Publications by authors named "Michael Rubenstein"

9 Publications

  • Page 1 of 1

Functional Loss of and Activates Alternative Lengthening of Telomeres (ALT) in LAPC4 Prostate Cancer Cells.

Mol Cancer Res 2019 12 14;17(12):2480-2491. Epub 2019 Oct 14.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

A key hallmark of cancer, unlimited replication, requires cancer cells to evade both replicative senescence and potentially lethal chromosomal instability induced by telomere dysfunction. The majority of cancers overcome these critical barriers by upregulating telomerase, a telomere-specific reverse transcriptase. However, a subset of cancers maintains telomere lengths by the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway. The presence of ALT is strongly associated with recurrent cancer-specific somatic inactivating mutations in the ATRX-DAXX chromatin-remodeling complex. Here, we generate an ALT-positive adenocarcinoma cell line following functional inactivation of ATRX and telomerase in a telomerase-positive adenocarcinoma cell line. Inactivating mutations in were introduced using CRISPR-cas9 nickase into two prostate cancer cell lines, LAPC-4 (derived from a lymph node metastasis) and CWR22Rv1 (sourced from a xenograft established from a primary prostate cancer). In LAPC-4, but not CWR22Rv1, abolishing ATRX was sufficient to induce multiple ALT-associated hallmarks, including the presence of ALT-associated promyelocytic leukemia bodies (APB), extrachromosomal telomere C-circles, and dramatic telomere length heterogeneity. However, telomerase activity was still present in these ATRX cells. Telomerase activity was subsequently crippled in these LAPC-4 ATRX cells by introducing mutations in the locus, the essential RNA component of telomerase. These LAPC-4 ATRX TERC cells continued to proliferate long-term and retained ALT-associated hallmarks, thereby demonstrating their reliance on the ALT mechanism for telomere maintenance. IMPLICATIONS: These prostate cancer cell line models provide a unique system to explore the distinct molecular alterations that occur upon induction of ALT, and may be useful tools to screen for ALT-specific therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1541-7786.MCR-19-0654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891209PMC
December 2019

Global & Community Health: Neurologic care for Latinos in South Philadelphia: Global health at home.

Neurology 2019 09;93(10):461-462

From the Department of Neurology, New York University, New York.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000008073DOI Listing
September 2019

Consequences of interleukin 1β-triggered chronic inflammation in the mouse prostate gland: Altered architecture associated with prolonged CD4 infiltration mimics human proliferative inflammatory atrophy.

Prostate 2019 05 22;79(7):732-745. Epub 2019 Mar 22.

Department of Biological Sciences, University of Maryland, Baltimore, Maryland.

Background: Elevated expression of the proinflammatory cytokine interleukin 1β (IL-1β) has been observed in expressed prostatic secretions of patients with chronic prostatitis/chronic pelvic pain syndrome, and genetic polymorphisms associated with the IL1B gene are linked to increased risk for aggressive prostate cancer.

Methods: To study the role of IL-1β expression in prostate inflammation, we examined IL1B expression in human prostatic proliferative inflammatory atrophy (PIA) lesions and developed a tetracycline-regulated human IL1B transgene in the mouse prostate.

Results: Here, we demonstrate that IL1B expression is a common finding in human PIA lesions, which harbored focal IL1B expression in epithelial and stromal compartments. Human IL1B expression in the mouse prostate elicited acute and chronic inflammation. Penetrance and expressivity were variable and tunable by altering transgene dosage and the presence of an exogenous inducible marker antigen (green fluorescent protein). Inflammation was characterized by infiltration of CD4 T cells, demonstrating an adaptive immune response. Chronic inflammation persisted after doxycycline (Dox) withdrawal. Reactive epithelia increased expression of downstream cytokines, and altered glandular architecture was observed upon sustained induction of IL1B. Immunohistochemical analyses revealed a higher proliferative index and decreased Nkx3.1 expression in inflamed mouse prostates.

Conclusions: These data implicate IL-1β in human prostate pathology and this model provides a versatile platform to interrogate molecular mechanisms of inflammation-associated prostate pathologies associated with episodic or sustained IL-1β expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pros.23784DOI Listing
May 2019

Lyme myelopathy: Case report and literature review of a rare but treatable disorder.

Mult Scler Relat Disord 2019 Apr 3;29:1-6. Epub 2019 Jan 3.

Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA. Electronic address:

The differential diagnosis for transverse myelitis is extensive, and the prognosis is highly variable depending on the etiology. We describe a rare case of a 56-year-old previously healthy male who presented with thoracic paresthesias and hyperesthesias involving the T6-11 dermatomes several weeks after a febrile illness. A thoracic MRI demonstrated a T7-10 transverse myelitis, and an exhaustive evaluation revealed neuroborreliosis. His symptoms improved significantly after an initial steroid course and 21 day course of ceftriaxone. We review neuroborreliosis and summarize the features of 23 previously reported cases of Lyme myelopathy. Although Lyme myelopathy is rare, including Lyme in the differential diagnosis of an acute transverse myelitis work up is important in endemic regions, as it is a potentially reversible disorder with a generally good prognosis when appropriately treated with antibiotics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.msard.2018.12.034DOI Listing
April 2019

MYC drives overexpression of telomerase RNA (hTR/TERC) in prostate cancer.

J Pathol 2018 01 14;244(1):11-24. Epub 2017 Nov 14.

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Telomerase consists of at least two essential elements, an RNA component hTR or TERC that contains the template for telomere DNA addition and a catalytic reverse transcriptase (TERT). While expression of TERT has been considered the key rate-limiting component for telomerase activity, increasing evidence suggests an important role for the regulation of TERC in telomere maintenance and perhaps other functions in human cancer. By using three orthogonal methods including RNAseq, RT-qPCR, and an analytically validated chromogenic RNA in situ hybridization assay, we report consistent overexpression of TERC in prostate cancer. This overexpression occurs at the precursor stage (e.g. high-grade prostatic intraepithelial neoplasia or PIN) and persists throughout all stages of disease progression. Levels of TERC correlate with levels of MYC (a known driver of prostate cancer) in clinical samples and we also show the following: forced reductions of MYC result in decreased TERC levels in eight cancer cell lines (prostate, lung, breast, and colorectal); forced overexpression of MYC in PCa cell lines, and in the mouse prostate, results in increased TERC levels; human TERC promoter activity is decreased after MYC silencing; and MYC occupies the TERC locus as assessed by chromatin immunoprecipitation (ChIP). Finally, we show that knockdown of TERC by siRNA results in reduced proliferation of prostate cancer cell lines. These studies indicate that TERC is consistently overexpressed in all stages of prostatic adenocarcinoma and that its expression is regulated by MYC. These findings nominate TERC as a novel prostate cancer biomarker and therapeutic target. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/path.4980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801764PMC
January 2018

19-Year-Old Male with Headaches and a Possible Seizure.

Brain Pathol 2017 07;27(4):557-558

Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bpa.12529DOI Listing
July 2017

Late onset progressive multifocal leukoencephalopathy in Hodgkin lymphoma.

J Clin Neurosci 2017 Sep 16;43:132-134. Epub 2017 May 16.

Department of Neurology, Hospital of the University of Pennsylvania, 3W Gates Building, 3400 Spruce Street, Philadelphia, PA 19104, USA. Electronic address:

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease resulting from infection of oligodendrocytes in the central nervous system with John Cunningham virus. Although PML is commonly diagnosed in immunocompromised patients with human immunodeficiency virus, it can also arise in other immunodeficient states. In this report, we present an unusual case of PML occurring 40years after chemoradiation therapy for Hodgkin lymphoma in a patient with normal total lymphocyte counts on annual surveillance. Although current guidelines recommend annual complete blood counts for patients in remission, this testing may be insufficient to monitor patients with chronic CD4+ lymphopenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jocn.2017.04.030DOI Listing
September 2017

Robotics. Programmable self-assembly in a thousand-robot swarm.

Science 2014 Aug 14;345(6198):795-9. Epub 2014 Aug 14.

School of Engineering and Applied Sciences and Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138, USA.

Self-assembly enables nature to build complex forms, from multicellular organisms to complex animal structures such as flocks of birds, through the interaction of vast numbers of limited and unreliable individuals. Creating this ability in engineered systems poses challenges in the design of both algorithms and physical systems that can operate at such scales. We report a system that demonstrates programmable self-assembly of complex two-dimensional shapes with a thousand-robot swarm. This was enabled by creating autonomous robots designed to operate in large groups and to cooperate through local interactions and by developing a collective algorithm for shape formation that is highly robust to the variability and error characteristic of large-scale decentralized systems. This work advances the aim of creating artificial swarms with the capabilities of natural ones.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.1254295DOI Listing
August 2014

Regenerative patterning in Swarm Robots: mutual benefits of research in robotics and stem cell biology.

Int J Dev Biol 2009 ;53(5-6):869-81

Information Sciences Institute and Computer Science Department, University of Southern California, 90292, USA.

This paper presents a novel perspective of Robotic Stem Cells (RSCs), defined as the basic non-biological elements with stem cell like properties that can self-reorganize to repair damage to their swarming organization. Self here means that the elements can autonomously decide and execute their actions without requiring any preset triggers, commands, or help from external sources. We develop this concept for two purposes. One is to develop a new theory for self-organization and self-assembly of multi-robots systems that can detect and recover from unforeseen errors or attacks. This self-healing and self-regeneration is used to minimize the compromise of overall function for the robot team. The other is to decipher the basic algorithms of regenerative behaviors in multi-cellular animal models, so that we can understand the fundamental principles used in the regeneration of biological systems. RSCs are envisioned to be basic building elements for future systems that are capable of self-organization, self-assembly, self-healing and self-regeneration. We first discuss the essential features of biological stem cells for such a purpose, and then propose the functional requirements of robotic stem cells with properties equivalent to gene controller, program selector and executor. We show that RSCs are a novel robotic model for scalable self-organization and self-healing in computer simulations and physical implementation. As our understanding of stem cells advances, we expect that future robots will be more versatile, resilient and complex, and such new robotic systems may also demand and inspire new knowledge from stem cell biology and related fields, such as artificial intelligence and tissue engineering.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1387/ijdb.092937mrDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874133PMC
September 2009