Mitochondrial dysfunction has been deeply implicated in the pathogenesis of several neurodegenerative diseases. Thus, to keep a healthy mitochondrial population, a balanced mitochondrial turnover must be achieved. Tauroursodeoxycholic acid (TUDCA) is neuroprotective in various neurodegenerative disease models; however, the mechanisms involved are still incompletely characterized. In this study, we investigated the neuroprotective role of TUDCA against mitochondrial damage triggered by the mitochondrial uncoupler carbonyl cyanide m-chlorophelyhydrazone (CCCP). Herein, we show that TUDCA significantly prevents CCCP-induced cell death, ROS generation, and mitochondrial damage. Our results indicate that the neuroprotective role of TUDCA in this cell model is mediated by parkin and depends on mitophagy. The demonstration that pharmacological up-regulation of mitophagy by TUDCA prevents neurodegeneration provides new insights for the use of TUDCA as a modulator of mitochondrial activity and turnover, with implications in neurodegenerative diseases.

cd T cells are a conserved population of lymphocytes that contributes to anti-tumor responses through its overt type 1 inflammatory and cytotoxic properties. We have previously shown that human cd T cells acquire this profile upon stimulation with IL-2 or IL-15, in a differentiation process dependent on MAPK/ERK signaling. Here, we identify microRNA-181a as a key modulator of human cd T cell differentiation. We observe that miR-181a is highly expressed in patients with prostate cancer and that this pattern associates with lower expression of NKG2D, a critical mediator of cancer surveillance. Interestingly, miR-181a expression negatively correlates with an activated type 1 effector profile obtained from in vitro differentiated cd T cells and miR-181a overexpression restricts their levels of NKG2D and TNF-a. Upon in silico analysis, we identify two miR-181a candidate targets, Map3k2 and Notch2, which we validate via overexpression coupled with luciferase assays. These results reveal a novel role for miR-181a as critical regulator of human cd T cell differentiation and highlight its potential for manipulation of cd T cells in next-generation immunotherapies.

The original version of this article unfortunately contained a mistake at the Article Title. The first word BTauroursodeoxycholicŵ as missing in the published paper. T h e A r t i c l e Ti t l e i s h e r e b y c o r r e c t e d t o r e a dBTauroursodeoxycholic Acid Protects Against Mitochondrial Dysfunction and Cell Death via Mitophagy in Human Neuroblastoma Cells^.The original article was also corrected.The online version of the original article can be found at http://dx.doi.

BackgroundCyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have changed the paradigm of Estrogen-receptor positive (ER+) / human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC) treatment and represent a new standard of care in metastatic setting. Neutropenia is a well-established adverse event associated with CDK4/6i treatment, but the impact of these agents in BC patients’ immune profile is unknown. This study aimed to characterize changes in host circulating immune cell subsets in BC patients undergoing CDK4/6i therapy and investigate how these changes associate with clinical benefit, by assessing progression-free survival (PFS). MethodsA prospective cohort of metastatic ER+/HER2- BC patients treated with CDK4/6i (palbociclib or ribociclib) was included. Baseline and every 12−14-week peripheral blood samples were collected and objective tumor status evaluated by RECIST criteria at the same time points. Cohort was categorized in CDK4/6i therapy non-responders (CDK4/6i NResp, progression < 6.0 months) and responders (CDK4/6i Resp, PFS ≥6.0 months) using primary resistance to endocrine therapy definition of metastatic BC. A total of 66 different immune populations were assessed by flow cytometry, mainly: B cells, natural killer T (NKT), natural killer (NK), effector (Eff; CD4+, CD8+ and γδ T), effector memory (EM; CD4+, CD8+ and γδ T), central memory (CM; CD4+, CD8+ and γδ T) and naive (CD4+, CD8+ and γδ T), and regulatory T (Treg subtypes I, II and III) cells. Statistical analysis of longitudinal data was performed using Linear Mixed Effects models (LME) and Generalized estimation equations models (GEE) in R (version 3.6.1) and RStudio (version 1.2.5019). Models allowed to estimate and compare variation rates of each cell population in time. ResultsA total of 26 patients were included, with a median age of 58 years (min-max, 27−79). All patients received letrozole or fulvestrant, together with LHRH agonist if premenopausal. Fifteen patients received palbociclib and 11 ribociclib, with 17 (65.4%) and 9 (34.6%) patients treated in 1st and 2nd line, respectively.With a median follow-up of 17.18 months (CI 95% 12.84 - 21.52), 6 (23.1%) patients were CDK4/6i NResp, with a median PFS (mPFS) of 3.61 months (IQR 2.28 - 4.42); only two patients in 1st line setting had PFS <6.0 months. Twenty (76.9%) patients were CDK4/6i Resp, with mPFS of 11.97 months (IQR 8.86 - 19.15), 16 (61.5%) of which treated in 1st line.In CDK4/6i NResp subgroup, an increase was identified in CD4/CD8 ratio (1.01%/month, p=0.001), Treg subtype III (2.74%/month, p=0.0008), CD8EM T cells (5.23%/month, p=0.029), and γδ1Eff subset of γδ T cells (6.30%/month, p=0.007). Interestingly, in CDK4/6i Resp subgroup no significant changes were observed in the same cell populations. Additionally, a decrease in total T (-2.38%/month, p=0.002), Treg subtype II (-2.52%/month, p=0.0076), CD8CM T (-3.30%/month, p=0.006), CD4CM T (-3.97%/month, p=0.002), γδ1CM subset of γδ T (-2.73%/month, p=0.047), NK (-0.99%/month, p=0.011), and CD8Eff T (-1.72%/month, p<0.001) cells was observed in CDK4/6i NResp subgroup, with no significant changes in Resp subgroup. Conclusions Results suggest that significant immune profile changes occur in metastatic ER+/HER2- BC patients with early progression to CDK4/6i and endocrine therapy. Citation Format: Soraia Lobo-Martins, Patrícia Corredeira, Patrícia Borges Alves, Marília Antunes, Ângela Rodrigues, António Quintela, André Mansinho, Pedro Filipe, Leonor Ribeiro, Rita Teixeira de Sousa, Conceição Pinto, Catarina Abreu, Gisela Gordino, Julie Ribot, Karine Serre, Marta Martins, Ana Cavaco, Sandra Casimiro, Bruno Silva-Santos, Luís Costa. Immune cell populations in peripheral blood of metastatic breast cancer patients under CDK4/6 inhibitors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-37.