The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD); however, pathways regulating LRRK2 subcellular localization, function, and turnover are not fully defined. We performed quantitative mass spectrometry-based interactome studies to identify 48 novel LRRK2 interactors, including the microtubule-associated E3 ubiquitin ligase TRIM1 (tripartite motif family 1). TRIM1 recruits LRRK2 to the microtubule cytoskeleton for ubiquitination and proteasomal degradation by binding LRRK2911-919, a nine amino acid segment within a flexible interdomain region (LRRK2853-981), which we designate the "regulatory loop" (RL). Phosphorylation of LRRK2 Ser910/Ser935 within LRRK2 RL influences LRRK2's association with cytoplasmic 14-3-3 versus microtubule-bound TRIM1. Association with TRIM1 modulates LRRK2's interaction with Rab29 and prevents upregulation of LRRK2 kinase activity by Rab29 in an E3-ligase-dependent manner. Finally, TRIM1 rescues neurite outgrowth deficits caused by PD-driving mutant LRRK2 G2019S. Our data suggest that TRIM1 is a critical regulator of LRRK2, controlling its degradation, localization, binding partners, kinase activity, and cytotoxicity

Breast Conservation Surgery and Mastectomy have Similar Locoregional Recurrence Following Neoadjuvant Chemotherapy: Results from 1,462 Patients on the Prospective, Randomized I-SPY2 Trial.

Neoadjuvant chemotherapy (NAC) increases rates of successful breast conserving surgery (BCS) in patients with breast cancer. However, some studies suggest that BCS after NAC may confer increased risk of locoregional recurrence (LRR). We assessed LRR rates and locoregional recurrence free survival (LRFS) in patients enrolled on I-SPY2 (NCT01042379), a prospective NAC trial for patients with clinical stage II-III, molecularly high-risk breast cancer. Cox proportional hazards models were used to evaluate associations between surgical procedure (BCS vs. mastectomy) and LRFS adjusted for age, tumor receptor subtype, clinical T category, clinical nodal status, and Residual Cancer Burden (RCB). In 1,462 patients, surgical procedure was not associated with LRR or LRFS on either univariate or multivariate analyses. The unadjusted incidence of LRR was 5.4% after BCS, and 7.0% after mastectomy, at median follow up time of 3.5 years. The strongest predictor of LRR was RCB class, with each increasing RCB class having significantly higher hazard ratio for LRR compared to RCB 0 on multivariate analysis. Triple negative receptor subtype was also associated with increased risk of LRR (HR 2.91, 95% CI 1.8-4.6, P\u3c0.0001), regardless of type of operation. In this large multi-institutional prospective trial of patients completing NAC, we found no increased risk of LRR or differences in LRFS following BCS compared to mastectomy. Tumor receptor subtype and extent of residual disease after NAC were significantly associated with recurrence. These data demonstrate that BCS can be an excellent surgical option after NAC for appropriately selected patients

Changes in Surgical Management of the Axilla Over 11 Years - Report on More Than 1500 Breast Cancer Patients Treated with Neoadjuvant Chemotherapy on the Prospective I-SPY2 Trial.

BACKGROUND: Axillary surgery after neoadjuvant chemotherapy (NAC) is becoming less extensive. We evaluated the evolution of axillary surgery after NAC on the multi-institutional I-SPY2 prospective trial. METHODS: We examined annual rates of sentinel lymph node (SLN) surgery with resection of clipped node, if present), axillary lymph node dissection (ALND), and SLN and ALND in patients enrolled in I-SPY2 from January 1, 2011 to December 31, 2021 by clinical N status at diagnosis and pathologic N status at surgery. Cochran-Armitage trend tests were calculated to evaluate patterns over time. RESULTS: Of 1578 patients, 973 patients (61.7%) had SLN-only, 136 (8.6%) had SLN and ALND, and 469 (29.7%) had ALND-only. In the cN0 group, ALND-only decreased from 20% in 2011 to 6.25% in 2021 (p = 0.0078) and SLN-only increased from 70.0% to 87.5% (p = 0.0020). This was even more striking in patients with clinically node-positive (cN+) disease at diagnosis, where ALND-only decreased from 70.7% to 29.4% (p \u3c 0.0001) and SLN-only significantly increased from 14.6% to 56.5% (p \u3c 0.0001). This change was significant across subtypes (HR-/HER2-, HR+/HER2-, and HER2+). Among pathologically node-positive (pN+) patients after NAC (n = 525) ALND-only decreased from 69.0% to 39.2% (p \u3c 0.0001) and SLN-only increased from 6.9% to 39.2% (p \u3c 0.0001). CONCLUSIONS: Use of ALND after NAC has significantly decreased over the past decade. This is most pronounced in cN+ disease at diagnosis with an increase in the use of SLN surgery after NAC. Additionally, in pN+ disease after NAC, there has been a decrease in use of completion ALND, a practice pattern change that precedes results from clinical trials

A cultural history of Western music

"Music has been significant in social, religious, and political ritual, and in education, art, and entertainment in all human cultures from antiquity to today. The Cultural History of Western Music presents the first study of music in all its forms - ritual, classical, popular and commercial - from antiquity to today. The work is divided into 6 volumes, with each volume covering the same topics, so readers can either study a period/volume or follow a topic across history. The volumes are: 1. A Cultural History of Western Music in Antiquity 2. A Cultural History of Western Music in the Middle Ages 3. A Cultural History of Western Music in the Renaissance 4. A Cultural History of Western Music in the Age of Enlightenment 5. A Cultural History of Western Music in the Industrial Age 6. A Cultural History of Western Music in the Modern Age. The topics are identity, communities and society; changing philosophies and ideas about music; politics and power; musical exchange and knowledge transfer between the West and the non-West; musical education; popular culture and musical entertainment; the places, practices, and experiences of performance; and the development of music technologies and media. The page extent for the pack is approximately 1536 pp. Each volume opens with Notes on Contributors and an Introduction and concludes with Notes, Bibliography, and an Index"-- Includes bibliographical references and inde