Citations

Abstract Spleen cells from a number of H-2 congenic mice were tested for their proliferative and/or cytolytic responses to partially purified products from CNBr cleavage of Sendai virus. In response to in vitro stimulation of Sendai-primed spleen cells with virus-infected cells, Sendai virus-specific cytolytic T lymphocytes restricted to H-2Kb, Kd, Kk, Kb, and Dd were generated. Of these, H-2Kb- and Kd-, but not H-2Kk-, Kb-, and Dd-, restricted cytolytic T cells were generated after stimulation with partially purified Sendai peptides. H-2Dd-restricted, virus-specific cytotoxicity was generated in response to unseparated products from CNBr cleavage of Sendai virus. Thus, the pool of partially purified peptides contains some but not all of the antigenic determinants that can stimulate a cytolytic response. These results suggest that each determinant on Sendai viral proteins may stimulate cytolytic T lymphocytes restricted to only a subset of the H-2K and D alleles which can be recognized by the sum of cytolytic T cells generated in response to all of the antigenic determinants on Sendai viral proteins. Thus, H-2K and D genes function as immune response genes regulating the cytolytic response to partially purified peptides and, by extension, possibly to individual antigenic determinants on Sendai viral proteins. Also, spleen cells from three mice differing only in the H-2I-S regions show differences in their proliferative responses to Sendai antigens. Only spleen cells from mice with the k haplotype in IA-IJ proliferate in response to partially purified peptides, whereas spleen cells from all three mice proliferate when virus is added to the cultures. These proliferating cells are sensitive to treatment with anti-Thy-1.2 and C, suggesting that immune response genes regulating T cell proliferative responses to individual viral determinants may also exist.

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.

Abstract Objective: The aim of the study was to quantify baseline estradiol (E2) and estrone (E1) concentrations according to selected patient characteristics in a substudy nested within the MAP.3 chemoprevention trial. Methods: E2 and E1 levels were measured in 4,068 postmenopausal women using liquid chromatography-tandem mass spectrometry. Distributions were described by age, years since menopause, race, body mass index (BMI), smoking status, and use and duration of hormone therapy using the Kruskal-Wallis test. Multivariable linear regression was also used to identify characteristics associated with estrogen levels. Results: After truncation at the 97.5th percentile, the mean (SD)/median (IQR) values for E2 and E1 were 5.41 (4.67)/4.0 (2.4-6.7) pg/mL and 24.7 (14.1)/21 (15-31) pg/mL, respectively. E2 and E1 were strongly correlated (Pearson correlation [ r ] = 0.8, P < 0.01). The largest variation in E2 and E1 levels was by BMI; mean E2 and E1 levels were 3.5 and 19.1 pg/mL, respectively for women with BMI less than 25 and 7.5 and 30.6 pg/mL, respectively, for women with BMI greater than 30. E2 and E1 varied by age, BMI, smoking status, and prior hormone therapy in multivariable models ( P < 0.01). Conclusions: There was large interindividual variability observed for E2 and E1 that varied significantly by participant characteristics, but with small absolute differences except in the case of BMI. Although the majority of participant characteristics were independently associated with E1 and E2, together, these factors only explained about 20% of the variation in E1 and E2 levels.

6018 Background: Disease free survival was significantly improved in women receiving letrozole after standard adjuvant tamoxifen in the MA.17 trial. Based on the results of MA.17 and of other trials of aromatase inhibitors in early stage breast cancer, chronic aromatase inhibitor therapy, in postmenopausal women free of breast cancer recurrence, is now being widely employed. We analyzed the toxicity of letrozole according to ethnic status among women enrolled in MA.17. Methods: The chi-square test was used for comparison of rates of side effects between the two groups, Caucasian vs. ethnic minority (defined as all non-Caucasians). In a subset of women, quality of life (QOL) was assessed by the SF-36 Health Survey. Mean change scores in QOL from baseline were compared between groups for summary measures and domains using the Wilcoxon test. Results: 352 minority women and 4,708 Caucasians were enrolled in MA.17, of which 183 minority women and 2,339 Caucasians were randomized to receive letrozole. Caucasians were older than minority women and had a slightly longer duration of treatment with prior tamoxifen. Tumor size and nodal status were not significantly different between the two groups. In women who received letrozole, minority women had significantly lower incidence of hot flashes (49% vs. 58%; p = 0.02), fatigue (29% vs. 39%; p = 0.005), and arthritis (2% vs. 7%; p = 0.006) compared with Caucasians. Mean QOL change scores of SF-36 domains for women who received letrozole were not different but minority women had better mental health at 6 month assessment (p = 0.02) and worse bodily pain at 12 month assessment (p = 0.046). Conclusions: Minority women tolerated letrozole considerably better than Caucasians in the MA.17 trial. These preliminary findings suggest that minority women respond differently to letrozole in terms of toxicity. Recent demonstration of genotypic variations in the aromatase gene in different ethnic groups plus likely pharmacogenomic differences suggests that further research is needed to clarify the clinical outcomes of aromatase inhibition in women of diverse ethnicities. Future research strategies should focus on examining in vivo genotype-phenotype correlations to determine the effects of genetic variation on response to anticancer therapy and on toxicities and end-organ effects. [Table: see text]

550 Background: 5187 postmenopausal women were originally randomized to NCIC CTG MA.17 to receive letrozole (LET) or placebo (PLAC) after 5 years of tamoxifen. The hazard ratio (HR) for disease-free survival (DFS) was 0.58 (0.450.76, p=0.00004) after a median follow-up of 30 months (mo). The trial was unblinded in October 2003 after the first interim analysis. Women randomized to PLAC were offered LET at the time of unblinding. The goal of this analysis was to determine whether women switching from PLAC to LET benefit in terms of disease outcome and to evaluate treatment related toxicities. Methods: LET and PLAC-LET have been compared to PLAC, based on the hazard ratio and adjusting for baseline patient and disease variables including, among others, tumor size, nodal status and prior adjuvant chemotherapy. Results: Information about their follow-up treatment after unblinding was available on 2268 women originally assigned to PLAC and who were free of recurrence and alive at the time of unblinding. Among them, 1655 crossed over from PLAC to LET while 613 elected no treatment. With 54 mo f/up the HR for DFS was 0.31 (0.18, 0.55: p<0.0001) favoring patients who crossed over to LET compared to those who stayed on no treatment. The treatment switch was well tolerated with no significant difference in bone fractures or cardiovascular events. An updated analysis of DFS, DDFS and OS by nodal and tumor receptor status, prior chemotherapy, menopausal status at the start of tamoxifen, and duration of prior tamoxifen therapy will be presented at the meeting. Conclusion: Women with hormone dependent breast cancer prescribed LET after a prolonged delay from completing tamoxifen experienced a significant improvement in outcome (DFS, DDFS, OS) and should be considered for this therapy. [Table: see text]

Pancreatic cancer, mostly pancreatic ductal adenocarcinoma (PDAC), is one of the most lethal cancer types, with an estimated 44,330 death in 2018 in the US alone. While targeted therapies and immune checkpoint inhibitors have significantly improved treatment options for patients with lung cancer and renal cell carcinomas, little progress has been made in pancreatic cancer, with a dismal 5-year survival rate currently at ~8%. Upon diagnosis, the majority of pancreatic cancer cases (~80%) are already metastatic. Thus, identifying ways to reduce pancreatic cancer metastasis is an unmet medical need. Furthermore, pancreatic cancer is notorious resistant to chemotherapy. While Kirsten RAt Sarcoma virus oncogene (K-RAS) mutation is the major driver for pancreatic cancer, specific inhibition of RAS signaling has been very challenging, and combination therapy is thought to be promising. In this study, we report that combination of hedgehog (Hh) and Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase (MEK) signaling inhibitors reduces pancreatic cancer metastasis in mouse models. In mouse models of pancreatic cancer metastasis using human pancreatic cancer cells, we found that Hh target gene Gli1 is up-regulated during pancreatic cancer metastasis. Specific inhibition of smoothened signaling significantly altered the gene expression profile of the tumor microenvironment but had no significant effects on cancer metastasis. By combining Hh signaling inhibitor BMS833923 with RAS downstream MEK signaling inhibitor AZD6244, we observed reduced number of metastatic nodules in several mouse models for pancreatic cancer metastasis. These two inhibitors also decreased cell proliferation significantly and reduced CD45+ cells (particularly Ly6G+CD11b+ cells). We demonstrated that depleting Ly6G+ CD11b+ cells is sufficient to reduce cancer cell proliferation and the number of metastatic nodules. In vitro, Ly6G+ CD11b+ cells can stimulate cancer cell proliferation, and this effect is sensitive to MEK and Hh inhibition. Our studies may help design novel therapeutic strategies to mitigate pancreatic cancer metastasis.

ABSTRACT Background: MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear. Objective: To study the role of MAPT variants in rapid eye movement sleep behavior disorder. Methods: Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and controls (n = 981); (B) dementia with Lewy bodies patients with rapid eye movement sleep behavior disorder (n = 271) and controls (n = 950). MAPT ‐associated variants and the entire coding sequence of MAPT were analyzed. Age‐, sex‐, and ethnicity‐adjusted analyses were performed to examine the association between MAPT , PD, and rapid eye movement sleep behavior disorder. Results: MAPT‐ H2 variants were associated with PD (odds ratios: 0.62‐0.65; P = 0.010‐0.019), but not with rapid eye movement sleep behavior disorder. In PD, the H1 haplotype odds ratio was 1.60 (95% confidence interval: 1.12‐2.28; P = 0.009), and the H2 odds ratio was 0.68 (95% confidence interval: 0.48‐0.96; P = 0.03). The H2/H1 haplotypes were not associated with rapid eye movement sleep behavior disorder. Conclusions: Our results confirm the protective effect of the MAPT ‐H2 haplotype in PD, and define its components. Furthermore, our results suggest that MAPT does not play a major role in rapid eye movement sleep behavior disorder, emphasizing different genetic background than in PD in this locus. © 2018 International Parkinson and Movement Disorder Society

LBA506 Background: MA.17R is a Canadian Cancer Trials Group (CCTG) led phase III randomized controlled trial comparing letrozole to placebo after 5 years of aromatase inhibitor (AI) as adjuvant therapy for hormone-receptor positive breast cancer. The primary endpoint was disease-free survival. Quality of life (QOL) was a secondary endpoint. Methods: QOL was measured with the SF-36 (2 summary scores and 8 domains) and menopause-specific QOL (MENQOL) (4 symptom domains) at baseline and every 12 months (mo) up to 60 mo. QOL assessment was mandatory for CCTG centres but optional to centres in other groups. Mean change scores from baseline were calculated at 12 and 36 mo. Between-arm differences were assessed with the Wilcoxon test. Results: 1918 patients were randomized and 1428 patients completed the baseline QOL assessment. Compliance with QOL measures was over 85%. Baseline summary scores for SF-36 physical (PCS, 47.5 for letrozole and 47.9 for placebo) and mental (MCS, 55.5 for letrozole and 54.8 for placebo) were close to population norms (50). No differences were seen between groups in mean change scores for the SF-36 PCS and MCS and the other 8 QOL domains. Patients randomized to letrozole reported worse vasomotor symptoms (12 mo p = 0.02, 36 mo p = 0.03) and worse sexual functioning (12 mo p = 0.01, 36 mo p = 0.01). Further analyses with follow up to 60 months will be presented. Conclusions: No differences were seen in overall QOL measured by the SF 36 summary measures between letrozole and placebo groups. Differences existed for vasomotor symptoms and sexual functioning which were worse in the letrozole group and attributed to improvements in mean scores seen for women randomized to placebo. The data indicate that continuation of AI therapy after 5 years prior treatment is not associated with a deterioration of overall QOL. Treatment related vasomotor and sexual functioning alterations occur with ongoing treatment. Clinical trial information: NCT00754845.