Research Spotlight

Sudhakaran, S. and Choi, J.W. (2020). “Coronary Chronic Total Occlusion Antegrade Wire Technique to Successfully Cross a Common Iliac Chronic Total Occlusion from Retrograde Access.” Am J Cardiol 129: 118-119

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Percutaneous endovascular intervention is the preferred modality of revascularization for iliac arterial obstructive disease. Chronic total occlusions (CTO) of the iliac arteries can be uniquely challenging, as typically utilized polymer jacketed 0.035 in wires have a tendency to enter subintimal planes within the iliac artery or aorta, which consequently require complicated re-entry wire techniques. We present a case of a common iliac chronic total occlusion, initially unable to be crossed with a traditional 0.035 in polymer jacketed guidewire due to subintimal entry. Instead, using an antegrade coronary CTO wire escalation technique with a 0.014 in coronary CTO guidewire, the iliac occlusion was successfully crossed via the true lumen.

Miyazaki, K., Watanabe, H., Yoshikawa, G., Chen, K., Hidaka, R., Aitani, Y., Osawa, K., Takeda, R., Ochi, Y., Tani-Ichi, S., Uehata, T., Takeuchi, O., Ikuta, K., Ogawa, S., Kondoh, G., Lin, Y.C., Ogata, H. and Miyazaki, M. (2020). “The transcription factor E2A activates multiple enhancers that drive Rag expression in developing T and B cells.” Sci Immunol 5(51).

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Cell type-specific gene expression is driven by the interplay between lineage-specific transcription factors and cis-regulatory elements to which they bind. Adaptive immunity relies on RAG-mediated assembly of T cell receptor (TCR) and immunoglobulin (Ig) genes. Although Rag1 and Rag2 expression is largely restricted to adaptive lymphoid lineage cells, it remains unclear how Rag gene expression is regulated in a cell lineage-specific manner. Here, we identified three distinct cis-regulatory elements, a T cell lineage-specific enhancer (R-TEn) and the two B cell-specific elements, R1B and R2B By generating mice lacking either R-TEn or R1B and R2B, we demonstrate that these distinct sets of regulatory elements drive the expression of Rag genes in developing T and B cells. What these elements have in common is their ability to bind the transcription factor E2A. By generating a mouse strain that carries a mutation within the E2A binding site of R-TEn, we demonstrate that recruitment of E2A to this site is essential for orchestrating changes in chromatin conformation that drive expression of Rag genes in T cells. By mapping cis-regulatory elements and generating multiple mouse strains lacking distinct enhancer elements, we demonstrate expression of Rag genes in developing T and B cells to be driven by distinct sets of E2A-dependent cis-regulatory modules.

Litton, J.K., Hurvitz, S.A., Mina, L.A., Rugo, H.S., Lee, K.H., Gonçalves, A., Diab, S., Woodward, N., Goodwin, A., Yerushalmi, R., Roché, H., Im, Y.H., Eiermann, W., Quek, R.G.W., Usari, T., Lanzalone, S., Czibere, A., Blum, J.L., Martin, M. and Ettl, J. (2020). “Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial.” Ann Oncol Aug 20;S0923-7534(20)42106-4. [Epub ahead of print.].

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BACKGROUND: In EMBRACA, talazoparib prolonged progression-free survival versus chemotherapy (hazard ratio [HR] 0.542 [95% CI 0.413-0.711]; P < 0.0001) and improved patient-reported outcomes (PRO) in germline BRCA1/2 (gBRCA1/2)-mutated advanced breast cancer (ABC). We report final overall survival (OS). PATIENTS AND METHODS: This randomized phase III trial enrolled patients with gBRCA1/2-mutated HER2-negative ABC. Patients received talazoparib or physician's choice of chemotherapy. OS was analyzed using stratified HR and log-rank test and prespecified rank-preserving structural failure time model to account for subsequent treatments. RESULTS: 431 patients were randomized (287 talazoparib/144 chemotherapy) with 412 patients treated (286 talazoparib/126 chemotherapy). By September 30, 2019, 216 deaths (75.3%) occurred for talazoparib and 108 (75.0%) chemotherapy; median follow-up was 44.9 and 36.8 months, respectively. HR for OS with talazoparib versus chemotherapy was 0.848 (95% CI 0.670-1.073; P = 0.17); median (95% CI) 19.3 months (16.6-22.5) versus 19.5 months (17.4-22.4). Kaplan-Meier survival percentages (95% CI) for talazoparib versus chemotherapy: Month 12, 71% (66-76)/74% (66-81); Month 24, 42% (36-47)/38% (30-47); Month 36, 27% (22-33)/21% (14-29). Most patients received subsequent treatments: for talazoparib and chemotherapy, respectively, 46.3%/41.7% received platinum and 4.5%/32.6% received a poly(ADP-ribose) polymerase (PARP) inhibitor. Adjusting for subsequent PARP and/or platinum use, HR for OS was 0.756 (95% bootstrap CI 0.503-1.029). Grade 3-4 adverse events occurred in 69.6% (talazoparib) and 64.3% (chemotherapy) patients, consistent with previous reports. Extended follow-up showed significant overall improvement and delay in time to definitive clinically meaningful deterioration in global health status/quality of life and breast symptoms favoring talazoparib versus chemotherapy (P < 0.01 for all), consistent with initial analyses. CONCLUSIONS: In gBRCA1/2-mutated HER2-negative ABC, talazoparib did not significantly improve OS over chemotherapy; subsequent treatments may have impacted analysis. Safety was consistent with previous observations. PRO continued to favor talazoparib.

Benge, J.F. and Kiselica, A.M. (2020). “Rapid communication: Preliminary validation of a telephone adapted Montreal Cognitive Assessment for the identification of mild cognitive impairment in Parkinson’s disease.” Clin Neuropsychol Aug 11;1-15. doi: 10.1080/13854046.2020.1801848. [Epub ahead of print.].

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OBJECTIVE: In the current pandemic, tele-screening of neuropsychological status has become a necessity. Instruments developed for telephone screening are not as well validated as traditional neuropsychological measures. Therefore, the current study presents preliminary validation of a telephone version of the Montreal Cognitive Assessment (T-MoCA) in individuals with Parkinson’s disease (PD). METHOD: Twenty-one persons with PD completed the T-MoCA along with a traditional neuropsychological battery. Diagnostic accuracy for the presence of PD-related mild cognitive impairment (MCI) and correlations with traditional neuropsychological measures are reported. RESULTS: Individuals with MCI (n = 9) scored lower than individuals without cognitive impairment (17.56 vs. 19.50; t = -2.28, p = .03, d = -1.00). Diagnostic accuracy for MCI ranged from 76% to 81%, with sensitivity ranging from 0.56 to 0.67 and specificity ranging from 0.92 to 1.00. Correlations of T-MoCA derived scores with traditional neuropsychological measures were quite modest, with the exception of the memory impairment scale. CONCLUSIONS: This rapid communication presents preliminary validation of the T-MoCA for use in individuals with PD. Caveats and implications for practical use in the current pandemic are discussed.

Benge, J.F. and Scullin, M.K. (2020). “Implications for technological reserve development in advancing age, cognitive impairment, and dementia.” Behav Brain Sci 43: e157.

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This commentary draws connections between technological culture emergence and recent trends in using assistive technology to reduce the burden of Alzheimer’s disease. By the technical-reasoning hypothesis, cognitively-impaired individuals will lack the cognitive ability to employ technologies. By the technological reserve hypothesis, social-motivational and cultural transmissibility factors can provide foundations for using technology as cognitive prosthetics even during neurodegenerative illnesses.