High Content Screening Identifies Decaprenyl-Phosphoribose 2′ Epimerase as a Target for Intracellular Antimycobacterial Inhibitors

Christophe, Thierry,Jackson, Mary,Jeon, Hee Kyoung,Fenistein, Denis,Contreras-Dominguez, Monica,Kim, Jaeseung,Genovesio, Auguste,Carralot, Jean-Philippe,Ewann, Fanny,Kim, Eun Hye,Lee, Sae Yeon,Kang, S Public Library of Science 2009 PLoS pathogens Vol.5 No.10

<▼1><P>A critical feature of <I>Mycobacterium tuberculosis</I>, the causative agent of human tuberculosis (TB), is its ability to survive and multiply within macrophages, making these host cells an ideal niche for persisting microbes. Killing the intracellular tubercle bacilli is a key requirement for efficient tuberculosis treatment, yet identifying potent inhibitors has been hampered by labor-intensive techniques and lack of validated targets. Here, we present the development of a phenotypic cell-based assay that uses automated confocal fluorescence microscopy for high throughput screening of chemicals that interfere with the replication of <I>M. tuberculosis</I> within macrophages. Screening a library of 57,000 small molecules led to the identification of 135 active compounds with potent intracellular anti-mycobacterial efficacy and no host cell toxicity. Among these, the dinitrobenzamide derivatives (DNB) showed high activity against <I>M. tuberculosis</I>, including extensively drug resistant (XDR) strains. More importantly, we demonstrate that incubation of <I>M. tuberculosis</I> with DNB inhibited the formation of both lipoarabinomannan and arabinogalactan, attributable to the inhibition of decaprenyl-phospho-arabinose synthesis catalyzed by the decaprenyl-phosphoribose 2′ epimerase DprE1/DprE2. Inhibition of this new target will likely contribute to new therapeutic solutions against emerging XDR-TB. Beyond validating the high throughput/content screening approach, our results open new avenues for finding the next generation of antimicrobials.</P></▼1><▼2><P><B>Author Summary</B></P><P>Tuberculosis is still a major threat to global health. The disease in humans is caused by a bacterium, <I>Mycobacterium tuberculosis</I>, and treatment of an infected individual requires more than six months of chemotherapy. Because such a long course of treatment is required, compliance is low, which can result in the development of multidrug resistant strains (MDR-TB) and even extremely resistant strains (XDR-TB). Identifying new drug targets and potential lead therapeutic compounds are needed to combat MDR-XDR-TB. We developed a new type of assay based on the visualization of mycobacterium replication within host cells and applied it for the search of compounds that are able to chase the pathogen from its hideout. As a result, we found 20 new series of drug candidates that are effective against the bacilli in its hiding place, potentially addressing a crucial aspect in the resilience of the disease. We also showed that one series of compounds acts by inhibiting a key enzyme required for the synthesis of an essential component from the mycobacterial cell wall that is not targeted by any of the commercially available antituberculosis drugs. Altogether, our results pave the way for development of the next generation of antibacterial agents.</P></▼2>

Distribution of depth to ice-cemented soils in the high-elevation Quartermain Mountains, McMurdo Dry Valleys, Antarctica

Marinova, Margarita M.,Mckay, Christopher P.,Pollard, Wayne H.,Heldmann, Jennifer L.,Davila, Alfonso F.,Andersen, Dale T.,Jackson, W. Andrew,Lacelle, Denis,Paulsen, Gale,Zacny, Kris Cambridge University Press 2013 Antarctic science Vol.25 No.4

<B>Abstract</B><P>We report on 475 measurements of depth to ice-cemented ground in four high-elevation valleys of the Quartermain Mountains, McMurdo Dry Valleys, Antarctica. These valleys have pervasive ice-cemented ground, and the depth to ice-cemented ground and the ice composition may be indicators of climate change. In University Valley, the measured depth to ice-cemented ground ranges from 0-98 cm. There is an overall trend of increasing depth to ice-cemented ground with distance from a small glacier at the head of the valley, with a slope of 32 cm depth per kilometre along the valley floor. For Farnell Valley, the depth to ice-cemented ground is roughly constant (<I>c.</I> 30 cm) in the upper and central parts of the valley, but increases sharply as the valley descends into Beacon Valley. The two valleys north of University Valley also have extensive ice-cemented ground, with depths of 20-40 cm, but exhibit no clear patterns of ice depth with location. For all valleys there is a tendency for the variability in depth to ice-cemented ground at a site to increase with increasing depth to ice. Snow recurrence, solar insolation, and surface albedo may all be factors that cause site to site variations in these valleys.</P>

STRONG LENS TIME DELAY CHALLENGE. II. RESULTS OF TDC1

Liao, Kai,Treu, Tommaso,Marshall, Phil,Fassnacht, Christopher D.,Rumbaugh, Nick,Dobler, Gregory,Aghamousa, Amir,Bonvin, Vivien,Courbin, Frederic,Hojjati, Alireza,Jackson, Neal,Kashyap, Vinay,Rathna Ku IOP Publishing 2015 The Astrophysical journal Vol.800 No.1

<P>We present the results of the first strong lens time delay challenge. The motivation, experimental design, and entry level challenge are described in a companion paper. This paper presents the main challenge, TDC1, which consisted of analyzing thousands of simulated light curves blindly. The observational properties of the light curves cover the range in quality obtained for current targeted efforts (e.g., COSMOGRAIL) and expected from future synoptic surveys (e.g., LSST), and include simulated systematic errors. Seven teams participated in TDC1, submitting results from 78 different method variants. After describing each method, we compute and analyze basic statisticsmeasuring accuracy (or bias) A, goodness of fit chi(2), precision P, and success rate f. For some methods we identify outliers as an important issue. Other methods show that outliers can be controlled via visual inspection or conservative quality control. Several methods are competitive, i.e., give vertical bar A vertical bar < 0.03, P < 0.03, and chi(2) < 1.5, with some of the methods already reaching sub-percent accuracy. The fraction of light curves yielding a time delay measurement is typically in the range f = 20%-40%. It depends strongly on the quality of the data: COSMOGRAIL-quality cadence and light curve lengths yield significantly higher f than does sparser sampling. Taking the results of TDC1 at face value, we estimate that LSST should provide around 400 robust time-delay measurements, each with P < 0.03 and vertical bar A vertical bar < 0.01, comparable to current lens modeling uncertainties. In terms of observing strategies, we find that A and f depend mostly on season length, while P depends mostly on cadence and campaign duration.</P>

Current Trends in Glioblastoma Multiforme Treatment; Radiation Therapy and Immune Checkpoint Inhibitors

( Sarah Nicholas ),( Dimitris Mathios ),( Jacob Ruzevick ),( Christopher Jackson ),( Isaac Yang ),( Michael Lim ) 대한뇌종양학회·대한신경종양학회·대한소아뇌종양학회 2013 Brain Tumor Research and Treatment Vol.1 No.1

Glioblastoma multiforme (GBM) is the most common primary brain cancer. Even with aggressive combination therapy, the median life expectancy for patients with GBM remains approximately 14 months. In order to improve the outcomes of patients with GBM, the development of newer treatments is critical. The concept of using the immune system as a therapeutic option has been suggested for several decades; by harnessing the body`s adaptive immune mechanisms, immunotherapy could provide a durable and targeted treatment against cancer. However, many cancers, including GBM, have developed mechanisms that protect tumor cells from being recognized and eliminated by the immune system. For new immunotherapeutic regimens to be successful, overcoming immunosuppression via immune checkpoint signaling should be taken into consideration.

Bisphosphonate enhances TRAIL sensitivity to human osteosarcoma cells via death receptor 5 upregulation

문명희,박상열,정재교,Jae-Suk Seo,설재원,이유진,Meilang Xue,Christopher J. Jackson 생화학분자생물학회 2011 Experimental and molecular medicine Vol.43 No.3

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily of cytokines, is one of the most promising candidates for cancer therapeutics. However, many osteosarcomas are resistant to TRAIL. Bisphosphonates are very effective in the treatment of bone problems associated with malignancies; the antitumor effects are due to the inhibition of protein prenylation that is essential for cell function and survival. The purpose of this study was to determine the effects of bisphosphonates on TRAIL-resistant MG 63 human osteosarcoma cells. The cells showed no response to TRAIL alone; however,pre-treatment with bisphosphonates significantly increased TRAIL-mediated apoptosis and cellular activation of caspase-3. Bisphosphonates significantly induced mRNA and protein expression of the TRAIL receptor, DR5. Bisphosphonates induced protein unprenylation in MG 63 cells; in addition, co-treatment with TRAIL also significantly increased protein unprenylation. Blocking of protein unprenylation using geranylgeraniol attenuated the cellular responses,including cell apoptosis and protein unprenylation induced by bisphosphonates and TRAIL. This is the first study to demonstrate that bisphosphonates markedly enhanced TRAIL-induced apoptosis in human osteosarcoma cells. These findings suggest that bisphosphonates may be a new and effective anticancer treatment with TRAIL proteins for TRAIL-resistant cancer cells.

Bisphosphonate enhances TRAIL sensitivity to human osteosarcoma cells $via$ death receptor 5 upregulation

Moon, Myung-Hee,Jeong, Jae-Kyo,Seo, Jae-Suk,Seol, Jae-Won,Lee, You-Jin,Xue, Meilang,Jackson, Christopher J.,Park, Sang-Youel Korean Society for Biochemistry and Molecular Bion 2011 Experimental and molecular medicine Vol.43 No.3

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily of cytokines, is one of the most promising candidates for cancer therapeutics. However, many osteosarcomas are resistant to TRAIL. Bisphosphonates are very effective in the treatment of bone problems associated with malignancies; the antitumor effects are due to the inhibition of protein prenylation that is essential for cell function and survival. The purpose of this study was to determine the effects of bisphosphonates on TRAIL-resistant MG 63 human osteosarcoma cells. The cells showed no response to TRAIL alone; however, pre-treatment with bisphosphonates significantly increased TRAIL-mediated apoptosis and cellular activation of caspase-3. Bisphosphonates significantly induced mRNA and protein expression of the TRAIL receptor, DR5. Bisphosphonates induced protein unprenylation in MG 63 cells; in addition, co-treatment with TRAIL also significantly increased protein unprenylation. Blocking of protein unprenylation using geranylgeraniol attenuated the cellular responses, including cell apoptosis and protein unprenylation induced by bisphosphonates and TRAIL. This is the first study to demonstrate that bisphosphonates markedly enhanced TRAIL-induced apoptosis in human osteosarcoma cells. These findings suggest that bisphosphonates may be a new and effective anticancer treatment with TRAIL proteins for TRAIL-resistant cancer cells.

Sphingosine-1-phosphate protects against bisphosphonate-induced HUVEC cell death via regulation of c-Jun-N-terminal kinase signaling

LEE, YOU-JIN,JEONG, JAE-KYO,LEE, JU-HEE,PARK, YANG-GYU,MOON, JI-HONG,SEOL, JAE-WON,JACKSON, CHRISTOPHER J.,PARK, SANG-YOUEL Spandidos Publications 2013 International journal of molecular medicine Vol.31 No.4