in implementation remain. An increased focus on research, policy and implementation strategies related to early alcohol use is warranted, granted its wide-ranging implications for public health and social functioning. In this summary of literature on alcohol use among younger children and adolescents, we show that younger children (aged 10 and younger) tend to be systematically overlooked. However, research, interventions and policy implementation strategies need to include younger children to mitigate the global burden of harmful alcohol use more effectively.publishedVersio