Ventricular divergence correlates with epicardial wavebreaks and predicts ventricular arrhythmia in isolated rabbit hearts during therapeutic hypothermia

INTRODUCTION: High beat-to-beat morphological variation (divergence) on the ventricular electrogram during programmed ventricular stimulation (PVS) is associated with increased risk of ventricular fibrillation (VF), with unclear mechanisms. We hypothesized that ventricular divergence is associated with epicardial wavebreaks during PVS, and that it predicts VF occurrence. METHOD AND RESULTS: Langendorff-perfused rabbit hearts (n = 10) underwent 30-min therapeutic hypothermia (TH, 30°C), followed by a 20-min treatment with rotigaptide (300 nM), a gap junction modifier. VF inducibility was tested using burst ventricular pacing at the shortest pacing cycle length achieving 1:1 ventricular capture. Pseudo-ECG (p-ECG) and epicardial activation maps were simultaneously recorded for divergence and wavebreaks analysis, respectively. A total of 112 optical and p-ECG recordings (62 at TH, 50 at TH treated with rotigaptide) were analyzed. Adding rotigaptide reduced ventricular divergence, from 0.13±0.10 at TH to 0.09±0.07 (p = 0.018). Similarly, rotigaptide reduced the number of epicardial wavebreaks, from 0.59±0.73 at TH to 0.30±0.49 (p = 0.036). VF inducibility decreased, from 48±31% at TH to 22±32% after rotigaptide infusion (p = 0.032). Linear regression models showed that ventricular divergence correlated with epicardial wavebreaks during TH (p<0.001). CONCLUSION: Ventricular divergence correlated with, and might be predictive of epicardial wavebreaks during PVS at TH. Rotigaptide decreased both the ventricular divergence and epicardial wavebreaks, and reduced the probability of pacing-induced VF during TH

Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma.

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B

EGFR feedback-inhibition by Ran-binding protein 6 is disrupted in cancer

Transport of macromolecules through the nuclear pore by importins and exportins plays a critical role in the spatial regulation of protein activity. How cancer cells co-opt this process to promote tumorigenesis remains unclear. The epidermal growth factor receptor (EGFR) plays a critical role in normal development and in human cancer. Here we describe a mechanism of EGFR regulation through the importin β family member RAN-binding protein 6 (RanBP6), a protein of hitherto unknown functions. We show that RanBP6 silencing impairs nuclear translocation of signal transducer and activator of transcription 3 (STAT3), reduces STAT3 binding to the EGFR promoter, results in transcriptional derepression of EGFR, and increased EGFR pathway output. Focal deletions of the RanBP6 locus on chromosome 9p were found in a subset of glioblastoma (GBM) and silencing of RanBP6 promoted glioma growth in vivo. Our results provide an example of EGFR deregulation in cancer through silencing of components of the nuclear import pathway.This research was supported by the National Brain Tumor Society (I.K.M.), the National Institutes of Health grants 1R01NS080944-01 (I.K.M.), 1 R35 NS105109 01 (I.K.M.), and P30CA008748 (MSKCC Core Grant), the Geoffrey Beene Cancer Research Foundation (I.K.M.), the Cycle of Survival (I.K.M.), and the Seve Ballesteros Foundation (M.S.). B.O. was supported by an American–Italian Cancer Foundation fellowship and a MSKCC Brain Tumor Center grant. W.-Y.H. is the recipient of a FY15 Horizon Award from the U.S. Department of Defense (W81XWH-15-PRCRP-HA). A.C.-G. is the recipient of the Severo-Ochoa PhD fellowship. Further support was provided by the Sontag Foundation (B.S.T.). We thank all members of the Mellinghoff laboratory for helpful suggestions. We thank Dr. Fiona Ginty (Diagnostic Imaging and Biomedical Technologies, GE Global Research Center, Niskayuna, New York, USA) for assistance with multiplexed immunofluorescence. We thank A.J. Schuhmacher and C.S. Clemente-Troncone for assistance with the in vivo experiments, M. Kaufmann for assistance in the luciferase assays and N. Yannuzzi for assistance in cloning.S

SJS/TEN 2019: From science to translation.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening, immune-mediated adverse reactions characterized by widespread erythema, epidermal necrosis, and detachment of skin and mucosa. Efforts to grow and develop functional international collaborations and a multidisciplinary interactive network focusing on SJS/TEN as an uncommon but high burden disease will be necessary to improve efforts in prevention, early diagnosis and improved acute and long-term management. SJS/TEN 2019: From Science to Translation was a 1.5-day scientific program held April 26-27, 2019, in Vancouver, Canada. The meeting successfully engaged clinicians, researchers, and patients and conducted many productive discussions on research and patient care needs

Characterization Of Ran-Binding Protein 6 As A Novel Regulator Of The Epidermal Growth Factor Receptor

The epidermal growth factor receptor (EGFR) regulates many key biological processes including cell proliferation, survival and differentiation. It is frequently altered or amplified in cancers. Regulation of physiological EGFR function occurs at multiple levels, such as negative feedback regulation. We previously identified RAN-Binding Protein 6 (RanBP6), a protein of unknown functions, as a candidate EGFR interactor from an EGFR interactome study. Here, we validated that RanBP6, a member of the importin ? superfamily, interacts with EGFR and the proteins involved in nucleo-cytoplasmic transport. In addition, depletion of RanBP6 raised EGFR mRNA and protein levels, and upregulated EGFR promoter activity. Further studies revealed that RanBP6 represses EGFR transcription by modulating the subcellular localization of Signal transducer and activator of transcription 3 (STAT3). Focal deletions of the RANBP6 locus on chromosome 9p were found in a subset of glioblastoma (GBM). Silencing of RanBP6 promoted glioma growth in vivo and conferred resistance to EGFR tyrosine kinase inhibitors. Lastly, examination of RanBP6 substrates suggested RanBP6 is an importin for many tumor suppressors or oncoproteins. Our results demonstrated that RanBP6 functions as a novel EGFR feedback regulator to maintain EGFR homeostasis, and an importin for cancer-associated cargoes

[[alternative]]Development the Program of Promting of Positive Mental Health at Befriends-Mindfulness-Identity

[[abstract]]為促使國民重視心理健康，研究試行與修編「正向心理健康BMI學習方案」專業人員指引手冊，透過師資培訓，將心理健康BMI學習方案在社區、校園推廣經驗作為指引手冊之調整。本研究屬於李玉嬋主持科技部專題研究計劃一部分，以李玉嬋(2018)衛生福利部「發展具實證基礎之老人心理健康BMI服務方案之試行成效研究計畫」作為發展心理健康BMI學習方案基礎。透過質性研究焦點訪談團體，計有47位研究對象及2位諮商心理師擔任團體主持人，分為A、B兩組分別在三階段培訓期間進行3次焦點團體訪談及1次專家訪談，每次進行1-1.5小時，及研究者參與培訓師資推廣「正向心理健康BMI學習方案」蒐集團體及觀察紀錄，本研究結果為：一、「正向心理健康BMI學習方案」分為單次宣導講座、四次基礎版及八次基礎及深化團體方案。二、本研究目的為促進國民心理健康，培訓推廣人員需具備心理健康BMI概念，同時融入焦點解決諮商操作步驟，以促進自我管理效能。　三、推廣「正向心理健康BMI學習方案」單元主題及單元目標需一致，提供青少年、一般民眾及特殊族群(失智症)調整方案設計、推廣方式建議以及推廣宗教、文化場域注意事項。關鍵詞：學習方案、焦點團體訪談、正向心理健康BMI[[abstract]]To encourage people to pay attention to mental health, this study piloted and revised the &quot;Direct Mental Health BMI Learning Program&quot; Professional Guidebook. Through teacher training, the promotion experience of the mental health BMI learning program in the community and campus was used as the adjustment of the guidebook. This research is part of the special research project of the Ministry of Science and Technology chaired by Yuchan, Li.(2018) Ministry of Health and Welfare's &quot;Development of a Pilot Effectiveness Research Program for the Development of an Empirical Basis Mental Health BMI Service Program&quot; as the basis for the development of a mental health BMI learning program to train teachers Promote the &quot;positive mental health BMI learning plan&quot; through qualitative research focus interview groups, there are 47 research subjects and 2 psychologists as group moderators, divided into A and B The group conducted three focus group interviews and one expert interview during the three stages of training, each for 1-1.5 hours,and researchers participated in the training of teachers to promote the &quot;positive mental health BMI learning program&quot; to collect group body and observation records, the results of this study are:1. The &quot;Positive Mental Health Learning Program&quot; is divided into a single publicity lecture, four basic versions, and eight basic and deepening group programs.2. The purpose of this study is to promote national mental health. The training and promotion personnel must have the concept of mental health BMI, and at the same time integrate into the focus of the consultation operation steps to promote self-management efficiency.　3. The theme and unit goal of the unit of &quot;Promoting Positive Mental Health Learning Program&quot; should be consistent, and provide the adjustment plan design of the youth, the general public and special ethnic groups (dementia), the promotion method recommendations and the precautions for the promotion of religious and cultural fields.Keyword：Learning program, Focused interviews, Positive mental health at Befriends-Mindfulness-Identity