Small but mighty: the causes and consequences of micronucleus rupture

권미정,Mitchell L. Leibowitz,Jae-Ho Lee 생화학분자생물학회 2020 Experimental and molecular medicine Vol.52 No.-

Micronuclei are small DNA-containing nuclear structures that are spatially isolated from the main nucleus. They are frequently found in pathologies, including cancer. It was recently shown that these nuclear structures are not only biomarkers of disease but also play an active role in tumor biology. Many consequences of micronucleus formation on tumor biology are dependent on the frequent and irreversible rupture of their nuclear envelopes, which results in the exposure of their DNA contents to the cytoplasm. In this review, we discuss models of defective nuclear envelope deposition on missegregated chromosomes that lead to nuclear envelope rupture. Furthermore, we expound upon the various downstream consequences of micronucleus nuclear envelope rupture on cells. These consequences include a massive DNA rearrangement phenomenon called chromothripsis and activation of the cGAS-STING innate immune signaling pathway, which can be a double-edged sword with tumorigenesis and tumor prevention functions. Although micronuclei are small structures, the impact they have on cells and their microenvironment is quite large.

A 2.3-mW, 5-Gb/s Low-Power Decision-Feedback Equalizer Receiver Front-End and its Two-Step, Minimum Bit-Error-Rate Adaptation Algorithm

Seuk Son,Han-Seok Kim,Myeong-Jae Park,Kyunghoon Kim,E-Hung Chen,Leibowitz, Brian,Jaeha Kim IEEE 2013 IEEE journal of solid-state circuits Vol.48 No.11

<P>This paper presents a low-power decision-feedback equalizer (DFE) receiver front-end and a two-step minimum bit-error-rate (BER) adaptation algorithm. A high energy efficiency of 0.46 mW/Gbps is made possible by the combination of a direct-feedback finite-impulse-response (FIR) DFE, an infinite-impulse-response (IIR) DFE, and a clock-and-data recovery (CDR) circuit with adjustable timing offsets. Based on this architecture, the power-hungry stages used in prior DFE receivers such as the continuous-time linear equalizer (CTLE), the current-mode summing circuit for a multitap DFE, and the fast selection logic for a loop-unrolling DFE can all be removed. A two-step adaptation algorithm that finds the equalizer coefficients minimizing the BER is described. First, an extra data sampler with adjustable voltage and timing offsets measures the single-bit response (SBR) of the channel and coarsely tunes the initial coefficient values in the foreground. Next, the same circuit measures the eye-opening and bit-error rates and fine tunes the coefficients in background using a stochastic hill-climbing algorithm. A prototype DFE receiver fabricated in a 65-nm LP/RF CMOS dissipates 2.3 mW and demonstrates measured eye-opening values of 174 mV pp and 0.66 UIpp while operating at 5 Gb/s with a -15-dB loss channel.</P>

Is There a "Trial Effect" on Outcome of Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib?

Daniel Keizman,Keren Rouvinov,Avishay Sella,Maya Gottfried,Natalie Maimon,Jenny J. Kim,Mario A. Eisenberger,Victoria Sinibaldi,Avivit Peer,Michael A. Carducci,Wilmosh Mermershtain,Raya Leibowitz-amit 대한암학회 2016 Cancer Research and Treatment Vol.48 No.1

Purpose Studies suggested the existence of a ‘trial effect,’ in which for a given treatment, participa- tion in a clinical trial is associated with a better outcome. Sunitinib is a standard treatment for metastatic renal cell carcinoma (mRCC). We aimed to study the effect of clinical trial participation on the outcome of mRCC patients treated with sunitinib, which at present, is poorly defined. Materials and Methods The records of mRCC patients treated with sunitinib between 2004-2013 in 7 centers across 2 countries were reviewed. We compared the response rate (RR), progression free survival (PFS), and overall survival (OS), between clinical trial participants (n=49) and a matched cohort of non-participants (n=49) who received standard therapy. Each clinical trial participant was individually matched with a non-participant by clinicopathologic factors. PFS and OS were determined by Cox regression. Results The groups were matched by age (median, 64), sex (male, 67%), Heng risk (favorable, 25%; intermediate, 59%; poor, 16%), prior nephrectomy (92%), RCC histology (clear cell 86%), pre-treatment neutrophil to lymphocyte ratio (> 3 in 55%, n=27), sunitinib induced hyper- tension (45%), and sunitinib dose reduction/treatment interruption (41%). In clinical trial participants versus non-participants, RR was partial response/stable disease 80% (n=39) versus 74% (n=36), and progressive disease 20% (n=10) versus 26% (n=13) (p=0.63; odds ratio, 1.2). The median PFS was 10 versus 11 months (hazard ratio [HR], 0.96; p=0.84), and the median OS 23 versus 24 months (HR, 0.97; p=0.89). Conclusion In mRCC patients treated with sunitinib, the outcome of clinical trial participants was similar to that of non-participants who received standard therapy.

Autophagy is a major regulator of beta cell insulin homeostasis

Riahi, Yael,Wikstrom, Jakob D.,Bachar-Wikstrom, Etty,Polin, Nava,Zucker, Hava,Lee, Myung-Shik,Quan, Wenying,Haataja, Leena,Liu, Ming,Arvan, Peter,Cerasi, Erol,Leibowitz, Gil Springer-Verlag 2016 Diabetologia Vol.59 No.7

<P>Aims/hypothesis We studied the role of protein degradation pathways in the regulation of insulin production and secretion and hypothesised that autophagy regulates proinsulin degradation, thereby modulating beta cell function. Methods Proinsulin localisation in autophagosomes was demonstrated by confocal and electron microscopy. Autophagy was inhibited by knockdown of autophagy-related (ATG) proteins and using the H+-ATPase inhibitor bafilomycin-A1. Proinsulin and insulin content and secretion were assessed in static incubations by ELISA and RIA. Results Confocal and electron microscopy showed proinsulin localised in autophagosomes and lysosomes. Beta-Atg7(-/-) mice had proinsulin-containing sequestosome 1 (p62 [also known as SQSTM1])(+) aggregates in beta cells, indicating proinsulin is regulated by autophagy in vivo. Short-term bafilomycin-A1 treatment and ATG5/7 knockdown increased steady-state proinsulin and hormone precursor chromogranin A content. ATG5/7 knockdown also increased glucose- and non-fuel-stimulated insulin secretion. Finally, mutated forms of proinsulin that are irreparably misfolded and trapped in the endoplasmic reticulum are more resistant to degradation by autophagy. Conclusions/interpretation In the beta cell, transport-competent secretory peptide precursors, including proinsulin, are regulated by autophagy, whereas efficient clearance of transport-incompetent mutated forms of proinsulin by alternative degradative pathways may be necessary to avoid beta cell proteotoxicity. Reduction of autophagic degradation of proinsulin increases its residency in the secretory pathway, followed by enhanced secretion in response to stimuli.</P>

Preliminary Study on the Development of Alternative Methods for the Treatment of TRISO Fuels

Jong-Hyeon Lee,Joon-Bo Shim,Byung-Gil Ahn,Sang-woon Kwon,Eung-Ho Kim,Jae-Hyung Yoo,Seong-Won Park,Christine T. Snyder,Leonard Leibowitz 한국방사성폐기물학회 2005 방사성폐기물학회지 Vol.3 No.3

본 연구에서는 사용후 TRISO 연료 처리를 위한 보다 효과적인 공정개발을 위하여 기존 전처리 기술에 대한 검토를 수행하였다. TRISO 연료 처리에 있어서 가장 중요한 사항은 연료입자에 포함되어 있는 탄소와 SiC성분을 효과적으로 분리하는데 있다. 공정개발 초기에 고려되었던 분쇄 후 배소공정의 경우 처리공정에서 발생되는 2차 폐기물로 인하여 분쇄 후 침출공정으로 대체 되었으나 여전히 해결해야 될 근본적인 문제점이 존재하고 있다. 따라서 본 논문에서는 TRISO 입자의 피복층 제거를 위한 새로운 개념의 열적 파쇄와 용융염 전해반응에 의한 피복층 제거 공정을 제안하였으며 각 공정에 대한 원리를 자세하게 기술하였다. In this study, conventional head-end processes of spent TRISO fuel have been reviewed to develope more effective treatment methods. The main concerns in the TRISO treatment are to effectively separate the carbon and SiC contained in the TRISO particles. The crush-burn scheme which was considered in the early stages of the development has been replaced by the crush-leach process because of problems as a second waste being generated during the process. However, there are still many obstacles to overcome in the reported processes. Hence, innovative thermomechanical concepts and a molten salt electrochemical approach to breach the coating layers of the TRISO particle with a minimized amount of second waste are proposed in this paper and their principles are described in detail.

The Mount Sinai Hospital Institute for critical care medicine response to the COVID-19 pandemic

Jennifer Wang,Evan Leibner,Jaime B. Hyman,Sanam Ahmed,Joshua Hamburger,Jean Hsieh,Neha Dangayach,Pranai Tandon,Umesh Gidwani,Andrew Leibowitz,Roopa Kohli-Seth,Mount Sinai Anesthesiology and Critical C 대한중환자의학회 2021 Acute and Critical Care Vol.36 No.3

Background: The coronavirus disease 2019 (COVID-19) pandemic resulted in a surge of critically ill patients. This was especially true in New York City. We present a roadmap for hospitals and healthcare systems to prepare for a Pandemic. Methods: This was a retrospective review of how Mount Sinai Hospital (MSH) was able to rapidly prepare to handle the pandemic. MSH, the largest academic hospital within the Mount Sinai Health System, rapidly expanded the intensive care unit (ICU) bed capacity, including creating new ICU beds, expanded the workforce, and created guidelines. Results: MSH a 1,139-bed quaternary care academic referral hospital with 104 ICU beds expanded to 1,453 beds (27.5% increase) with 235 ICU beds (126% increase) during the pandemic peak in the first week of April 2020. From March to June 2020, with follow-up through October 2020, MSH admitted 2,591 COVID-19-positive patients, 614 to ICUs. Most admitted patients received noninvasive support including a non-rebreather mask, high flow nasal cannula, and noninvasive positive pressure ventilation. Among ICU patients, 68.4% (n=420) received mechanical ventilation; among the admitted ICU patients, 42.8% (n=263) died, and 47.8% (n=294) were discharged alive. Conclusions: Flexible bed management initiatives; teamwork across multiple disciplines; and development and implementation of guidelines were critical accommodating the surge of critically ill patients. Non-ICU services and staff were deployed to augment the critical care work force and open new critical care units. This approach to rapidly expand bed availability and staffing across the system helped provide the best care for the patients and saved lives.

TRISO 연료 대체 처리방법 개발에 관한 선행연구

Lee Jong-Hyeon,Shim Joon-Bo,Ahn Byung-Gil,Kwon Sang-Woon,Kim Eung-Ho,Yoo Jae-Hyung,Park Seong-Won,Snyder Christine T.,Leibowitz Leonard 한국방사성폐기물학회 2005 방사성폐기물학회지 Vol.3 No.3

In this study, conventional head-end processes of spent TRISO fuel have been reviewed to develope more effective treatment methods. The main concerns in the TRISO treatment are to effectively separate the carbon and SiC contained in the TRISO particles. The crush-burn scheme which was considered in the early stages of the development has been replaced by the crush-leach process because of $^{14}C$ problems as a second waste being generated during the process. However, there are still many obstacles to overcome in the reported processes. Hence, innovative thermomechanical concepts and a molten salt electrochemical approach to breach the coating layers of the TRISO particle with a minimized amount of second waste are proposed in this paper and their principles are described in detail.