Citations

Abstract Recent thymic emigrants are newly generated T cells that need to undergo postthymic maturation to gain functional competency and enter the long-lived naive T cell pool. The mechanism of T cell maturation remains incompletely understood. Previously, we demonstrated that the transcriptional repressor NKAP is required for T cell maturation. Because NKAP associates with histone deacetylase 3 (HDAC3), we examined whether HDAC3 is also required for T cell maturation. Although thymic populations are similar in CD4-cre HDAC3 conditional knockout mice compared with wild-type mice, the peripheral numbers of CD4+ and CD8+ T cells are dramatically decreased. In the periphery, the majority of HDAC3-deficient naive T cells are recent thymic emigrants, indicating a block in T cell maturation. CD55 upregulation during T cell maturation is substantially decreased in HDAC3-deficient T cells. Consistent with a block in functional maturation, HDAC3-deficient peripheral T cells have a defect in TNF licensing after TCR/CD28 stimulation. CD4-cre HDAC3 conditional knockout mice do not have a defect in intrathymic migration, thymic egress, T cell survival, or homeostasis. In the periphery, similar to immature NKAP-deficient peripheral T cells, HDAC3-deficient peripheral T cells were bound by IgM and complement proteins, leading to the elimination of these cells. In addition, HDAC3-deficient T cells display decreases in the sialic acid modifications on the cell surface that recruit natural IgM to initiate the classical complement pathway. Therefore, HDAC3 is required for T cell maturation.

This study describes medical burden among individuals ⩾ 65 years hospitalized for depression in order to determine its associations with depression and quality of life (QOL) and thus provide suggestions for spiritual care providers. Using reliable, validated measures, the 45 participants who completed the study demonstrated moderate medical burden that was significantly associated with physical QOL but not with mental QOL or depression. Irrespective of the level of medical burden, subjects exhibited significant improvement of both depression and QOL during hospitalization. Results suggest that advocacy by spiritual care providers is essential.

The objective of this analysis of 4500 inpatients was to identify the experience and expectations of 18–35 year olds regarding chaplain visitation and to compare results with data from older adults. 71% of young adults reported wanting to be visited by a chaplain; 45.5% were visited; 68% indicated that this was important. Young adults value chaplains' role as a sign of God's care and presence (77.4%), in providing support for family (73.6%), being present during times of anxiety (66.0%), and praying/reading scripture with them (62.3%). Results were similar to older respondents, but young adults were more likely to value ethical counsel from chaplains (58.5% vs. 38.2%). This study provides clinically relevant information and suggestions for further research.

SummaryIntroductionThe performance of factor XI activity (FXI) by laboratories in the North American Specialized Coagulation Laboratory Association proficiency testing program was analyzed.MethodsOver 10 years (2003–2013), 80 samples were distributed; 33–55 laboratories participated per exercise providing 3833 total responses. Analysis was performed on numeric results and qualitative classification of results.ResultsThe sample FXI levels ranged from 3.8 to 154.0 IU/dL. The overall interlaboratory average coefficient of variation (CV%) was 17.5%; the CV was higher for a sample with low (3.8 IU/dL) FXI. Results were correctly classified as abnormal (100%) for a sample with 3.8 IU/dL FXI and normal/borderline normal (97.7%) for 45 samples with 80 to < 140 IU/dL FXI. The classification was heterogeneous for samples with FXI of 50 to < 80 IU/dL. Six specimens were repeat‐tested from 2007 to 2013. The mean FXI was not significantly different in laboratories using the same method on both exercises, suggesting good intralaboratory precision over time. Univariate analysis of data from 2011 to 2012 did not find a consistent significant difference among the activators, analyzers, calibrators, and FXI‐deficient plasmas.ConclusionLaboratories generally performed well in assessment of FXI based on interlaboratory precision when FXI >30 IU/dL and on classification of samples with very low or normal FXI.

Abstract Background: High body mass index (BMI) is consistently linked to increased risk of colorectal cancer for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and colorectal cancer. Methods: We used data from 10,226 colorectal cancer cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study–identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis. Results: Individuals carrying greater numbers of BMI-increasing alleles had higher colorectal cancer risk [per weighted allele OR, 1.31; 95% confidence interval (CI), 1.10–1.57]. Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for colorectal cancer (IV-OR per 5 kg/m2, 1.50; 95% CI, 1.13–2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of colorectal cancer among women (IV-OR per 5 kg/m2, 1.82; 95% CI, 1.26–2.61). For men, genetically influenced BMI was not associated with colorectal cancer (IV-OR per 5 kg/m2, 1.18; 95% CI, 0.73–1.92). Conclusions: High BMI was associated with increased colorectal cancer risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation. Impact: Overall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(7); 1024–31. ©2015 AACR.

Abstract Background: Although breast cancer (BC) may occur at any age, its prevalence is greater postmenopause. Greater than 75 % of postmenopausal BCs are hormone dependent. Aromatase inhibitors suppress postmenopausal estrogen biosynthesis. Letrozole has demonstrated efficacy against BC in the adjuvant and metastatic setting at the treatment dose of 2.5 mg daily. Its potential role in BC prevention has been inferred from reductions in contralateral BCs. Its side effect profile, similar to other AIs, includes exacerbation of menopausal symptoms that negatively impact quality of life (QOL) and may result in discontinuation of the drug. Both anastrazole and exemestane have been demonstrated to reduce BC in high-risk women. Hypothesis: Lower and intermittent doses of letrozole effectively suppress estrogen in the high-risk postmenopausal woman and provide a better side effect profile. Methods: A randomized, double-blind study comparing the impact of varying letrozole doses (2.5 mg daily, 2.5 mg MWF, 1.0 mg MWF, or 0.25 mg MWF) on estrogen suppression and side effects--lipids, bone resorption, menopause, and QOL-- was conducted. Participants randomized to intermittent dosing received placebo on nontreatment days. Results: 112 participants were enrolled at 2 clinical sites. Mean patient age was 62.8 years, and average BMI was 29.8. Analysis of available data after 24 weeks of therapy revealed statistically significant increase in triglycerides (N=94): 114.67±48.39 to 125.79±54.31 (p&lt;0.01); vasomotor symptoms (N=95): 2.25±1.26 to 2.74±1.67 (p&lt;0.01); and C-telopeptide (N=75): 0.39±0.23 to 0.55±0.28 (p&lt;0.0001). Statistically significant decrease in estradiol (N=68): 5.57±5.19 to 1.26±1.41 (p&lt;0.0001) and estrone (N=68): 22.39±13.02 to 1.64±2.66 (p&lt;0.0001) were observed. No differences in QOL (SF 36) were noted after letrozole treatment. P-values were derived from paired t-test (signed rank test) for the difference between baseline and after 24 weeks of study drug. Conclusions: De-escalating doses of letrozole suppress postmenopausal estrogen effectively and result in statistically significant increases in triglycerides, C-telopeptide and vasomotor symptoms without impact on QOL. Presentation will include unblinded intervention arm outcomes. Citation Format: Ana Maria Lopez, Hsiao Hui Sherry Chow, Denise Frank, Sandhya Puthi, Judy Boughey, Paul Hsu, Jose Guillen, Marjorie Perloff, Michelle Ley, Julie E Lang. De-escalating doses of letrozole in post menopausal women at high risk for breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-12-04.

Abstract To identify genetic variants that contribute to colorectal cancer (CRC) susceptibility, we performed a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, followed by a replication of genome-wide statistically significant associations (P &lt; 5E-8) in 16,823 cases and 18,211 controls of European ancestry. This study revealed a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A; P=1.5E-9), providing additional insight into the etiology of CRC and highlighting the value of association mapping in diverse populations. Citation Format: Hansong Wang, Terrilea Burnett, Suminori Kono, Christopher Haiman, Motoki Iwasaki, Lynne Wilkens, Lenora Loo, David Van Den Berg, Laurence Kolonel, Brian Henderson, Temitope Keku, Robert Sandler, Lisa Signorello, William Blot, Polly Newcomb, Mala Pande, Christopher Amos, Dee West, Stéphane Bézieau, Sonja Berndt, Brent Zanke, Li Hsu, Noralane Lindor, Robert Haile, John Hopper, Mark Jenkins, Steven Gallinger, Graham Casey, Stephanie Stenzel, Fredrick Schumacher, Ulrike Peters, Stephen Gruber, Shoichiro Tsugane, Dan Stram, Loic Le Marchand. Transethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-282. doi:10.1158/1538-7445.AM2014-LB-282

AbstractB lymphopoiesis in bone marrow (BM) is critical for maintaining a diverse peripheral B cell pool to fight infection and establish lifelong immunity. The generation of immature B cells is reduced in Flt3‐ligand (FL‐/‐) mice leading to deficiencies in splenic B cells. Here, we sought to understand the cellular basis of the spleen B cell deficiency in FL‐/‐ mice. Significant reductions in transitional (TS) and follicular (FO) B cells were found in FL‐/‐ mice, and increased frequencies, but not absolute numbers, of marginal zone (MZ) B cells. BAFF‐R expression on splenic B cells and serum levels of B cell activating factor (BAFF) was comparable to wildtype (WT) mice. Mixed BM chimeras revealed that the reductions in TS and FO B cells were cell extrinsic. FL administration into FL‐/‐ mice restored the deficiency in TS B cells and normalized the MZ compartment. Ki67 analysis revealed a significant decrease in the proliferative capacity of TS B cells in FL‐/‐ mice. A Bcl2 transgene did not rescue TS cells in FL‐/‐ mice, uncoupling FL‐deficiency to Bcl2‐dependent survival pathways. Upregulation of CD1d expression and adoptive transfer experiments suggested MZ skewing in FL‐/‐ mice. These findings support an integral role for Flt3 signaling in peripheral B cell maturation.