Citations

AbstractExcessive activation of the thrombin receptor, protease activated receptor 1 (PAR1) is implicated in diverse neuropathologies from neurodegenerative conditions to neurotrauma. PAR1 knockout mice show improved outcomes after experimental spinal cord injury (SCI), however information regarding the underpinning cellular and molecular mechanisms is lacking. Here we demonstrate that genetic blockade of PAR1 in female mice results in improvements in sensorimotor co‐ordination after thoracic spinal cord lateral compression injury. We document improved neuron preservation with increases in Synapsin‐1 presynaptic proteins and GAP43, a growth cone marker, after a 30 days recovery period. These improvements were coupled to signs of enhanced myelin resiliency and repair, including increases in the number of mature oligodendrocytes, their progenitors and the abundance of myelin basic protein. These significant increases in substrates for neural recovery were accompanied by reduced astrocyte (Serp1) and microglial/monocyte (CD68 and iNOS) pro‐inflammatory markers, with coordinate increases in astrocyte (S100A10 and Emp1) and microglial (Arg1) markers reflective of pro‐repair activities. Complementary astrocyte‐neuron co‐culture bioassays suggest astrocytes with PAR1 loss‐of‐function promote both neuron survival and neurite outgrowth. Additionally, the pro‐neurite outgrowth effects of switching off astrocyte PAR1 were blocked by inhibiting TrkB, the high affinity receptor for brain derived neurotrophic factor. Altogether, these studies demonstrate unique modulatory roles for PAR1 in regulating glial‐neuron interactions, including the capacity for neurotrophic factor signaling, and underscore its position at neurobiological intersections critical for the response of the CNS to injury and the capacity for regenerative repair and restoration of function.

The terms autoimmune dementia and autoimmune encephalopathy may be used interchangeably; autoimmune dementia is used here to emphasize its consideration in young-onset dementia, dementia with a subacute onset, and rapidly progressive dementia. Given their potential for reversibility, it is important to distinguish the rare autoimmune dementias from the much more common neurodegenerative dementias. The presence of certain clinical features [e.g. facio-brachial dystonic seizures that accompany anti-leucine-rich-glioma-inactivated-1 (LGI1) encephalitis that can mimic myoclonus] can be a major clue to the diagnosis. When possible, objective assessment of cognition with bedside testing or neuropsychological testing is useful to determine the degree of abnormality and serve as a baseline from which immunotherapy response can be judged. Magnetic resonance imaging (MRI) head and cerebrospinal fluid (CSF) analysis are useful to assess for inflammation that can support an autoimmune etiology. Assessing for neural autoantibody diagnostic biomarkers in serum and CSF in those with suggestive features can help confirm the diagnosis and guide cancer search in paraneoplastic autoimmune dementia. However, broad screening for neural antibodies in elderly patients with an insidious dementia is not recommended. Moreover, there are pitfalls to antibody testing that should be recognized and the high frequency of some antibodies in the general population limit their diagnostic utility [e.g., anti-thyroid peroxidase (TPO) antibodies]. Once the diagnosis is confirmed, both acute and maintenance immunotherapy can be utilized and treatment choice varies depending on the accompanying neural antibody present and the presence or absence of cancer. The target of the neural antibody biomarker may help predict treatment response and prognosis, with antibodies to cell-surface or synaptic antigens more responsive to immunotherapy and yielding a better overall prognosis than those with antibodies to intracellular targets. Neurologists should be aware that autoimmune dementias and encephalopathies are increasingly recognized in novel settings, including post herpes virus encephalitis and following immune-checkpoint inhibitor use.

60 Background: Mapping algorithms informing economic evaluations are often derived using baseline data from clinical trials. It is unclear if these algorithms can predict health utilities accurately in post-intervention data. Thus, this study examines the longitudinal predictive ability of mapping algorithms derived from baseline trial data and explores the factors associated with prediction errors. Methods: This methodological study utilized data from an international, multicenter, randomized controlled trial of patients with low-risk prostate cancer (PC), conducted by NRG Oncology (NCT00331773). In addition to patient demographic and clinical data, this study utilized PRO data collected at baseline and 6, 12 and 24 months post-intervention. The Expanded Prostate Cancer Index Composite (EPIC) questionnaire measures health-related quality-of-life (HRQoL) and has four domains (urinary, sexual, hormonal, and bowel) and two subdomains per domain (function and bother); EuroQOL-5D-3L (EQ5D) captures health utilities. Ordinary Least Squares (OLS) regression models were used to map EPIC scores to EQ5D utilities in the baseline data through 5-fold cross-validation. Predictive performance was tested in the post-intervention data; predicted and reported utilities were compared using t-tests, and the absolute prediction error was modeled using fixed effects, as a function of baseline demographic and clinical covariates, as well as observed and predicted EQ5D utilities. Results: A total of 267 (199) patients had complete EQ5D and EPIC domain (or subdomain) data at baseline and all subsequent assessments. In the EPIC domain sample, mean ± standard deviation observed EQ5D utility was 0.90±0.13 at baseline, 0.92±0.11 at 6 months, 0.90±0.13 at 12 months and 0.89±0.14 at 24 months. Mean absolute differences (MDs) between reported and predicted were lower for models using EPIC subdomain data compared to EPIC domain data, and generally decreased as the time of assessment increased. The mapping functions over-predicted utilities for patients in perfect health while the prediction errors were increasingly negative for lower reported EQ5D scores. According to the fixed effects model for EPIC domain data, lower observed and predicted baseline EQ5D scores, and time of assessment were significant predictors of the absolute prediction error; for EPIC subdomain data, lower observed and predicted baseline EQ5D scores, hormonal bother and function, and bowel function significantly predicted the absolute prediction error. Conclusions: This study is the first to demonstrate the longitudinal validity of EPIC questionnaire, and builds upon existing research on longitudinal validity of mapping functions. The low MDs in prediction errors in post-intervention data indicate that the mapping functions are sensitive to treatment effect, thereby increasing confidence in their use in economic evaluations in PC.

Abstract Background: Benign breast disease (BBD) is a risk factor for breast cancer (BC); however, little is known about the genetic alterations present at the time of BBD diagnosis, and how these relate to risk of incident BC. Methods: A subset of a long-term BBD cohort was selected to examine DNA variation across three BBD groups (42 future estrogen receptor-positive (ER+) BC, 36 future estrogen receptor-negative (ER-) BC and 42 controls cancer-free for at least 16 years post-BBD). DNA extracted from archival formalin fixed, paraffin-embedded (FFPE) tissue blocks was tested and analyzed for presence of DNA alterations using a targeted panel of 93 BC-associated genes. To address artifacts frequently observed in FFPE tissues (e.g., C>T changes), we applied three filtering strategies based on alternative allele frequencies and nucleotide substitution context. Gene-level associations were performed using two burden tests, SKAT-O and logistic regression, and adjusted for clinical and technical covariates including epithelial percentage, histologic impression, patient age and year of BBD biopsy. Results: After filtering, the variant frequency of SNPs in our samples was highly consistent with population allele frequencies reported in 1KG/ExAC (0.986, p <1e-16). Ten genes were found to be associated with later cancer status by four of 12 association methods, with nominal p-values <0.05: MED12, MSH2, BRIP1, PMS1, GATA3, MUC16, FAM175A, EXT2, MLH1 and TGFB1. Additionally, analysis revealed 11 and 19 gene-level associations with p-values <0.05 and OR<1 for all cancer cases and ER- cases, respectively. Comparing between the three case groups, BBD ER+ cases were closer to controls in mutation profile, while BBD ER- cases were distinct. Notably, the variant burden was significantly higher in controls than in either ER+ or ER- cases. CD45 expression was associated with mutational burden (p=0.003).Conclusions: Somatic mutations were more frequent in benign breast tissue from women who did not develop cancer, opening questions of clonal diversity or immune-mediated restraint on future cancer development. CD45 expression was positively associated with mutational burden, most strongly in controls. Further studies in both normal and premalignant tissues are needed to better understand the role of somatic gene mutations and their contribution to future cancer development.

Significance Phase separation of proteins is increasingly thought to play a fundamental role in biological processes. Recent studies show that tau protein phase separates, but the biological significance is unknown since artificial crowding agents are typically used and the resulting tau is not toxic. We now demonstrate that TIA1 potentiates RNA-mediated phase separation of tau, thereby enabling a process that occurs at physiological concentrations and also directs the formation of biologically active, highly neurotoxic oligomeric tau. Coordinated phase separation of functionally related proteins provides a general mechanism through which membraneless organelles can direct biological activities.

Abstract Background: Approximately 1% of all new cases of breast cancer (BC) occur in men. Care of male BC is largely based on extrapolation from treatment strategies and management of symptoms in women. The impact of BC diagnosis and therapy on Quality of Life (QoL) in women with BC is well documented. Comprehensive, prospective data about QoL in men treated for BC are sparse. Due to the lack of a validated male BC QoL questionnaire, we previously evaluated the QoL of the male BC using the original EORTC QLQ-C30 and breast module QLQ BR23 with “female” items replaced by male-specific items from the EORTC QoL prostate module (EORTC QLQ-PR25). The development of a validated worldwide questionnaire for male BC is sponsored by EORTC QoL Group and will be completed in cooperation with EORTC Breast Group and the International Male BC Program (a cooperation between EORTC-BCG, TBCRC, within the BIG and NABCG networks) Trial design: The evaluation of the QoL issues relevant for male BC, as well as the translation of issues into items to build the tool for QoL assessment in male BC will be carried out through four phases: 1. A systematic Literature review 2. Interviews with patients 3. Interviews with Health Care Professionals (HCP) 4. Consultation of experts in Oncology and QoL Inclusion criteria: • Histologically proven early BC or metastatic BC in male patients • Age ≥ 18 years • Ability to understand and fill out questionnaires • Written informed consent Exclusion criteria: • Other cancer in the past 5 years except non-melanotic skin cancer • Patients participating in interventional clinical studies with QoL as primary endpoint • Any condition potentially hampering compliance with the study protocol Aims: The study proposes to carry out an evaluation of the QoL issues relevant for male patients with BC, and translating the issues into questions to build the tool for an adequate QoL assessment in these patients. The specific aims are: 1) To carry out an evaluation of the existing EORTC QLQ-BR 45 (adapting for male BC) and for suitability of use in male BC patients 2) To carry out an evaluation of the EORTC QLQ-PR25 (adapting for male BC) for suitability of use in male BC patients 3) To provide recommendations to the EORTC on a suitable assessment approach to assess QOL in male BC Statistical methods: A systematic literature review to assess what factors are unique to male BC patients in influencing their QoL and what QoL measures exist for them will be performed. This will be conducted by reviewing all studies with male BC participants and including investigator brochures describing side effects in male BC patients, as well as by evaluating issues captured by other existing EORTC modules. The final list of potential QoL issues relevant to the male BC will be tested for relevance and importance in semi-structured qualitative interviews with patients and HCP. A total of 2-5 patients per year will be recruited from collaborating hospitals/countries. At least 40 in total will be interviewed before, during, or after treatment for male BC. At least 2 experts/country from the all collaborating centres will be included in the interview to discuss and consider the potential issues. Finally, the issue list will be translated into questions to build the tool for a QoL assessment in male BC patients. Present accrual and target accrual This study started in October 2019. A systematic literature review has been completed. Seventeen centres from worldwide are participating in the study. New centers may still join. Contact information for people with a specific interest in the trial Vesna Bjelic-Radisic E-Mail: Vesna.Bjelic-Radisic@helios-gesundheit.de Fatima Cardoso e-mail: fatimacardoso@fundacaochampalimaud.pt Citation Format: Vesna Bjelic-Radisic, Fatima Cardoso, Joachim Weis, Eveline Bleiker, David Cameron, Galina Velikova, Karatzyna Pogoda, Samantha Serpentini, Kevin Punie, Rinat Yerushalmi, Erika Matos, Birgit Carly, Ivana Bozovic-Spasojevic, Markus Fleisch, Zoe Luisa Probst, Sina Maria Schafer, Nicola Russell, Sofie Tombeur, Joanna Vermeij, Heidi Roelstraete, Kathryn Ruddy, Juan I Arraras, Andrew Bottomley. Adaption of the EORTC quality of life breast cancer module for male breast cancer - phase I [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 OT-14-01.

ABSTRACT Background With pathway‐specific trials in PD associated with variants in the glucocerebrosidase gene (PD GBA ) under way, we need markers that confirm the impact of genetic variants in patient‐derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read‐out for target engagement. Objective To explore GBA‐pathway‐specific biomarker profiles cross‐sectionally (TUEPAC‐MIGAP, PPMI) and longitudinally (PPMI). Methods We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by‐products) and CSF levels of total α‐synuclein in PD GBA patients compared to PD GBA_wildtype patients. Results Cross‐sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PD GBA compared to PD GBA_wildtype . (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PD GBA compared to PD GBA_wildtype . (3) CSF levels of total α‐synuclein were lower in PD GBA compared to PD GBA_wildtype . All of these findings were most pronounced in PD GBA with severe mutations (PD GBA_severe ). Cross‐sectionally in TUEPAC‐MIGAP and longitudinally in PPMI, CSF levels of downstream‐products (ceramides) were higher in PD GBA_severe . Cross‐sectionally in TUEPAC‐MIGAP by‐products sphinganine and sphingosine‐1‐phosphate and longitudinally in PPMI species of by‐products lactosylceramides and sphingomyelin were higher in PD GBA_severe . Interpretation These findings confirm that GBA mutations have a relevant functional impact on biomarker profiles in patients. Bridging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PD GBA with severe variants. © 2021 International Parkinson and Movement Disorder Society

ABSTRACT Endochondral ossification is tightly controlled by a coordinated network of signaling cascades including parathyroid hormone (PTH). Pleckstrin homology (PH) domain and leucine rich repeat phosphatase 1 (Phlpp1) affects endochondral ossification by suppressing chondrocyte proliferation in the growth plate, longitudinal bone growth, and bone mineralization. As such, Phlpp1−/− mice have shorter long bones, thicker growth plates, and proportionally larger growth plate proliferative zones. The goal of this study was to determine how Phlpp1 deficiency affects PTH signaling during bone growth. Transcriptomic analysis revealed greater PTH receptor 1 (Pth1r) expression and enrichment of histone 3 lysine 27 acetylation (H3K27ac) at the Pth1r promoter in Phlpp1-deficient chondrocytes. PTH (1-34) enhanced and PTH (7-34) attenuated cell proliferation, cAMP signaling, cAMP response element-binding protein (CREB) phosphorylation, and cell metabolic activity in Phlpp1-inhibited chondrocytes. To understand the role of Pth1r action in the endochondral phenotypes of Phlpp1-deficient mice, Phlpp1−/− mice were injected with Pth1r ligand PTH (7-34) daily for the first 4 weeks of life. PTH (7-34) reversed the abnormal growth plate and long-bone growth phenotypes of Phlpp1−/− mice but did not rescue deficits in bone mineral density or trabecular number. These results show that elevated Pth1r expression and signaling contributes to increased proliferation in Phlpp1−/− chondrocytes and shorter bones in Phlpp1-deficient mice. Our data reveal a novel molecular relationship between Phlpp1 and Pth1r in chondrocytes during growth plate development and longitudinal bone growth. © 2021 American Society for Bone and Mineral Research (ASBMR).

Abstract Background The survival benefit of combination antifungal therapy for invasive mucormycosis (IM) in patients with hematologic malignancy (HM) and hematopoietic cell transplant (HCT) is not well defined. Methods This multicenter, retrospective study included HM and HCT recipients with proven or probable IM between January 1, 2007 and December 31, 2017 from 10 transplant centers across North America. Results Sixty-four patients with proven (n = 47) or probable (n = 17) IM defined by 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) consensus definitions were included. Thirty-nine (61%) were HCT recipients (95% allogeneic). Sites of infection included rhino-orbital-cerebral (33), pulmonary (30%), disseminated (19%), gastrointestinal (3%), and cutaneous (3%). Surgical debridement was performed in 66%. Initial antifungal treatment consisted of the following: lipid formulation of amphotericin B (AmB) alone (44%), AmB + posaconazole (25%), AmB + echinocandin (13%), AmB + isavuconazole (8%), posaconazole alone (5%), and isavuconazole alone (3%). All-cause mortality at 30 days and 1 year were 38% and 66%, respectively. Initial treatment with AmB plus posaconazole or isavuconazole (n = 28) was associated with a trend toward lower treatment failure compared with AmB (n = 21) (42% vs 64%, P = .136). Conclusions Long-term survival with IM among HM and HCT populations remains poor. However, initial use of AmB + azole in conjunction with surgery may result in less treatment failure. More evidence from prospective controlled studies is needed to confirm this observation.