Citations

Leigh syndrome embodies degenerative disorders with a collection of symptoms secondary to inborn errors of metabolism. Combinations of hypomorphic and loss‐of‐function alleles in many genes have been shown to result in Leigh syndrome. Interestingly, deficiency for the tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH) can lead to Leigh‐like syndrome in some circumstances and to cancer (paraganglioma, renal cell carcinoma, gastrointestinal stromal tumor) in others. In our experiments originally intended to create an inducible whole‐body SDH‐loss mouse model of tumorigenesis, we generated a condition reminiscent of Leigh‐like syndrome that is lethal to mice within 4 wk. Remarkably, as has been shown for other mitochondrial diseases, chronic hypoxia offers substantial protection to mice from this condition after systemic SDH loss, allowing survival in the context of profoundly impaired oxidative metabolism.—Al Khazal, F., Holte, M. N., Bolon, B., White, T. A., LeBrasseur, N., Maher, L. J. III. A conditional mouse model of complex II deficiency manifesting as Leigh‐like syndrome. FASEB J. 33, 13189–13201 (2019). www.fasebj.org

In this work related to familial aggregation of familial venous thromboembolism, the investigators report genomic and transcriptomic association of 16 novel susceptibility loci for venous thromboembolism.

Objective: Fatigue due to game play is often cited as a factor in musculoskeletal injuries; however, it is unclear whether or not this view is supported by published research findings. Given the importance researchers and practitioners place on the potential effects of game play with respect to injury, it is important to understand what inferences can be drawn from the collective research in this realm. This meta-analysis will consider the time of season and segment of the game, as it relates anterior cruciate ligament (ACL), groin, and hamstring injury occurrence. Data Sources: Database searches were run in PubMed, MEDLINE, SportDiscus, CINAHL, and Ausport, in addition to the inclusion of articles identified manually. Study Selection: Search terms were chosen to identify articles related to each of the 3 injuries of interest. There were no date limitations placed on the articles, as such, all published articles listed in the databases up to November 2017 were eligible for selection if they met the search criteria. Data Extraction: Initial searches yielded 1349 articles, and this was eventually reduced to 15 articles deemed suitable for inclusion in the meta-analysis, which provided 21 data sets. Data Synthesis: Comparing the first half with the second half of the season, there were no differences in ACL, groin, or hamstring injury occurrences [ACL: odds ratio (OR), 1.27; confidence interval (CI), 0.43-3.78, groin: OR, 1.79; CI, 0.63-5.06, and hamstring: OR, 1.16; CI, 0.88-1.53]. Similarly, there were no differences in injury occurrence between the first and second halves of the game for the ACL or hamstring injuries (ACL: OR, 0.43; CI, 0.47-7.92, hamstring: OR, 0.85; CI, 0.58-1.24). Conclusions: Findings from this meta-analysis determined that time in season or time in game does not influence risk of the ACL, groin, or hamstring injury. Commonly, many studies did not provide sufficient detail to be included in the meta-analysis. Consequently, it is recommended that future studies report data related to the timing of the injury within the season or game.

Abstract Background: Immunoprevention via targeting antigens aberrantly expressed on colorectal cancers and adenomatous polyps offers the potential for a less invasive prevention strategy than endoscopic surveillance. Specificity of the immune response and long-term memory provide the potential for prolonged protection. Leveraging the infrastructure of the NCI-funded Cancer Prevention Network (CPN) consortium, we are conducting a double-blind randomized trial in individuals with a diagnosis of advanced colorectal adenomas within the previous year. We are evaluating MUC1 vaccine with the TLR-3 agonist polyICLC as an adjuvant, for its immunogenicity, ability to elicit immune memory and prevent recurrence of colorectal adenomas. Aims: We previously reported on the vaccine immunogenicity at week 12 (vaccine administered at 0, 2, and 10 weeks) compared to placebo. Here we report the ability of the vaccine to elicit long-term memory by measuring increase in anti-MUC1 antibody levels following a booster administered at one year. Methods: Subjects with endoscopically resected advanced adenoma (defined as ≥1cm, tubululovillous or villous histology, or with high grade dysplasia) were randomized. The primary endpoint was the response to the vaccine at week 12 assessed by monitoring anti-MUC1 IgG antibody titer ratio defined as t12/t0, where t0 was the titer pre-vaccination, and t12 was the titer at week 12. The key secondary endpoint was to assess anti-MUC1 IgG response at week 55 to a booster at week 52 in the vaccine arm compared to placebo. Results: 102 eligible subjects were randomized at 6 centers, 52 received MUC1 vaccine and 50 placebo. The mean age was 59.4±7.0 (range 40-70), 60.8% male, 88.2% white, and 18.6% Hispanic or Latino ethnicity. At 12 weeks the IgG ratio was ≥2.0 in 13/52 (25%) of individuals receiving vaccine (ratio range -0.5-17.3), vs. 0/50 in placebo group (2-sided p=.0001), and was ≥1.5 in 19/52 (36.5%) individuals receiving vaccine compared to 1/50 (2%) in placebo group (P<.0001). To evaluate immune memory, 1-year booster data available for 95 patients (51-MUC1, 44-placebo) were analyzed. 10/13 (76.9%) of the week 12 vs. week 0 vaccine responders showed a response at week 52 vs. baseline and 11/13 (84.6%) at week 55 vs. week 52. Using an IgG ratio of 2 (per-protocol), the response rate was 33% for MUC1 vs. 5% for placebo (1-sided p=0.0003). Using a ratio of 1.5 yielded similar results (37% MUC1 vs. 9% Placebo (1-sided p=0.0008). The MUC1 arm had significantly higher IgG at week 52 (1-sided p=0.0294), week 55 (1-sided p=0.0048), and significantly higher week 55 to week 52 IgG ratio values (1-sided p=0.0293). Conclusions: Subjects with a recent history of advanced adenoma receiving a MUC1 vaccine compared with a placebo were significantly more likely to develop an immune response at week 12, confirming the vaccine’s immunogenicity, and to respond again at week 55 to a booster injection on week 52, confirming the vaccine’s ability to elicit immune memory. Follow-up colonoscopy to evaluate the vaccine’s potential to lower adenomatous polyp recurrence rates are in progress. Citation Format: Olivera J. Finn, Lisa Boardman, Marcia Cruz-Correa, Ajay Bansal, David Kastenberg, Chin Hurr, Sharon Kaufman, Colleen Akerley, Lynda Dzubinski, April Felt, Karrie Fursa, L.M. Rodriguez, Ellen Richmond, Asad Umar, Eva Szabo, John McKolanis, Ryan McMurray, Nathan Foster, Andres Salazar, Paul Limburg, Robert Schoen. Randomized, double-blind, placebo-controlled trial of preventative MUC1 vaccine in patients with newly diagnosed advanced adenomas: Results from one-year booster [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT236.

Abstract Background: Smoking is the most common etiology for lung cancer. Smoking cessation, even when successful, does not eliminate risk of lung cancer. With inconsistent results of lung chemoprevention trials, an emerging area of interest is immunoprevention, in particular vaccines. MUC1 is a transmembrane glycoprotein aberrantly overexpressed in adenocarcinomas, including lung cancer. Abnormal MUC1 expression is also characteristic of premalignant lesions, including bronchial dysplasia and atypical adenomatous hyperplasia. This suggests that immunization with a MUC1 vaccine in the premalignant or high-risk setting, before the tumor and cytotoxic therapy could suppress the immune system, might be effective in inducing strong immunity and reducing cancer risk. Trial design: Leveraging the infrastructure of the NCI-funded Cancer Prevention Network (CPN) consortium, we are conducting a two-center pilot trial to evaluate co-primary endpoints: immunogenicity of the MUC1 peptide plus polyICLC adjuvant vaccine (assessed at 12 weeks) and safety (assessed at up to 24 weeks) in current and former smokers who are at high risk for lung cancer. 50 participants will be screened in order to have 40 evaluable participants for baseline and 12-week immunogenicity assessments. Eligibility: Smoking history of ≥30 pack-years and either current smoker (still smoking or quit < 1 year prior to pre-registration) or former smoker (quit 1-15 years prior to pre-registration); ages 55-80 years; ECOG performance status ≤1; CT scan of the chest done ≤ 6 months prior to pre-registration showing either negative findings (no nodules) or solid or part-solid nodules < 6 mm in size (consistent with < 1% probability of malignancy, Lung-RADs Version 1.0). Exclusion criteria are standard. Immunogenicity and safety: MUC1 peptide plus polyICLC adjuvant vaccine will be administered at week 0, 2 and 10. The primary endpoint is anti-MUC1 IgG titer that is ≥2 fold higher at week 12 compared to baseline. Based on previous studies of this vaccine, we expect that 40 evaluable participants will provide 96% power to detect immunogenicity response rate of 15% versus 40% using a 2-sided test of proportions with type I error rate of 0.05. AEs and toxicities will be monitored for up to 24 weeks from the first vaccine. Secondary Objectives: We will explore differences, if any, in vaccine immunogenicity in current vs. former smokers. Smoking induces chronic inflammation (hallmark of cancer) associated with immunosuppression. We will evaluate pre-vaccination levels of circulating myeloid derived suppressor cells (MDSC) and correlate with the response to the vaccine. We will explore the impact, if any, of this vaccine on the markers of inflammation (hsCRP, IL-6) and the effect of baseline levels of these markers on the ability to successfully vaccinate. We will also assess the relationship between COPD status and immune response in current versus former smokers. The trial is open to accrual. Citation Format: Olivera J. Finn, Julie Ward, Tami Krpata, Lisa Bengtson, John McKolanis, Sharon Kaufman, Colleen Akerley, April Felt, Karrie Fursa, Anne Holland, Nathan Foster, Andres Salazar, Malgorzata Wojtowicz, Eva Szabo, Paul Limburg, David Midthun, Arjun Pennathur. A pilot study of a MUC1 vaccine in current and former smokers at high risk for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT222.