Citations

Abstract After a primary immune response, T cell memory occurs when a subset of Ag-specific T cells resists peripheral selection by acquiring resistance to TCR-induced death. Recent data have implicated Bcl-2 interacting mediator of death (Bim) as an essential mediator of the contraction phase of T cell immunity. In this article, we describe that stromal-derived factor-1α (SDF-1α) ligation of CXCR4 on activated T cells promotes two parallel processes that favor survival, phospho-inactivation of Foxo3A, as well as Bim extralong isoform (BimEL) degradation, both in an Akt- and Erk-dependent manner. Activated primary CD4 T cells treated with SDF-1α therefore become resistant to the proapoptotic effects of TCR ligation or IL-2 deprivation and accumulate cells of a memory phenotype. Unlike SDF-1α, gp120 ligation of CXCR4 has the opposite effect because it causes p38-dependent BimEL upregulation. However, when activated CD4 T cells are treated with both gp120 and SDF-1α, the SDF-1α–driven effects of BimEL degradation and acquired resistance to TCR-induced death predominate. These results provide a novel causal link between SDF-1α–induced chemotaxis, degradation of BimEL, and the development of CD4 T cell memory.

Abstract Background: Based on recent breast cancer literature, we hypothesized that there could be substantive differences in apparent efficacy estimates using a log-normal (LN) survival model rather than with standard Kaplan-Meier (K-M) or Cox model methods. While both Cox and LN survival analyses offer greater specification by individual patient characteristics, the LN model may more robustly estimate survival under model misspecification. Methods: We recently pooled data for 5 NCIC CTG primary breast cancer trials: MA.5, MA.12, MA.14, MA.21, and MA.27. The total patient count for patients who received at least 1 dose of trial therapy is 11,253. Compilation included definition of STEEP endpoints (C Hudis, JCO, 2008) and standardized factor categorizations. The primary endpoint is Breast Cancer Free Interval (BCFI) defined as the time from randomization until recurrence: first local invasive or DCIS; regional, or distant; contralateral invasive or DCIS; or death from breast cancer. We found substantive evidence of non-proportionality for 7 factors compiled for the meta-analyses. In this work, we fit multivariate Cox and LN models with these 7 factors, lymph node status and pathologic T status. We then compare BCFI efficacy estimates for patient and tumour characteristics at 1-, 3-, and 5-years obtained with K-M, Cox, and LN models. Results: There was evidence that the Cox assumption of proportional hazards was violated for 7 factors: age, menopausal status, hormone receptor status, anthracycline use, chemotherapy use, race, and ECOG performance status. Differences between models were intrinsically affected by timing and extent of non-proportionality; there was no consistent pattern. In particular, investigations to date indicate efficacy estimates with absolute differences between K-M, Cox and LN estimates which varied by time of assessment: at 1-year 0.0 to 6.7%, at 3-years 0.4 to 18.6%, and at 5-years 0.2 to 17.0%. BCFI estimates with the K-M were inconsistently closer to those with the LN or Cox model: for K-M to Cox at 1-year 0.4 to 5.2%, at 3-years 0.4 to 15%, at 5-years 0.4 to 14.3%; for K-M to LN at 1-year 0.0 to 6.7%, at 3-years 0.5 to 18.6%, at 5-years 0.2 to 17.0%; for Cox to LN at 1-year 0.8 to 1.8%, at 3-years 1.9 to 6.0%, at 5-years 0.6 to 5.7%. K-M and Cox models have step-wise adjustments at events for K-M and Cox, rather than smooth modeling with the LN. Discussion: Even with reasonably large population subgroups, there were substantive differences in apparent survival (0.0 to 18.6%) between K-M, Cox and LN model types. The magnitude of differences in survival estimates was large enough to be clinically relevant and warrant further consideration as we evaluate new therapies and prognostic/predictive factors. We will be statistically investigating framework robustness under differing levels of model misspecification. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-01.

We present here a novel case of an atypical Omenn syndrome (OS) phenotype due to mutations in theADAgene encoding adenosine deaminase. This case is noteworthy for a significant increase in circulating CD56brightCD16- cytokine-producing NK cells after treatment with steroids for skin rash.

The secretin receptor is a prototypic class B G protein-coupled receptor that is activated by binding of its natural peptide ligand. The signaling effects of this receptor are mediated by coupling with Gs, which activates cAMP production, and Gq, which activates intracellular calcium mobilization. We have explored the molecular basis for the coupling of each of these G proteins to this receptor using systematic site-directed mutagenesis of key residues within each of the intracellular loop regions, and studying ligand binding and secretin-stimulated cAMP and calcium responses. Mutation of a conserved histidine in the first intracellular loop (H157A and H157R) markedly reduced cell surface expression, resulting in marked reduction in cAMP and elimination of measurable calcium responses. Mutation of an arginine (R153A) in the first intracellular loop reduced calcium, but not cAMP responses. Mutation of a dibasic motif in the second intracellular loop (R231A/K232A) had no significant effects on any measured responses. Mutations in the third intracellular loop involving adjacent lysine and leucine residues (K302A/L303A) or two arginine residues separated by a leucine and an alanine (R318A/R321A) significantly reduced cAMP responses, while the latter also reduced calcium responses. Additive effects were elicited by combining the effective mutations, while combining all the effective mutations resulted in a construct that continued to bind secretin normally, but that elicited no significant cAMP or calcium responses. These data suggest that, while some receptor determinants are clearly shared, there are also distinct determinants for coupling with each of these G proteins.

Abstract An immunoinhibitory role of B7 homologue 1 (B7-H1) expressed by non-T cells has been established; however, the function of B7-H1 expressed by T cells is not clear. Peak expression of B7-H1 on Ag-primed CD8 T cells was observed during the contraction phase of an immune response. Unexpectedly, B7-H1 blockade at this stage reduced the numbers of effector CD8 T cells, suggesting B7-H1 blocking Ab may disturb an unknown function of B7-H1 expressed by CD8 T cells. To exclusively examine the role of B7-H1 expressed by T cells, we introduced B7-H1 deficiency into TCR transgenic (OT-1) mice. Naive B7-H1–deficient CD8 T cells proliferated normally following Ag stimulation; however, once activated, they underwent more robust contraction in vivo and more apoptosis in vitro. In addition, B7-H1–deficient CD8 T cells were more sensitive to Ca-dependent and Fas ligand-dependent killing by cytotoxic T lymphocytes. Activation-induced Bcl-xL expression was lower in activated B7-H1–deficient CD8 T cells, whereas Bcl-2 and Bim expression were comparable to the wild type. Transfer of effector B7-H1–deficient CD8 T cells failed to suppress tumor growth in vivo. Thus, upregulation of B7-H1 on primed T cells helps effector T cells survive the contraction phase and consequently generate optimal protective immunity.

Abstract Background: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium. Methods: Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression. Results: For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08–1.14, P = 7 × 10−18) for invasive breast cancer and 1.10 (95% CI = 1.01–1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR = 1.07, 95%CI = 0.99–1.15, P = 0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR = 1.16, 95% CI = 1.12–1.20, P = 1 × 10−18 vs. OR = 1.03, 95% CI = 0.99–1.07, P = 0.2 for PR-negative disease; Pheterogeneity = 2 × 10−7); heterogeneity by ER status was not observed (P = 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per-allele OR (95% CI) = 1.20 (1.14–1.25), 1.13 (1.09–1.16), and 1.04 (0.99–1.08) for grade 1, 2, and 3/4, respectively; Ptrend = 5 × 10−7]. Conclusion: 5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer. Impact: Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants. Cancer Epidemiol Biomarkers Prev; 20(10); 2222–31. ©2011 AACR.

The outcome of critical illness depends not only on life threatening pathophysiologic disturbances, but also on several complex “system” dimensions: health care providers’ performance, organizational factors, environmental factors, family preferences and the interactions between each component. Systems engineering tools offer a novel approach which can facilitate a “systems understanding” of patient-environment interactions enabling advances in the science of healthcare delivery. Due to the complexity of operations in critical care medicine, certain assumptions are needed in order to understand system behavior. Patient variation and uncertainties underlying these assumptions present a challenge to investigators wishing to model and improve health care delivery processes. In this chapter we present a systems engineering approach to modeling critical care delivery using sepsis resuscitation as an example condition.

AbstractLung cancer in lifetime never smokers is distinct from that in smokers, but the role of separate or overlapping carcinogenic pathways has not been explored. We therefore evaluated a comprehensive panel of 11,737 single-nucleotide polymorphisms (SNP) in inflammatory-pathway genes in a discovery phase (451 lung cancer cases, 508 controls from Texas). SNPs that were significant were evaluated in a second external population (303 cases, 311 controls from the Mayo Clinic). An intronic SNP in the ACVR1B gene, rs12809597, was replicated with significance and restricted to those reporting adult exposure to environmental tobacco smoke. Another promising candidate was an SNP in NR4A1, although the replication OR did not achieve statistical significance. ACVR1B belongs to the TGFR-β superfamily, contributing to resolution of inflammation and initiation of airway remodeling. An inflammatory microenvironment (second-hand smoking, asthma, or hay fever) is necessary for risk from these gene variants to be expressed. These findings require further replication, followed by targeted resequencing, and functional validation.Significance: Beyond passive smoking and family history of lung cancer, little is known about the etiology of lung cancer in lifetime never smokers that accounts for about 15% of all lung cancers in the United States. Our two-stage candidate pathway approach examined a targeted panel of inflammation genes and has identified novel structural variants that appear to contribute to risk in patients who report prior exposure to sidestream smoking. Cancer Discovery; 1(5): 420–9. ©2011 AACR.This article is highlighted in the In This Issue feature, p. 367

Objective— Left atrial blood stasis is associated with increased risk for left atrial appendage thrombus (LAAT) and stroke in atrial fibrillation (AF). Von Willebrand factor (VWF) is associated with thromboembolism in AF. VWF thrombogenic activity is proportional to multimer size, which is regulated by VWF-cleaving protease (ADAMTS13). Methods and Results— To assess the association between left atrial blood stasis and VWF-ADAMTS13 system, plasma VWF antigen (VWF:Ag), VWF activity (VWF:Act), and ADAMTS13 activity were measured in 414 consecutive patients with nonvalvular AF (age 63±13 years; 25% women) and in 100 patients (age 64±14 years; 39% women) with normal sinus rhythm. Spontaneous echocardiographic contrast (SEC), left atrial appendage emptying velocity, and LAAT were assessed by transesophageal echocardiography. Presence and intensity of SEC varied directly with VWF:Ag and VWF:Act but not with ADAMTS13 activity. AF patients with LAAT had higher VWF:Ag (200±61 versus 155±52, P =0.0006) and VWF:Act (179±57 versus 141±51 P =0.0026) compared with those without LAAT. VWF:Ag and VWF:Act were independent predictors of LAAT after adjustment for CHADS 2 score ( P =0.0179 and P =0.0497, respectively). Conclusion— The association between VWF and SEC may explain the thrombotic propensity in AF. Elevated VWF:Ag may help identify AF patients at risk for LAAT.